Ebook Cancer epidemiology and prevention (4/E): Part 1

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 i Schottenfeld and Fraumeni Cancer Epidemiology and Prevention ii  iii Schottenfeld and Fraumeni Cancer Epidemiology and Prevention Fourth Edition Lead Editor MICHAEL J THUN, MD, MS Epidemiology and Surveillance Research (Retired) American Cancer Society Atlanta, Georgia Co-​Editors MARTHA S LINET, MD, MPH Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda, Maryland JAMES R CERHAN, MD, PHD Department of Health Sciences Research Mayo Clinic Rochester, Minnesota CHRISTOPHER HAIMAN, SCD Department of Preventive Medicine Keck School of Medicine, University of Southern California Los Angeles, California DAVID SCHOTTENFELD, MD, MSC Department of Epidemiology (Retired) University of Michigan School of Public Health Ann Arbor, Michigan Project Manager ANNELIE M. LANDGREN, MPH, PMP iv Oxford University Press is a department of the University of Oxford It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide Oxford is a registered trade mark of Oxford University Press in the UK and certain other countries Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America © Oxford University Press 2018 Third Edition published 2006 Second edition published 1996 First edition published 1982 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Library of Congress Cataloging-in-Publication Data Names: Thun, Michael J., editor | Linet, Martha S., editor | Cerhan, James R., editor | Haiman, Christopher, editor | Schottenfeld, David, editor Title: Schottenfeld and Fraumeni Cancer Epidemiology and Prevention / lead editor, Michael J Thun ; co-editors, Martha S Linet, James R Cerhan, Christopher Haiman, David Schottenfeld ; project manager, Annelie M Landgren Other titles: Cancer epidemiology and prevention Description: Fourth edition | New York, NY : Oxford University Press, [2018] | Preceded by Cancer epidemiology and prevention / edited by David Schottenfeld, Joseph F Fraumeni Jr 3rd ed 2006 | Includes bibliographical references and index Identifiers: LCCN 2017038170 | ISBN 9780190238667 (hardcover : alk paper) Subjects: | MESH: Neoplasms—epidemiology | Neoplasms—prevention & control Classification: LCC RA645.C3 | NLM QZ 220.1 | DDC 614.5/999—dc23 LC record available at https://lccn.loc.gov/2017038170 9 8 7 6 5 4 3 2 1 Printed by Sheridan Books, Inc., United States of America  v Contents Acknowledgments  Contributors  Preface  ix xi xix Introduction  Michael J Thun, Martha S Linet, James R Cerhan, Christopher A Haiman, and David Schottenfeld I  BASIC CONCEPTS Biology of Neoplasia  Michael Dean and Karobi Moitra Morphological and Molecular Classification of Human Cancer  Mark E Sherman, Melissa A Troester, Katherine A Hoadley, and William F Anderson 19 Genomic Landscape of Cancer: Insights for Epidemiologists  Christopher J Maher and Elaine R. Mardis 43 Genetic Epidemiology of Cancer  Kathryn L Penney, Kyriaki Michailidou, Deanna Alexis Carere, Chenan Zhang, Brandon Pierce, Sara Lindström, and Peter Kraft 53 Application of Biomarkers in Cancer Epidemiology  Roel Vermeulen, Douglas A Bell, Dean P Jones, Montserrat Garcia-​Closas, Avrum Spira, Teresa W Wang, Martyn T Smith, Qing Lan, and Nathaniel Rothman 77 Causal Inference in Cancer Epidemiology  Steven N Goodman and Jonathan M. Samet 97 II  THE MAGNITUDE OF CANCER Patterns of Cancer Incidence, Mortality, and Survival  Ahmedin Jemal, D Maxwell Parkin, and Freddie Bray 107 Socioeconomic Disparities in Cancer Incidence and Mortality  Candyce Kroenke and Ichiro Kawachi 141 10 The Economic Burden of Cancer in the United States  K Robin Yabroff, Gery P Guy Jr., Matthew P Banegas, and Donatus U Ekwueme 169 vi vi Contents III  THE CAUSES OF CANCER 11 Tobacco  Michael J Thun and Neal D Freedman 185 12 Alcohol and Cancer Risk  Susan M Gapstur and Philip John Brooks 213 13 Ionizing Radiation  Amy Berrington de González, André Bouville, Preetha Rajaraman, and Mary Schubauer-​Berigan 227 14 Ultraviolet Radiation  Adèle C Green and David C Whiteman 249 15 Electromagnetic Fields  Maria Feychting and Joachim Schüz 259 16 Occupational Cancer  Kyle Steenland, Shelia Hoar Zahm, and A. Blair 275 17 Air Pollution  Jonathan M Samet and Aaron J. Cohen 291 18 Water Contaminants  Kenneth P Cantor, Craig M Steinmaus, Mary H Ward, and Laura E. Beane Freeman 305 19 Diet and Nutrition  Marjorie L McCullough and Walter C Willett 329 20 Obesity and Body Composition  NaNa Keum, Mingyang Song, Edward L Giovannucci, and A Heather Eliassen 351 21 Physical Activity, Sedentary Behaviors, and Risk of Cancer  Steven C Moore, Charles E Matthews, Sarah Keadle, Alpa V Patel, and I-​Min Lee 377 22 Hormones and Cancer  Robert N Hoover, Amanda Black, and Rebecca Troisi 395 23 Pharmaceutical Drugs Other Than Hormones  Marie C Bradley, Michael A O’Rorke, Janine A Cooper, Søren Friis, and Laurel A. Habel 411 24 Infectious Agents  Silvia Franceschi, Hashem B El-​Serag, David Forman, Robert Newton, and Martyn Plummer 433 25 Immunologic Factors  Eric A Engels and Allan Hildesheim 461 IV  CANCERS BY TISSUE OF ORIGIN 26 Nasopharyngeal Cancer  Ellen T Chang and Allan Hildesheim 489 27 Cancer of the Larynx  Andrew F Olshan and Mia Hashibe 505 28 Lung Cancer  Michael J Thun, S Jane Henley, and William D. Travis 519 29 Oral Cavity, Oropharynx, Lip, and Salivary Glands  Mia Hashibe, Erich M Sturgis, Jacques Ferlay, and Deborah M. Winn 543 30 Esophageal Cancer  William J Blot and Robert E. Tarone 579  vi vii Contents 31 Stomach Cancer  Catherine de Martel and Julie Parsonnet 593 32 Cancer of the Pancreas  Samuel O Antwi, Rick J Jansen, and Gloria M Petersen 611 33 Liver Cancer  W Thomas London, Jessica L Petrick, and Katherine A McGlynn 635 34 Biliary Tract Cancer  Jill Koshiol, Catterina Ferreccio, Susan S Devesa, Juan Carlos Roa, and Joseph F Fraumeni, Jr 661 35 Small Intestine Cancer  Jennifer L Beebe-​Dimmer, Fawn D Vigneau, and David Schottenfeld 671 36 Cancers of the Colon and Rectum  Kana Wu, NaNa Keum, Reiko Nishihara, and Edward L.Giovannucci 681 37 Anal Cancer  Andrew E Grulich, Fengyi Jin, and I Mary Poynten 707 38 Leukemias  Martha S Linet, Lindsay M Morton, Susan S Devesa, and Graỗa M.Dores 715 39 Hodgkin Lymphoma Henrik Hjalgrim, Ellen T Chang, and Sally L. Glaser 745 40 The Non-​Hodgkin Lymphomas  James R Cerhan, Claire M Vajdic, and John J Spinelli 767 41 Multiple Myeloma  Mark P Purdue, Jonathan N Hofmann, Elizabeth E Brown, and Celine M. Vachon 797 42 Bone Cancers  Lisa Mirabello, Rochelle E Curtis, and Sharon A. Savage 815 43 Soft Tissue Sarcoma  Marianne Berwick and Charles Wiggins 829 44 Thyroid Cancer  Cari M Kitahara, Arthur B Schneider, and Alina V Brenner 839 45 Breast Cancer  Louise A Brinton, Mia M Gaudet, and Gretchen L Gierach 861 46 Ovarian Cancer  Shelley S Tworoger, Amy L Shafrir, and Susan E Hankinson 889 47 Endometrial Cancer  Linda S Cook, Angela L. W Meisner, and Noel S. Weiss 909 48 Cervical Cancer  Rolando Herrero and Raul Murillo 925 49 Vulvar and Vaginal Cancers  Margaret M Madeleine and Lisa G Johnson 947 50 Choriocarcinoma  Julie R. Palmer 953 51 Renal Cancer  Wong-​Ho Chow, Ghislaine Scelo, and Robert E. Tarone 961 52 Bladder Cancer  Debra T Silverman, Stella Koutros, Jonine D Figueroa, Ludmila Prokunina-​Olsson, and Nathaniel Rothman 977 53 Prostate Cancer  Catherine M Tangen, Marian L Neuhouser, and Janet L Stanford 997 vi viii Contents 54 Testicular Cancer  Katherine A McGlynn, Ewa Rajpert-​De Meyts, and Andreas Stang 1019 55 Penile Cancer  Morten Frisch 1029 56 Nervous System  E Susan Amirian, Quinn T Ostrom, Yanhong Liu, Jill Barnholtz-​Sloan, and Melissa L. Bondy 1039 57 Melanoma  Bruce K Armstrong, Claire M Vajdic, and Anne E. Cust 1061 58 Keratinocyte Cancers  Anala Gossai, Dorothea T Barton, Judy R Rees, Heather H Nelson, and Margaret R Karagas 1089 59 Childhood Cancers  Eve Roman, Tracy Lightfoot, Susan Picton, and Sally Kinsey 1119 60 Multiple Primary Cancers  Lindsay M Morton, Sharon A Savage, and Smita Bhatia 1155 V  CANCER PREVENTION AND CONTROL 61 Framework for Understanding Cancer Prevention  Michael J Thun, Christopher P Wild, and Graham Colditz 1193 62 Primary Prevention of Cancer  1205 62.1 Tobacco Control  Jeffrey Drope, Clifford E Douglas, and Brian D. Carter 1207 62.2 Prevention of Obesity and Physical Inactivity  Ambika Satija and Frank B. Hu 1211 62.3 Prevention of Infection-​Related Cancers  Marc Bulterys, Julia Brotherton, and Ding-​Shinn Chen 1217 62.4 Protection from Ultraviolet Radiation  Robyn M Lucas, Rachel E Neale, Peter Gies, and Terry Slevin 1221 62.5 Preventive Therapy  Jack Cuzick 1229 62.6 Regulation  Jonathan M Samet and Lynn Goldman 1239 63 Cancer Screening  Jennifer M Croswell, Russell P Harris, and Barnett S. Kramer 1255 Index 1271  ix Acknowledgments We are indebted to the more than 190 chapter authors who generously contributed their time, labor, and expertise to produce this comprehensively updated fourth edition The multi-​authored text reflects the increasingly interdisciplinary and collaborative nature of the field; it provides a resource for researchers seeking to harness the unprecedented advances in genetic and molecular research into large-​scale population studies of cancer etiology, and ultimately into effective preventive interventions We owe special thanks to Ms Annelie Landgren, whose energy, enthusiasm, and organizational expertise as project manager have been invaluable in bringing this text to completion We also thank Dr. Stephen Chanock for his early and unfailing encouragement and for supporting the critical infrastructure necessary for such a collaborative enterprise This book would not have been possible without the generous forbearance of our spouses and families Finally, Michael Thun thanks Dr. Lynne Moody for her insights as a sounding board throughout this process ix 578  579 30 Esophageal Cancer WILLIAM J BLOT AND ROBERT E. TARONE OVERVIEW Cancer of the esophagus is the eighth most common malignancy worldwide in terms of incident cases, and the sixth most common for cancer deaths The two main histopathologic subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EADC), have strikingly different clinical and epidemiologic features ESCC occurs throughout the esophagus and is the most common histologic subtype globally; over 90% of cases in the traditionally high-​risk regions of Eastern Asia and Eastern and Southern Africa are ESCC The incidence of ESCC is decreasing worldwide; in some high-​risk areas in Asia the decrease was preceded by economic development and improvements in diet, whereas in high-​income countries the decrease followed reductions in cigarette smoking In contrast, the incidence of EADC continues to increase in many high-​and middle-​income countries, especially among white men EADC develops in the lower third of the esophagus, primarily because of gastroesophageal reflux disease (GERD) and obesity This chapter will review the dynamic changes in the two histologic subtypes of esophageal cancer and will consider their natural history, molecular pathogenesis, etiology, and the potential for primary and secondary prevention INTRODUCTION The two main histopathologic subtypes of esophageal cancer are squamous cell carcinomas (ESCC) and adenocarcinomas (EADC) Striking differences exist in the geographic distribution, temporal trends, natural history, and etiology of these two histologic subtypes This chapter will focus on the two most common forms of esophageal cancer and will emphasize research advances that have occurred since the previous edition of Cancer Epidemiology and Prevention (Blot et al., 2006) We will not discuss other rare malignancies of the esophagus, such as small cell carcinoma, melanoma, and sarcoma Collectively, the latter subtypes account for less than 1%–​2% of all esophageal cancers (National Cancer Institute, 2015) They are discussed in Chapters 28, 43, and 57 of this volume CLASSIFICATION BY ANATOMIC SITE The International Classification of Diseases for Oncology, version ICD-​O-​2/​3, classifies esophageal cancers as C15.0–​15.9, based on the anatomic location of the tumor Squamous cell carcinomas occur throughout the esophagus, although somewhat more often in the middle third in high-​income countries For example, among cases of ESCC reported to the US Surveillance, Epidemiology, and End Results (SEER) registries between 2000 and 2012, 21% were in the upper third, 46% in the middle third, and 33% in the lower third (National Cancer Institute, 2015) In contrast, the great majority (89%) of EADC in SEER during this period involved the lower third of the esophagus, often just above the gastric-​esophageal (GE) junction; only 1.5% arose in the upper third, with 9.5% in the middle third DISEASE BURDEN According to the International Agency for Research on Cancer (IARC), an estimated 456,000 new cases and 400,000 deaths from esophageal cancer occurred in 2012 (Ferlay et al., 2013) These estimates combine the two major subtypes, which together represent the eighth most common malignancy in terms of incident cases and the sixth most common for cancer deaths ESCC predominates globally, accounting for over 90% of cases in the extremely high-​risk regions of Eastern Asia and Eastern and Southern Africa The incidence rate of ESCC varies widely within and among countries, as discussed later in this chapter in the section on descriptive epidemiology In certain high-​risk regions in China and Iran, ESCC is reported to be the most common form of cancer (Blot et al., 2006) NATURAL HISTORY Although both histologic subtypes of esophageal cancer usually develop in areas of chronic inflammation, their precursor lesions and natural history differ ESCCs arise from the multilayered epithelium comprising the innermost lining of the esophagus, and dysplasia is an established precursor of ESCC (Blot et  al., 2006; Taylor et  al., 2013) With the exception of high-​risk geographic regions, relatively few dysplasia cases undergo malignant transformation into in situ or invasive cancer, but ESCC risk rises rapidly with increasing severity of dysplasia (Taylor et al., 2013) In a high-​risk area of China, only 8% of ESCC arose in people without a prior diagnosis of esophageal dysplasia (Taylor et al., 2013) In contrast, adenocarcinomas of the esophagus arise from glandular columnar tissue that has displaced squamous cells in the lining of the lower esophagus Metaplastic columnar tissue known as Barrett’s esophagus is a well-​established precursor lesion for EADC (Wild and Hardie, 2003) Nearly all EADCs are thought to arise from Barrett’s esophagus (Chen and Yang, 2001) This abnormal columnar tissue develops during the healing phase of severe, recurrent gastroesophageal reflux and supplants damaged squamous epithelium (Rustgi and El-​Serag, 2014; Verbeek et al., 2014; Yousef et al., 2008) Both Barrett’s esophagus and EADC occur in the same areas of the lower esophagus and GE junction Likewise, their epidemiologic characteristics are similar Both have increased in prevalence during the last 30  years in Western countries, are more common in men than women and in Caucasians than African Americans or Asians, and are associated with obesity and tobacco smoking (Blot et al., 2006; Runge et al., 2015; Schneider and Corley, 2015; Spechler, 2013) For squamous cell carcinomas, the strongest evidence connecting the severity of the premalignant lesions to cancer risk was seen in Linxian, China, where in a 13-​year follow-​up, 50% of individuals with moderate and 74% of those with severe esophageal dysplasia developed ESCC (Taylor et al., 2013) Not surprisingly, it has been easier to study the risk of progression from Barrett’s esophagus to EADC in high-​income countries than to monitor progression to ESCC in remote areas of Asia or Africa Older studies estimated the annual risk of progression to EADC to be as high as 1%; more recent data indicate an overall progression rate of less than 0.5% (Falk, 2015; Gatenby et al., 2014; Spechler, 2013) Patients with Barrett’s esophagus but with no dysplasia have an annual probability of developing EADC of approximately 0.25% per year; this increases to about 6% per year for patients with Barrett’s esophagus and high-​grade dysplasia (Spechler, 2013) 579 580 580 PART IV:  Cancers by Tissue of Origin TREATMENT, PROGNOSIS, AND SURVIVAL Treatment successes have been limited for both histologic subtypes of esophageal cancer, partly because most tumors are diagnosed at an advanced stage The percentage of esophageal cancers diagnosed at a local stage in the United States has remained stubbornly under 30% for four decades (Hur et  al., 2013) Five-​year relative survival was less than 10% prior to 1980 (Blot et al., 2006; Hur et al., 2013), and relatively small improvements have occurred since then For cases of esophageal cancer diagnosed from 2000 through 2012 in the United States, the 5-​year relative survival for ESCC was 15%; that for EADC was 19% (National Cancer Institute, 2015) For both cell types, relative survival was slightly better among whites than blacks For ESCC, survival was slightly better among men than women; no sex difference was observed for EADC (National Cancer Institute, 2015) DESCRIPTIVE EPIDEMIOLOGY International Variation Table 30–1 shows esophageal cancer incidence rates by sex for various geographic regions of the world in 2012, along with the estimated percentage contributed by squamous cell cancers Esophageal cancer exhibits great international variation, with more than 20-​fold differences in rates between world regions in both sexes (Ferlay et  al., 2015) Highest overall rates in both sexes are observed in Eastern Asia, Eastern and Southern Africa, and South-​Central Asia, and the lowest rates are observed in Western Africa and Central America (Table 30–1) Mortality data on esophageal cancer usually cannot be partitioned by subsite (i.e., into ESCC or EADC) The geographic variation is even greater if histologic subtype is considered in addition to the overall incidence rate Table 30–1 shows that in regions with the highest overall esophageal cancer incidence rates, ESCC predominates (> 90%), whereas in high-​income Western countries, which have relatively low overall incidence rates, the percentage of ESCC is low, especially among men Approximately 96% of cases among men in Eastern Asia are ESCC, corresponding to an annual incidence rate for this subtype of approximately 16.2 per 100,000 In contrast, only 33% of cases among men in North America are ESCC, corresponding to an incidence rate of about 1.8 per 100,000 Low-​and middle-​income regions have a high percentage of ESCC, regardless of their total incidence rates of esophageal cancer, whereas high-​income countries in North America, Northern Europe, Australia, and New Zealand have a low percentage of ESCC and relatively low overall incidence rates of esophageal cancer (Arnold et al., 2015) Countries with the highest overall esophageal cancer incidence rates (per 100,000 annually) for men and women combined include China (10.9), Mongolia (15.5), Malawi (22.9), Kenya (16.5), Uganda (15.9), Burundi (12.2), Lesotho (13.9), Turkmenistan (18.5), Tajikistan (13.6), and Bangladesh (11.7) (Ferlay et al., 2013) Because the incidence rates are highly variable within countries, however, the actual geographic variation is much larger than is reflected by national averages For example, the age-​standardized incidence rate in some parts of North-​Central China exceeds 100 per 100,000 annually (Blot et al., 2006) While squamous cell carcinomas are the predominant histologic subtype throughout most of the world, adenocarcinomas are more common among men in high-​income countries (Table 30–1; Arnold et al., 2015) The seven countries with the highest incidence rates (per 100,000) of EADC among men include the United Kingdom (7.2), The Netherlands (7.1), Ireland (5.4), New Zealand (4.0), Iceland (3.9), the United States (3.6), and Belgium (3.5) (Arnold et al., 2015) Temporal Trends By the late 1980s and early 1990s, it had become apparent that there was a major shift in esophageal cancer occurrence in the United States and certain other high-​income Western nations Incidence rates for ESCC, which had previously been rising as a result of cigarette smoking patterns, began to plateau, or even fall, while incidence rates of EADC began to increase (Blot et  al., 1991, 2006; Bosetti et  al., 2008) The trends in incidence by histologic subtype, race, and sex are shown for the United States in Figure 30–1 The incidence rate of ESCC has decreased by over 40% since the early 1980s in male and female whites and African Americans In contrast, the incidence rate of adenocarcinoma has increased over the past three decades in all subgroups, but especially among white men The proportion of esophageal cancers that are adenocarcinomas rose steadily in white men from less than 15% around 1970, to 34% by the mid-​1980s, to 60% by 1992–​1994, and currently to 80% (Blot et al., 2006; National Cancer Institute, 2015) The increase in the incidence rate of EADC appears to have slowed, and possibly ended, in the United States (Figure 30–1; Hur et al., 2013), although mathematical models suggest that EADC rates may continue to rise slowly until 2030 (Kong et al., 2014) Table 30–1 International Esophageal Cancer Incidence Rates by Sex Incidence Rate* Country North America Central America South America Western Europe Central and Eastern Europe Northern Europe Southern Europe Australia and New Zealand Eastern Asia Southeast Asia South-​Central Asia Western Asia Eastern Africa Western Africa Southern Africa Northern Africa Squamous Cell Cancer (%) Male Female Male Female 5.4 1.7 7.0 6.8 5.6 1.1 0.6 2.0 1.6 0.8 33 76 78 62 85 62 77 78 72 81 8.1 3.2 5.4 2.7 0.6 1.7 31 72 34 61 77 70 16.9 3.6 6.5 2.9 11.9 0.8 13.7 2.4 5.4 1.0 3.9 2.1 7.8 0.4 6.7 1.5 96 92 91 71 94 96 93 75 96 91 94 90 95 95 90 84 * Rates per 100,000 person-​years, age-​adjusted using World Standard Source: Globocan 2012 (Ferlay et al., 2013); Arnold et al (2015) Gender The incidence of esophageal cancer is consistently higher in men than women for both ESCC and EADC in virtually all populations studied Table 30–2 shows incidence rates in the United States for cases diagnosed in 2003–​2012 by gender, race/​ethnicity, and histology The male:female ratio is higher for adenocarcinoma than for squamous cell carcinoma Barrett’s esophagus is more common among men than women, but differences in known risk factors not appear to explain the male excess of EADC, with limited evidence that hormonal factors may play a role (Xie and Lagergren, 2016) The male:female ratios vary widely worldwide for both EADC and ESCC, with male rates almost always exceeding female rates (Arnold et al., 2015) In Northern Africa and Western Asia, however, regions where rates are more similar by sex (Table 30–1), some countries have reported higher ESCC rates among women than among men (Al-​Samawi and Aulaqi, 2014; Arnold et al., 2015; Mohammed et al., 2012) Race/​Ethnicity The reasons underlying the variation in the incidence rates of esophageal cancer subtypes by race or ethnicity are as yet incompletely understood The incidence of ESCC is about four times higher in black than in white men in the United States (Table 30–2) This is in marked contrast to the low incidence of esophageal cancer in Western Africa  581 581 Esophageal Cancer Squamous Cell Carcinoma 100 10 1 0.1 0.1 0.01 0.01 19 19 White Female White Male Adenocarcinoma 3– 19 19 77 76 – 19 19 81 80 – 19 19 85 84 – 19 19 89 88 – 19 19 93 92 – 19 19 97 96 – 20 20 01 00 – 20 20 05 04 – 20 20 09 08 –2 01 10 3– 19 197 77 – 19 198 81 – 19 198 85 – 19 198 89 – 19 199 93 – 19 199 97 – 20 200 01 – 20 200 05 – 20 200 09 –2 01 Rate per 100,000 person-years 100 Black Male Black Female Figure 30–1.  Trends for esophageal cancer incidence rates by histology in the United States for blacks and whites by sex (Table 30–1), the historical region of origin for most American slaves For EADC, the incidence rate is over four times higher in white than black men The ESCC rates are similar for Hispanic and non-​Hispanic whites, but Hispanic whites have EADC rates one-​half those for non-​ Hispanic whites This is in contrast to gastric adenocarcinoma, for which Hispanic whites have incidence rates twice as high as those for non-​Hispanic whites (National Cancer Institute, 2015) The percentages of esophageal cancers with adenocarcinoma histology are higher among African Americans and Asian Americans than the 10% or less observed in most Asian and African countries Socioeconomic Status Table 30–2 Incidence Rates* for Squamous Cell Carcinomas and Adenocarcinomas of the Esophagus, by Racial/​Ethnic Group and Sex, SEER Program (2003–​2012) Tobacco Use Males Number Squamous Cell Carcinoma Whites 5,020 Blacks 2,319 Asians 789 Native Americans 45 White (non-​Hispanic) 4,322 White (Hispanic) 698 Adenocarcinoma Whites 17,760 Blacks 434 Asians 331 Native Americans 83 White (non-​Hispanic) 16,583 White (Hispanic) 1,177 Females Rate Number Rate 1.65 6.64 2.51 1.32 1.61 1.99 3,152 1,021 295 28 2,919 233 0.84 2.18 0.75 0.68 0.89 0.53 5.73 1.23 1.05 2.05 6.13 2.99 2,839 145 74 27 2,640 199 0.74 0.32 0.19 0.62 0.79 0.43 * Rates per 100,000 person-​years, age-​adjusted using 2000 US Standard Source: SEER (National Cancer Institute, 2015) ESCC has long been associated with low socioeconomic status This association persists, even after adjustment for tobacco and alcohol, although residual confounding may still exist (Blot et  al., 2006) In contrast, EADC has not been consistently linked to socioeconomic status (Blot et al., 2006) ETIOLOGIC FACTORS Tobacco smoking has long been established as a major cause of esophageal cancer (IARC, 1986), with early studies documenting the association in populations in which ESCC predominated Among smoking-​associated cancers, few have higher relative risks than ESCC (IARC, 2004; Vineis et al., 2004) Early cohort and case-​ control studies consistently showed that risk of esophageal cancers increased nearly 5-​fold among current cigarette smokers compared to nonsmokers, with the excess reaching nearly 10-​fold among heaviest smokers (Blot et  al., 2006) Alcohol consumption and cigarette smoking are correlated, and alcohol is also a risk factor for ESCC, but numerous studies have demonstrated that smoking increases ESCC risk independent of alcohol consumption (Table 30–3; Blot et  al., 2006; Freedman et  al., 2007) Studies assessing ESCC risk among smokers who did not consume alcohol also reported elevated risk (Blot et al., 2006; Prabhu et al., 2014) ESCC risk declines following cessation of smoking (Blot et al., 2006; Freedman et al., 2007), and the attributes required for establishing a cause-​and-​effect relationship between smoking and ESCC hold (IARC, 1986) It is highly likely that much of the decline in ESCC incidence rates since the early 1980s in the United States (Figure 30–1) is due to reductions in cigarette consumption Smoking prevalence in adult men peaked in the 1960s, when about 60% were smokers, and steadily decreased to 20% in 2012 (Agaku et al., 2014) 582 582 PART IV:  Cancers by Tissue of Origin Cigarette smoking is the only exposure known to increase risk of both ESCC and EADC Although cigarette smoking affects adenocarcinoma risk to a lesser extent than squamous cell carcinoma risk in the esophagus, it is still an important risk factor for this histology (Table 30–3; Cook et al., 2010; Drahos et al., 2016; Tramacere et al., 2011) The pattern of lower smoking-​associated risk for EADC compared to ESCC has been consistently observed (Blot et al., 2006; Freedman et al 2007; Vineis et al., 2004) Cigarette smoking also increases the risk of the adenocarcinoma precursor, Barrett’s esophagus (Andrici et al., 2013; Cook et al., 2012) Although the risk of adenocarcinoma declines after smoking cessation, there is evidence that the rate of decline for adenocarcinoma is much slower than the relatively rapid rate of decline for ESCC (Blot et al., 2006; Cook et al., 2010; Freedman et al., 2007; Schneider and Corley, 2015) This may partly explain why the sharp decline in smoking prevalence in the United States over the past five decades has not had an apparent dampening effect on the increase in adenocarcinoma rates over the past two decades (Figure 30–1) The impact of smoking on the esophageal cancer rate in a given population will depend heavily on the mix of histologic subtypes, but a recent pooled analysis of deaths in five US cohorts during the period 2000–​2011 reported that the relative risk for esophageal cancer was markedly elevated, even though EADC was the predominant histology during those years (Carter et al., 2015) Data on cigar and pipe smoking are more limited than that for cigarettes, but the available evidence indicates that the effects on esophageal cancer (predominantly ESCC) resemble those associated with cigarettes (Chang et  al., 2015; IARC, 2012b; National Cancer Institute, 1998) Evaluation of esophageal cancer risk from use of smokeless tobacco products is complicated by extreme geographic variation in the magnitude of relative risk estimates Asian studies consistently show evidence of greater than 2.5-​fold elevations in esophageal cancer risk among smokeless tobacco users, but relative risk estimates from Western countries are much smaller, and the slight to moderate increases in Western risk estimates may be affected by residual confounding from socioeconomic status and other personal habits (Lagergren et al., 2000; Lee and Hamling, 2009; Siddiqi et al., 2015; Sinha et al., 2016) The geographic variation in risk estimates is likely explained in part by the different composition of some smokeless tobacco products in Asia (e.g., some contain betel leaves, betel nuts, or areca nuts) IARC has concluded that smokeless tobacco use is a cause of esophageal cancer in humans (2012b) Alcohol Consumption Alcohol consumption, like smoking, was identified early as a major risk factor for esophageal cancer (IARC, 1968) Unlike smoking, alcohol consumption only increases the risk of ESCC (IARC, 2012b) Only oral cavity and pharynx cancers have estimated alcohol-​associated relative risks as high as those for ESCC (Bagnardi et al., 2015) Multiple studies have shown a strong dose–​ response relationship with the amount of alcohol consumed and ESCC risk (Bagnardi et al., 2015; Blot et al., 2006; Freedman et al., 2011; Islami et al., 2011) Relative risks of or higher for heavy alcohol consumption have been consistently reported (Table 30–4) Large studies have had sufficient numbers to demonstrate a rising risk of ESCC with increasing alcohol intake in nonsmokers, and ESCC risk declines following quitting drinking (Blot et al., 2006; IARC, 1988; Islami et al., 2011) Table 30–3 Relative Risks* of Esophageal Cancer by Histology, According to Cigarette Smoking History Pack Years of Smoking 1–​29 30–​39 40–​49 50–​59 60+ Squamous Cell Carcinoma Table 30–4 Relative Risks* of Esophageal Cancer by Histology, According to Alcohol Intake Alcohol Intake (Drinks/​Day) > 0–​< 0.5 0.5–​< 1.0 1.0–​< 3.0 3.0–​< 5.0 5.0–​< 7.0 ≥7 Squamous Cell Carcinoma 1.0 0.80 (0.56–​1.14)† 1.23 (0.55–​2.74) 2.56 (1.10–​5.96) 4.56 (2.32–​8.96) 7.17 (2.98–​17.3) 9.62 (4.26–​21.7) * Relative risks adjusted for age, sex, education, alcohol, and BMI † 95% confidence interval Source: BEACON consortium pooled analysis (Lubin et al., 2012) 1.0 1.66 (1.1–​2.4) 1.45 (0.8–​2.5) 2.22 (1.2–​4.0) 1.92 (1.0–​3.6) 2.77 (1.4–​5.6) 1.0 0.86 (0.65–​1.13) 0.63 (0.41–​0.99) 0.81 (0.60–​1.09) 0.86 (0.59–​1.24) 0.93 (0.66–​1.31) 0.97 (0.68–​1.36) * Relative risks adjusted for age, sex, BMI, education, cigarette smoking, and if available, GERD † 95% confidence interval Source: BEACON consortium pooled analysis (Freedman et al., 2011) Alcohol consumption is responsible for the clustering of ESCC in several hot-​spot areas of the world These include clusters of elevated rates in northern France associated with Calvados apple brandies, in the South African Transkei associated with maize beer, in Puerto Rico and South America associated with rum and sugar-​cane distilled beverages, and in coastal South Carolina associated with moonshine whiskies (Blot, 1994) The common ingredient is alcohol (ethanol), although a role for other compounds in the alcoholic beverages is possible These diverse findings also suggest that all forms of alcoholic beverage, convey risk of ESCC, and studies comparing spirit, wine, and beer intake tend to report increased risks regardless of the type of alcoholic beverage drunk (Blot, 1992) In certain very high risk areas of the world, including Linxian China and along the Caspian littoral of Iran, alcohol consumption does not appear to be involved in the excess ESCC risk (Muñoz and Day, 1996) The lack of association between alcohol consumption and EADC is striking, especially among those who report high levels of consumption A  meta analysis taking into account data from 20 case-​ control and four cohort studies showed a summary relative risk for EADC of 0.87 (95% CI = 0.74–​1.01) for drinkers versus nondrinkers (Tramacere et  al., 2012) The risk of EADC did not increase even for those who reported consumption of seven or more drinks per day, as shown in Table 30–4 Two studies that assessed risk of both Barrett’s esophagus and EADC found no association with alcohol consumption for either endpoint (Freedman et al., 2011; Thrift et al., 2014a) Interaction Between Smoking and Drinking The combination of smoking and alcohol consumption produces a much greater increase in ESCC risk than either exposure alone or than the sum of their independent effects Table 30–5 presents risk estimates from a case-​control study in a high-​risk area of France showing one of the strongest reported links between drinking and smoking and esophageal cancer (in early studies, cell type was generally not specified, but nearly all tumors were of squamous cell histology) Both smoking and drinking independently increased risk The combination Table 30–5 Relative Risks of Esophageal Cancer Associated with Alcohol Drinking and Tobacco Smoking in Brittany, France Tobacco (g/​day) Adenocarcinoma 1.0 2.63 (1.8–​4.0)† 2.69 (1.6–​4.6) 3.93 (2.2–​7.1) 4.62 (2.5–​8.5) 5.63 (2.7–​11.7) Adenocarcinoma Alcohol (g/​day) 0–​40 41–​80 81–​120 ≥121 0–​9 1.0* 7.3 11.8 49.6 10–​19 3.4 8.4 13.6 65.9 20–​29 3.2 8.8 12.6 137.6 * Reference category Source: Muñoz and Day (1996) Adapted from Tuyns et al (1977) ≥ 30 7.8 35.0 83.0 155.6  583 Esophageal Cancer of heavy smoking and drinking was associated with a 100-​ fold increase in ESCC risk compared to that of nonsmoking nondrinkers Combined exposure to alcohol and tobacco smoking accounts for a very high percentage of ESCCs in many Western regions of the world, but tobacco accounts for a small fraction of EADCs, with no contribution from alcohol Tobacco use is not as strongly related to risk of ESCC in Asia However, a recent meta-​analysis of five studies showed increased risk from smoking, particularly among those who both smoked cigarettes and drank alcoholic beverages (Prabhu et al., 2014) Betel Quid In India and Southeast Asia, elevated ESCC risk was linked to betel nut chewing (Znaor et al., 2003), with a recent meta-​analysis reporting a 3-​fold increased risk associated with areca nut chewing, independent of tobacco smoking (Akhtar, 2013) Betel quid has been classified as an esophageal carcinogen in humans (IARC, 2012b) Obesity Obesity is firmly established as a major risk factor for EADC, and the association between obesity and EADC may be the strongest observed among obesity-​associated cancers (Lagergren, 2011) The most commonly used measure of obesity, particularly in early studies, is body mass index (BMI), and elevated BMI has consistently been shown to be associated with increased EADC risk (Hoyo et al., 2012; Kubo and Corley, 2006; O’Doherty et al., 2012; Ryan et al., 2011; Steffen et al., 2015; Turati et al., 2013) The positive association between BMI and EADC risk has been corroborated in a Mendelian randomization study (Thrift et al., 2014c) In sharp contrast to the strong association between BMI and EADC risk, there is no evidence of increased ESCC risk among those with elevated BMI (Blot et al., 2006; Corley et al., 2008) Table 30–6 presents data from the US multicenter study showing rising risk of EADC, but no increase in ESCC risk, with increasing BMI The pattern of risk for ESCCs, with no evidence of increased risk among overweight and obese individuals, and high risk often observed among those with lowest weight, may be due to poor nutritional status as well as residual confounding from tobacco and alcohol consumption among those with low BMI In Table 30–6 the increases in EADC risk are substantial, reaching 3-​fold among those in the highest BMI quartile (with a lower bound in this study of 27 kg/​m2) Even higher relative risks have been reported elsewhere for BMI values exceeding 30 or 40 kg/​m2 (Hoyo et al., 2012; Lagergren et al., 1999) Height appears to be inversely associated with risk of both Barrett’s esophagus and EADC, in contrast to the positive associations observed between height and many other types of cancers (Thrift et al., 2014b) This suggests a high-​risk phenotype for EADC characterized by short stature and overweight Recent studies investigating obesity have reported that central (or abdominal) adiposity (measured as waist circumference, abdominal diameter, or waist-​to-​hip ratio) is a consistent risk factor for EADC, with some of the studies showing that abdominal adiposity is a stronger risk factor than BMI (Corley et al., 2008; Lagergren, 2011; O’Doherty et al., 2012; Singh et al., 2013b; Steffen et al., 2015) The Table 30–6 Relative Risks* of Esophageal Cancer, by Cell Type, Associated with Obesity BMI Quartile I (low) II III IV Squamous Cell Carcinoma 1.0 0.5 (0.3–​0.9)† 0.8 (0.5–​1.3) 0.6 (0.3–​1.0) * Relative risks adjusted for age, sex, race, smoking † 95% confidence interval Source: Chow et al (1998) Adenocarcinoma 1.0 1.3 (0.8–​2.2) 2.0 (1.3–​3.3) 2.9 (1.8–​4.7) 583 prevalence of abdominal obesity is higher in men than women, and thus the positive association between central adiposity and EADC risk likely contributes to the striking male predominance of EADC (Lagergren, 2011; Singh et  al., 2013b) Two reviews concluded that BMI and measures of central adiposity produced similar relative risk estimates for EADC (Runge et al., 2015; Singh et al., 2013b), but in a more recent follow-​up study of nearly 400,000 European adults, risk of EADC was strongly associated with waist circumference, and the association between BMI and EADC risk was nearly eliminated after adjustment for waist circumference (Steffen et al., 2015) The conclusion that central adiposity is a risk factor for EADC independent of BMI led Singh et al (2013b) to recommend that future studies aimed at understanding the mechanistic effect of obesity on EADC should focus on measures of visceral fat rather than overall obesity The rise in the incidence of EADC in the United States and other Western countries seems at least in part due to the concomitant rise in obesity The prevalence of obesity in the United States has steadily increased over the past three decades, with a leveling off only recently beginning (Kroep et al., 2014) With a 2-​fold higher risk among the obese versus non-​obese individuals, and an increase in obesity prevalence of 20% (say from 10%–​30% in the US after 1980), the expected increase in EADC can be estimated to be just under 20% In the United States, age-​adjusted EADC incidence rates among white males increased nearly 100% from 1990 to 2010 (Figure 30–1), outpacing the rise attributable solely to the obesity epidemic It is also the case that differences in obesity prevalence and trends not explain differences among countries in rates or trends of EADC (Kroep et al., 2014) It is paradoxical that the prevalence of obesity in the United States is highest among black women (Ogden et al., 2014), the group with the lowest incidence of EADC It is difficult to assemble adequately powered studies of EADC among black women to explore this paradox because of their low EADC incidence rate (Table 30–2) Gastroesophageal Reflux Disease (GERD) Barrett’s esophagus develops as a consequence of GERD, a condition caused by reflux into the lower esophagus of gastric acid and/​or bile salts and alkaline duodenal contents (Spechler, 2014; Wild and Hardie, 2003) GERD is among the strongest risk factors for both Barrett’s esophagus and EADC (Cook et al., 2014; Drahos et al., 2016; Lada et al., 2013; Lagergren and Lagergren, 2013; Rubenstein et al., 2011; Runge et  al., 2015), and obesity is a major risk factor for GERD (Friedenberg et al., 2008; Lagergren, 2011) Increasing GERD prevalence over time may be contributing to the increase in EADC rates in developed countries (Lagergren and Lagergren, 2013) The strong association between central adiposity and EADC has led to suggestions that obesity may influence adenocarcinoma risk via a mechanical mechanism, that is, an increase in intra-​abdominal pressure leading to promotion of GERD with transition to Barrett’s esophagus (Chandar and Iyer, 2015) Consistent with this hypothesized mechanism, obesity is a strong risk factor for both GERD and Barrett’s esophagus (Chandar and Iyer, 2015; Corley et al., 2007; Lagergren, 2011; Runge et al., 2015) The observation that associations between central adiposity and Barrett’s esophagus and EADC risk are independent of GERD has led to suggestions that visceral fat may also increase EADC risk through non-​mechanical mechanisms (Lagergren, 2011; Singh et al., 2013b) Thus it has been suggested that visceral fat plays a metabolic role in the etiology of EADC, perhaps through the secretion of adipokines and cytokines (Chang and Friedenberg, 2014; Chandar and Iyer, 2015; Lagergren, 2011; Lagergren and Lagergren, 2013; Singh et al., 2013b) Hiatal Hernia Obesity increases the risk of hiatal hernias, and hiatal hernias are associated with increased risk of GERD (Friedenberg et al., 2008; Chang and Friedenberg, 2014) Although not widely investigated as a risk factor for EADC in epidemiologic studies, hiatal hernia appears to be a risk factor for Barrett’s esophagus (Nguyen et al., 2014; Spechler, 2013) A recent study indicates that both a family history of hiatal hernia and a personal history of hiatal hernia may increase the risk of EADC (Jiang et al., 2014) 584 584 PART IV:  Cancers by Tissue of Origin Nutritional Deficiency Earlier research identified several diseases that predispose to nutritional deficiency, such as Plummer-​Vinson syndrome, celiac disease, and pernicious anemia, as risk factors for ESCC These conditions are uncommon in most populations, however, and there have been few subsequent reports of associations (Blot et al., 2006) Nutritional deficiencies were suspected as major factors in the clustering of the very high incidence of squamous cell cancers of the esophagus in Central Asia, partly because tobacco and alcohol seemed not to be major determinants in these areas (Blot et  al., 2006) Indeed, the Linxian nutritional intervention trials were launched in the mid-​1980s to evaluate whether supplementation of a high-​risk rural population, with limited variety in food and nutrient intake, could help reduce the substantial impact of these cancers in this region of North-​Central China Two trials were conducted, one randomizing nearly 30,000 residents into four groups of vitamin/​mineral supplement combinations (retinol and zinc; riboflavin and niacin; ascorbic acid and molybdenum; and beta carotene, alpha tocopherol and selenium) The other trial randomized nearly 3,000 persons with esophageal dysplasia to a multivitamin/​mineral pill or placebo (Blot et al., 2006) After 5 years of supplementation, cancer mortality rates were significantly lower among those who received a combination of beta-​carotene, vitamin E, and selenium, although the reduction was more pronounced for stomach than for esophageal cancer In subgroup analyses, those with high baseline levels of selenium and alpha tocopherol, but not beta-​carotene or vitamin C, had lower esophageal cancer mortality (Blot et al., 2006; Lam et al., 2013) Supplementation ended after 5 years, but an additional 10-​year follow-​up of the trial participants indicated that the benefit in the beta carotene/​alpha tocopherol/​ selenium group persisted into the 2000s (Qiao et al., 2009) No significantly reduced cancer occurrence was seen for the other three vitamin/​ mineral combinations either at the end of supplementation or in the extended follow-​up The Linxian trials were initially heralded as providing evidence that simple nutrient supplementation with beta carotene, vitamin E, or selenium might reduce the burden of cancer in humans However, hopes for a generalized reduction in cancer incidence were soon dashed when randomized clinical trials of beta carotene and/​or retinol supplementation were reported to increase rather than decrease risk of lung cancer in the US Carotene and Retinol Efficacy Trial (Omenn et al., 1996) and Finnish Alpha-​Tocopherol, Beta-​Carotene Cancer Prevention Study (ATBC Study Group, 1994) In the two decades since the Linxian trials, strong evidence of a protective role for vitamin or mineral supplementation on cancer in general, and esophageal cancer in particular, has yet to emerge (Myung and Yang, 2013) The benefits of supplementation may be limited to populations with extreme nutritional deficiency, such as in Linxian Other Dietary Factors Dietary factors long have been thought to be important in the development of esophageal cancer (Blot et  al., 2006), but quantifying risks associated with food and nutrient consumption has been difficult, and it remains unclear to what extent diet (other than alcohol drinking) contributes to risk of either ESCC or EADC The most comprehensive review of dietary factors and cancer lists no specific foods or nutritional factors as having “convincing” evidence of a causal relationship with esophageal cancer (World Cancer Research Fund/​ American Institute for Cancer Research [WCRF/​AICR], 2007) Fruits, vegetables, and foods containing beta carotene or vitamin C are designated “probable” protective factors, and red and processed meats as “possible” risk factors Reduced risks associated with vegetable and fruit intake have been observed among multiple case-​control studies, as well as the few cohort studies that have reported on esophageal cancer (Blot et al., 2006) Most early studies applied largely to squamous cell carcinomas, but similar findings have since been reported for adenocarcinomas (Abnet et  al., 2015; Kubo et  al., 2010; Petrick et al., 2015; Steevens et al., 2011) Increased risks associated with red and processed meat consumption have been observed in most observational studies, with generally similar findings for both ESCC and EADC (Abnet et al., 2015; Cross et al., 2011; O’Doherty et al., 2011; Petrick et al., 2015; Zhu et al., 2014) Consumption of exceptionally hot beverages, including maté and very hot teas in South America and Asia, has been associated with increased risk of ESCC (Andrici and Eslick, 2013; Chen et al., 2015; Islami et al., 2009; Tang et al., 2013) Two meta-​analyses have reported increased risk of ESCC, but not EADC, associated with consumption of very hot beverages and foods (Andrici and Eslick, 2015; Chen et al., 2015) Tea drinking itself, however, has been associated with reduced risk of these cancers in China (Wu et al., 2009; Zheng et al., 2013), mainly for green and oolong teas with higher concentrations of flavonoids and other agents that have been shown to inhibit esophageal cancer in experimental animals (Lambert and Yang, 2003) Studies of overall dietary patterns have been more promising than studies of individual foods Those who reported following a healthy diet had significantly lower risk of ESCC in a meta-​analysis of nine case-​control studies (Liu et al., 2014), and consumption of a healthy diet was associated with reduced risk of EADC in a case-​control study (Chen et  al., 2002) In the National Institutes of Health–​American Association of Retired Persons (NIH-​AARP) cohort tracking nearly 500,000 adults, those in the highest quintile of a composite Healthy Eating Index-​2005 score had significantly reduced risks of both ESCC (HR = 0.51) and EADC (HR = 0.75) (Li et al., 2013c) Analyses of a Mediterranean diet score in the same cohort demonstrated lower risk of ESCC (HR = 0.44), but not EADC (HR = 0.91) (Li et al., 2013c) Collectively, these studies suggest that consumption of a healthy, balanced diet may reduce the risk of esophageal cancers, although the data on individual food items remain inconclusive Occupation Occasional reports have suggested increased risks of esophageal cancer, primarily ESCC, among various occupational groups These associations tend to be neither consistent nor strong, however, and have not always been adjusted for smoking, alcohol, and social class (Blot et al., 2006) Many of these associations were derived from record-​linkage or other exploratory studies that examined multiple occupations, and are thus subject to the problem of false positives arising from multiple statistical comparisons Early research among insulation workers heavily exposed to asbestos initially suggested an increased risk of ESCC, but two reviews and meta-​analyses have concluded that there is no evidence of increased risk One meta-​analysis reported a summary risk estimate of 1.02 (Goodman et al., 1999) A review by the US Institute of Medicine reported a summary risk estimate of 0.99 (National Academies of Science [NAS], 2006) Fewer studies have assessed occupational risk factors for EADC, but again, the occasional associations reported in individual studies not provide compelling evidence of carcinogenicity A  few studies suggested that chlorinated solvent exposure might be associated with increased EADC risk, but an IARC working group review found no consistent or reliable evidence to support this finding (IARC, 2014) Based on current information, esophageal cancer appears to have little or no association with occupational exposures Radiation Studies of populations exposed to ionizing radiation have established that both short-​term high-​level exposure and chronic low-​level exposure increases risk of esophageal cancer The diverse study populations include Japanese atomic bomb survivors, patients who received X-​ray therapy for ankylosing spondylitis, patients receiving radiotherapy for breast cancer and Hodgkin lymphoma, medical diagnostic X-​ray workers, and people exposed to ionizing radiation from environmental pollutants released from a plutonium production plant (Blot et al., 2006; Davis et al., 2015; Kamiya et al., 2015; Morton et al., 2012, 2014; Wang et al., 2015) The dose of radiation to the esophagus was estimated in a study of long-​term breast cancer survivors There was little evidence of increased risk of esophageal cancer in women who received less than 20 Gy, but a monotonic increase in ESCC risk in those receiving higher doses Women with over 35 Gy exposure to the  58 Esophageal Cancer esophagus had an 8-​fold increase in ESCC risk (Morton et al., 2012) In contrast, EADC risk did not increase significantly with increasing radiation dose ESCC comprised nearly all (97%) esophageal cancers in women who received more than 20 Gy, but 79% among those who received less than this amount (Morton et al., 2012) Another review of second cancer risk after radiotherapy for breast cancer reported a summary relative risk estimate of 2.2 (95% CI = 1.1–​4.2) for women who survived 15 or more years after breast cancer diagnosis (Grantzau and Overgaard, 2015) A study of esophageal cancer following radiotherapy for Hodgkin lymphoma also found significantly increased risk in those with high estimated doses to the esophagus (Morton et  al., 2014) A nested case-​control study of X-​ray technicians occupationally exposed to radiation reported significantly increased risk of both esophageal and breast cancer (Wang et  al., 2015) A study of solid cancer incidence associated with environmental radiation exposure in the Techna River cohort in Russia reported significantly increased risk for esophageal and uterine cancer (Davis et al., 2015) There is now convincing evidence that ESCC is a radiogenic malignancy, but whether EADCs are caused by ionizing radiation remains uncertain Medications When the epidemic rise of EADC first became apparent, one of the hypothesized causes was the rising use of medications used to treat GERD These drugs included H2 receptor antagonists, proton-​pump inhibitors, and over-​the-​counter antacids Drugs that relax the gastroesophageal sphincter and thus could increase gastric reflux, including tricyclic antidepressants, calcium channel blockers, asthma drugs containing theophylline or ß agonists, and anticholinergics, were also hypothesized to increase the risk of EADC However, studies in the 1990s tended to dispel this notion, despite the difficulty in sorting out effects of drugs from the effects of the underlying conditions for which the drugs were applied (Blot et al., 2006) Notably, a nested case-​control study in a US prepaid health plan showed that the 4-​fold increase in EADC risk among those using H2 blockers was nearly eliminated after control for GERD (Chow et al., 1995) Since that time, no further conclusive evidence has implicated these medications, including proton pump inhibitors, in EADC risk (Spechler, 2013; Thrift, 2015) Indeed, recent research has focused on the possible protective effects of medications on esophageal cancer (Thrift, 2015) Observational studies suggest that proton pump inhibitors can prevent EADC, particularly among patients with Barrett’s esophagus (Dunbar et al., 2015; Krishnamoorthi et al., 2016; Singh et al., 2014; Thrift, 2015) This benefit has not been confirmed in clinical trials (Dunbar et al., 2015) Early observational studies suggested that non-​steroidal anti-​inflammatory drugs (NSAIDs) might protect against esophageal cancer (Blot et al., 2006), and evidence from recent studies now strongly supports a preventive benefit from NSAIDs for both EADCs and ESCCs (Beales et al., 2013; Drahos et al., 2016; Lagergren and Lagergren, 2013; Liao et al., 2012; Sun and Yu, 2011; Wang et al., 2011) NSAID use also appears to protect against Barrett’s esophagus (Schneider et al., 2015) In long-​ term follow-​up of participants in three low-​dose aspirin trials in the United Kingdom conducted primarily for the evaluation of cardiovascular events, significantly lower esophageal cancer (type not specified) mortality was observed among those randomized to the aspirin arms (Rothwell et al., 2011) Statin use may decrease the risk of EADC, particularly among patients with Barrett’s esophagus, although evidence of a protective effect is more limited than for NSAIDs (Beales et al., 2013; Krishnamoorthi et  al., 2016; Lagergren and Lagergren, 2013; Singh et al., 2013a) Statin use may also protect against development of Barrett’s esophagus (Beales et al., 2016) Although the observational evidence for pharmacologic prevention of esophageal cancer appears strong, more definitive evidence is needed to establish the efficacy and safety of these agents for the prevention of either EADC or ESCC Infectious Agents Infectious agents have been suspected of affecting risk of both ESCCs and EADCs, with most attention focused on human papillomaviruses 585 (HPV) for ESCC and Helicobacter pylori (H pylori) for EADC Numerous studies, especially in Asia, have reported associations between HPV infection and increased risk of ESCC (Blot et al., 2006) Meta-​analyses have reported relative risk estimates of approximately for the association between HPV and ESCC (Hardefeldt et al., 2014; Liyanage et al., 2013) Caution is advised in interpreting these results, however, because the prevalence of HPV in tumor tissue varied by almost 2-​fold among the individual studies included in the meta-​analyses (Li et al., 2014) The prevalence of HPV detected in tumor tissue from ESCC averaged 28% across samples, but varied by almost 2-​fold depending on the detection method, with the highest prevalence occurring in China (Petrick et al., 2014) Data from six case-​control studies that assessed serologic markers of 14 HPV types in several parts of the world reported positive associations between the risk of ESCC and two subtypes of HPV (16 and 6), suggesting a limited causal role (Sitas et  al., 2012) Moreover, not all studies have found an association between HPV and ESCC, including some negative studies in China (Koshiol et al., 2010; Peixoto et al., 2001; Teng et al., 2014) Accordingly, an evaluation of the evidence for the association between HPV and ESCC in 2011 noted that the overall evidence for a causal role for HPV was inconclusive (IARC, 2012a), a conclusion shared by other recent reviews (Ludmir et  al., 2015; Rustgi and El-​Serag, 2014; Zandberg et al., 2013) It would be difficult to reconcile a strong causal association between HPV and ESCC with the downward secular trend observed for ESCC (Figure 30–1) since the late 1990s among white men in the United States, especially given the large increase in the HPV-​related squamous cell carcinomas of the oropharynx, tonsil, and base of the tongue (Simard et al., 2012) HPV infection has been reported to be unrelated to risk of EADC or Barrett’s esophagus (El-​Serag et al., 2013) While bacterial H. pylori infection is a major risk factor for gastric cancer, and may contribute to increased risk of colorectal and perhaps other cancers, it has now been consistently associated with lower risk of EADC (IARC, 2012a; Nie et  al., 2014; Runge et  al., 2015; Xie et al., 2013) A number of meta-​analyses have reported evidence that H.  pylori infection is associated with a reduced risk of EADC, particularly when infection involves CagA-​positive strains (Islami and Kamangar, 2008; Rokkas et  al., 2007; Xie et  al., 2013) In contrast, H.  pylori infection seems generally to be unrelated to ESCC risk (IARC, 2012a; Nie et al., 2014; Rokkas et al., 2007; Xie et al., 2013), although a finding of significantly reduced risk among Asian populations warrants further investigation (Xie et al., 2013) The mechanism(s) by which H. pylori might protect against EADC have been hypothesized to involve a reduction of gastric acid secretion resulting from gastric atrophy due to chronic infection with H. pylori H.  pylori infection has been consistently associated with reduced risk of Barrett’s esophagus (Blot et  al., 2006; Fishbach et  al., 2012; Rubenstein et al., 2014) The association between H. pylori infection and GERD is uncertain, however, with recent studies indicating that H.  pylori may be associated with a reduced risk of GERD in Asian populations, but not Western populations (Rubenstein et  al., 2014) H. pylori prevalence has been declining in Western countries due to improvements in sanitation and widespread use of antibiotics This decline coincides with the rise in EADC incidence The trends may be linked (Blaser, 1999, 2008), as might be the higher H. pylori infection rates and lower EADC rates among blacks compared to whites in the United States Analysis of the esophageal microbiome is in the early stages, but based on a comprehensive review of existing studies it has been hypothesized that an emerging Campylobacter species may be involved in the etiology of EADC (Kaakoush et al., 2015; Neto et al., 2016) HOST FACTORS Predisposing Medical Conditions Several medical conditions predispose to the development of ESCC or EADC Plummer-​Vinson syndrome, celiac disease, and pernicious anemia increase the risk of ESCC (Blot et al., 2006) Tylosis, a rare 586 586 PART IV:  Cancers by Tissue of Origin genetic syndrome characterized by autosomal dominant inheritance and palmar and plantar hyperkeratosis, is associated with increased risk of ESCC (Blaydon et al., 2012; Robertson et al., 2008) Mutations in the RHBDF2 gene within chromosomal region 17q25 have been identified as the cause of tylosis (Blaydon et al., 2012) The relative contribution of RHBDF2 mutations to sporadic esophageal cancer risk is currently unknown Another rare condition linked to squamous cell carcinomas is achalasia, in which the gastro-​esophageal sphincter fails to relax due to disturbance of the autonomic nervous system This allows food to be retained in the esophagus for extended periods (Blot et al., 2006; Eckardt and Eckardt, 2010) Achalasia appears to increase the risk of EADC as well as ESCC (Leeuwenburgh, et  al., 2013; Zendehdel et al., 2011) Family History Familial associations are less strong for esophageal cancer than for a number of other cancers, especially in Western countries (Blot et al., 2006; Gao et al., 2009; Jiang et al., 2014) It is difficult to distinguish the effects of inherited risk from those caused by shared environmental exposures This challenge is compounded in high-​risk areas of the world where ESCC predominates In a case-​control study of ESCC in China, for example, the relative risk estimate for having a first-​degree relative with esophageal cancer was 2.3, but the relative risk estimate was nearly the same for having a non-​blood relative with esophageal cancer (Gao et al., 2009) Inherited Susceptibility Genes Candidate Gene Studies Because of the strong associations of tobacco smoking and alcohol consumption with ESCC risk, genetic studies in the era preceding genome-​wide association studies (GWAS) concentrated on genes that might be likely to modify the risk associated with these known risk factors The CYP1A1 gene was studied extensively because of the ability of the enzyme CYP1A1 to convert polycyclic aromatic hydrocarbons to reactive carcinogenic metabolites (Wang et  al., 2012) A large meta-​analysis reported a strong association between CYP1A1 polymorphisms and ESCC risk in people in Asia and in Western countries (Shen et al., 2013) No association with CYP1A1 polymorphisms was observed for EADC in this meta-​analysis The CYP2E1 gene may also be associated with ESCC risk; CYP2E1 can activate a number of potential carcinogens (Wang et al., 2012) Alcohol is metabolized to acetaldehyde, which when associated with consumption of alcoholic beverages is classified as a human carcinogen (IARC, 2012b) Alcohol metabolism is under genetic control, with polymorphic variation in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes and substantial differences in the prevalence of slow versus fast metabolizers across broad population groups Early candidate gene studies extensively investigated polymorphisms in ADH and ALDH, and identified three genes, ALDH2, ADH1B, and ADH2, as likely genes associated with ESCC risk (Yokoyama et al., 2002; Zhang et al., 2010) A meta-​analysis reported significant associations between ADH1B and ALDH2 polymorphisms and ESCC risk (Zhang et al., 2010) As was the case for head and neck cancers (Brennan et al., 2004; Chang et  al., 2012), increased risk of esophageal cancer was observed among slow metabolizers based on the ADH1B genotype A recent case-​control study provided compelling evidence that ADH4 polymorphisms may be associated with squamous cell carcinoma risk (Xu et  al., 2015) A small candidate gene study implicated germline mutations in MSR1 as possibly being associated with Barrett’s esophagus and esophageal adenocarcinoma (Orloff et al., 2011) Genome-​Wide Association Studies Although the findings of candidate gene studies are often not replicated in GWAS, the first two GWAS of esophageal carcinoma, conducted in China and Japan, confirmed that ALDH2 and ADH1B polymorphisms were associated with risk of ESCC, with strong interactions for alcohol consumption and smoking (Cui et al., 2009; Tanaka et al., 2010) Subsequent large GWAS in Chinese populations identified several genes or gene regions associated with ESCC (Abnet et al., 2010; Wang et al., 2010; Wu et al., 2011, 2012, 2014) Genes identified in multiple GWAS included ADH1B, ALDH2, PLCE1, and CHEK2 In a GWAS conducted in a region where alcohol consumption and smoking are not major risk factors, the alcohol dehydrogenase genes were not significantly associated with cancer risk (Abnet et al., 2010) In another study, the alcohol dehydrogenase genes were only associated with cancer risk in analyses restricted to smokers and drinkers (Wang et al., 2010) One small GWAS found no association between the PLCE1 gene and ESCC in Caucasians, although this gene has been consistently found to be associated with ESCC risk in Asians (Dura et al., 2013b) However, the null study was based on only 83 patients with ESCC and 258 with EADC A Chinese GWAS found no evidence that common variants in the SLC39A6 gene were associated with survival among ESCC patients (Wu et al., 2013) Because almost all GWAS have been conducted in Eastern Asian populations, the extent to which these results apply to Western populations is uncertain Two recent studies have evaluated genes in specific pathways for evidence of an association with ESCC and gastric adenocarcinomas in a Chinese population Alterations in DNA repair pathway genes were associated with ESCC (but not gastric cancer) risk; CHEK2 was the most significant single gene (Li et al., 2013a) The epidermal growth factor receptor pathway was significant for gastric cancer but not for ESCC (Li et al., 2013b) Far fewer GWAS have been conducted of EADC Many studies are based on populations that combined EADC and Barrett’s esophagus patients It is noteworthy that analysis of germline mutations indicates that EADC shares an underlying genetic basis with Barrett’s esophagus, but not with GERD (Ek et al., 2013) GWAS of Barrett’s esophagus and esophageal adenocarcinoma have identified polymorphisms at FOXF1, CRTC1, BARX1, FOXP1, and within the major histocompatibility complex (MHC) as being associated with risk (Levine et al., 2013; Palles et al., 2015; Su et al., 2012) A  case-​control study confirmed associations between esophageal adenocarcinoma and polymorphisms at FOXF1 and within the MHC (Dura et al., 2013a) A large GWAS evaluating miRNA-​related single nucleotide polymorphisms (associated with 389 genes) found no evidence of an association with risk of esophageal adenocarcinoma or Barrett’s esophagus (Buas et al., 2015) An integrative post-​ GWAS analysis suggested that germline CDKN2A mutations may be associated with progression from Barrett’s esophagus to esophageal adenocarcinoma (Buas et al., 2014) Somatic Mutations Sequencing of the genome in cancer tissue has identified several genes that are mutated at high frequencies in ESCC TP53 is by far the most frequently mutated gene; other genes frequently mutated include CDKN2A, PIK3CA, NFE2L2, NOTCH1, MLL2, FAT1, and ZNF750 (Abedi-​Ardekani and Hainaut, 2014; Gao et al., 2014; Lin et al., 2014; Sawada et al., 2016; Song et al., 2014; Zhang et al., 2015) Based on a detailed analysis of mutational signatures, the APOEC family of cytidine deaminases has been implicated in the mutation process for as many as 50% of the ESCCs examined (Sawada et  al., 2016; Zhang et al., 2015) Sequencing of the genomes in disease tissue has indicated a high frequency of mutations in several genes in EADC and Barrett’s esophagus TP53 is the most frequently mutated gene, perhaps more so for EADC than for ESCC Other frequently mutated genes include CDKN2A, SMAD4, ARID1A, PIK3CA, and MYO18B (Abedi-​ Ardekani and Hainaut, 2015; Dulak et  al., 2013; Galipeau et  al., 2007; Ross-​Innes et al., 2015; Stachler et al., 2015; Weaver et al., 2014) ARID1A has been identified as a suppressor gene in Barrett’s esophagus (Streppel et  al., 2014) TP53 mutations appear to be  587 Esophageal Cancer associated with Barrett’s esophagus, particularly Barrett’s esophagus with high-​grade dysplasia (Galipeau et  al., 2007; Ross-​Innes et al., 2015; Stachler et al., 2015; Weaver et al., 2014) Progression to adenocarcinoma is frequently associated with chromosomal gain (increases in aneuploidy and copy number) or loss (deletions/​loss of heterozygosity) of genomic material (Galipeau et  al., 2007; Ross-​ Innes et al., 2015; Stachler et al., 2015) Molecular Pathogenesis The molecular pathogenesis of esophageal cancer is poorly understood Commonly mutated genes associated with ESCC risk are involved in cell cycle control, apoptosis, and histone modification Cellular pathways affected by mutated genes in ESCC are the RTK-​MAPK-​PI3K, Wnt, Hippo, and Notch pathways Based on evidence from mouse studies, it has been hypothesized that an unfolded protein response to stress in the endoplasmic reticulum, which may be linked to the Notch pathway, might play a role in the etiology of ESCC (Rosekrans et al., 2015b) Imputation analysis of an ESCC GWAS identified XBP1, a gene involved in the unfolded protein response, as possibly being associated with ESCC risk (Wu et al., 2012) The possible roles played by the various implicated pathways in the etiology of ESCC remain to be elucidated Although the stepwise development of EADC is relatively well characterized, the roles of various pathways in cancer development are poorly understood Frequently mutated genes associated with EADC risk are involved in cell signaling, apoptosis, and genomic stability Cellular pathways affected by mutated genes in EADC are the Wnt pathway and the Bmp signaling pathway (Rosekrans et  al., 2015a) Several genes identified as being associated with Barrett’s esophagus or EADC are involved in the Bmp pathway, which may play a role in the development of Barrett’s esophagus (Rosekrans et al., 2015a) Recent studies that have evaluated the development and carcinogenic progression of Barrett’s esophagus have suggested that the Notch and Sonic Hedgehog pathways may also be involved in early steps in the development of EADC (Saraggi et al., 2016; Streppel et al., 2014) The relative contributions of the various implicated pathways to the etiology of EADC remain uncertain PREVENTIVE MEASURES The poor survival following a diagnosis of esophageal cancer highlights the need for measures aimed at cancer prevention Primary Prevention Eliminating or reducing the exposures that cause ESCC and EADC offers the greatest potential to reduce the incidence and mortality of both cancer subtypes Thus for ESCC, curtailment of tobacco smoking (by helping smokers quit and ensuring that nonsmokers never take up the habit) and limiting alcohol consumption to moderate or low (including abstention) amounts may provide the best means currently available to reduce the incidence of this cancer in Western societies The advantages of quitting smoking will be seen in the near term, since risk of ESCC declines rapidly following smoking cessation The impact of declining smoking prevalence has already been reflected in the declining rates of this cancer subtype in the United States For EADC, cigarette smoking also increases risk; quitting smoking will result in reduced risk of these esophageal cancers, although the reduction is slower than for ESCC and may not be evident for over a decade following cessation In areas of the world with clusters of ESCC related to high alcohol intake, and in Western societies generally, reduction in alcohol consumption is critical to prevention, since excess risk occurs mainly among heavy drinkers Alcohol consumption seems unrelated to EADC risk, so reducing consumption will be of benefit only for ESCC Dietary factors may be involved in risk of both types of esophageal cancer, but if and until more specific components are identified, 587 the most prudent approach to risk reduction will be the adoption of a balanced diet For EADC, obesity and GERD are clear risk factors Large-​scale clinical trials to investigate reductions in adenocarcinoma incidence following weight loss or control of GERD are not practical given the relative rarity of the cancers, but the strong observational epidemiologic evidence indicates that measures aimed at obesity control should be helpful in lowering adenocarcinoma risk Whether treatment of GERD will lower risk of esophageal adenocarcinoma is also unclear but seems plausible However, the complexity of the gastric-​esophageal microbiome hinders evaluation of how treatment of GERD, or H. pylori or other microbes, may influence subsequent risk of cancers near the gastroesophageal junction Chemoprevention There is promise that aspirin and other NSAIDs may reduce the risk of both forms of esophageal cancer, since the epidemiologic evidence of lowered risk among users of these drugs has become more convincing over the past decade In a meta-​analysis combining data across 51 randomized controlled trials designed primarily to assess cardiovascular outcomes, significantly reduced incidence of GI tract cancers was found among those taking daily aspirin, but the numbers were too small to sort out an effect for esophageal cancers (Rothwell et al., 2012) However, in an up to 20-​year follow-​up of participants in three large randomized prevention trials in the United Kingdom, with 62 deaths from esophageal cancer observed, mortality was less than half as high among those prescribed aspirin (HR = 0.42; 95% CI = 0.25–​0.71) (Rothwell et al., 2011) In the Linxian intervention trials, reduced incidence of the primary ESCC/​stomach cancer endpoint was found among those randomized to receive a combination of beta carotene, selenium, and vitamin E supplementation (Blot et al., 1993), although applicability beyond the nutritionally limited local setting is questionable While no new strong candidates appear on the immediate horizon, prospects for chemoprevention may emerge as more is learned about the potential mechanisms of esophageal carcinogenesis and the human microbiome (Chung et al., 2015; Neto et al., 2016) Secondary and Tertiary Prevention One approach to prevent esophageal cancer onset is to block the formation of its precursor lesions and/​or their transformation to malignancy Both ESCC and EADC develop through a multistage sequence of events with detectable early lesions (esophagitis and dysplasia for the former, and Barrett’s metaplasia and dysplasia for the latter), providing targets for inhibition of the carcinogenic process Methods to prevent the occurrence of these early lesions are not yet available, however Targeted secondary prevention will require further characterization of molecular markers that predict the progression of dysplasia and Barrett’s esophagus, which may in turn depend upon host factors related to the metabolism and detoxification of esophageal carcinogens The multistage process also provides opportunities for surveillance of those at high risk and early detection of cancers at a stage when they may be more amenable to surgical or other treatment Adults with Barrett’s esophagus can be followed more intensely, although screening the general population for Barrett’s and subsequently following those in whom the lesions are found has not yet been shown to lower mortality from esophageal cancer and may not be efficient due to the low rate of transition from Barrett’s to cancer (Conio et al., 2003; Falk, 2015; Spechler, 2013) FUTURE RESEARCH The epidemiologic evidence accumulated to date indicates that most ESCC in Western countries are preventable by reductions in tobacco and alcohol consumption and suggests that pathways to reduce risk of EADC will involve the prevention or treatment of obesity and reflux disease Further characterization of the roles of central obesity, sedentary activity, and diet in esophageal cancer risk may yield better 58 588 PART IV:  Cancers by Tissue of Origin strategies for risk reduction, especially for EADC In other countries with pockets of excess ESCC incidence, preventive options seem less clear Continued research in genomic, metabolomic, microbiome, and other molecular approaches toward personalized precision medicine may provide new insights and clues into the mechanisms of the development of esophageal cancers and clues toward their prevention and control References Abedi-​Ardekani B, Hainaut P 2014 Cancers of the upper gastro-​intestinal tract: a review of somatic mutation distributions Arch Iran Med 17:286–​ 292 PMID: 24724606 Abnet CC, Corley DA, Freedman ND, Kamangar F 2015 Diet and upper gastrointestinal malignancies Gastroenterol 148:1234–​1243 PMCID: PMC4414068 Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, et al 2010 A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma Nature Genet 9:764–​767 PMCID: PMC2947317 Agaku IT, King BA, Dube SR 2014 Current cigarette smoking among adults: United States, 2005–​2012 MMWR 63:29–​34 PMID: 24430098 Akhtar S 2013 Areca nut chewing and esophageal squamous-​cell carcinoma risk in Asians:  a meta-​analysis of case-​control studies Cancer Causes Control 24:257–​265 PMID: 23224324 Al-​ Samawi AS, Aulaqi SM 2014 Esophageal cancer in Yemen J Coll Physicians Surg Pak 24:182–​185 PMID: 24613114 Andrici J, Cox MR, Eslick GD 2013 Cigarette smoking and the risk of Barrett’s esophagus:  a systematic review and meta-​ analysis J Gastroenterol Hepatol 28:1258–​1273 PMID: 23611750 Andrici J, Eslick GD 2013 Maté consumption and the risk of esophageal squamous cell carcinoma: a meta-​analysis Dis Esophagus 26:807–​816 PMID: 22891687 Andrici J, Eslick GD 2015 Hot food and beverage consumption and the risk of esophageal cancer:  a meta-​analysis Am J Prev Med 49:952–​960 PMID: 26590941 Arnold M, Soerjomataram I, Ferlay J, Forman D 2015 Global incidence of oesophageal cancer by histological subtype in 2012 Gut 64:381–​387 PMID: 25320104 ATBC Study Group 1994 The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers N Engl J Med 330:1029–​1035 PMID: 8127329 Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et  al 2015 Alcohol consumption and site-​ specific cancer risk:  a comprehensive dose-​response meta-​analysis Br J Cancer 112:580–​593 PMCID: PMC4453639 Beales ILP, Vardi I, Dearman L, Broughton T 2013 Statin use is associated with a reduction in the incidence of esophageal adenocarcinoma: a case control study Dis Esophagus 26:838–​846 PMID: 22989236 Beales ILP, Dearman L, Vardi I, Loke Y 2016 Reduced risk of Barrett’s esophagus in statin users:  case-​control study and meta-​analysis Dig Dis Sci 61:238–​246 PMID: 26386857 Blaser MJ 1999 Hypothesis: the changing relationships of Helicobacter pylori and humans: implications for health and disease J Infect Dis 179:1523–​ 1530 PMID: 10228075 Blaser MJ 2008 Disappearing microbiota:  Helicobacter pylori protection against esophageal adenocarcinoma Cancer Prev Res 1:308–​311 PMID: 19138974 Blaydon DC, Etheridge SL, Risk JM, Hennies HC, Gay LJ, Carroll R, et al 2012 RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome Am J Hum Genet 90:340–​346 PMCID: PMC3276661 Blot WJ 1992 Alcohol and cancer Cancer Res 52:2119s–​2123s PMID: 1544150 Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al 1993 Nutrition intervention trials in Linxian, China:  supplementation with specific vitamin/​ mineral combinations, cancer incidence, and disease-​ specific mortality in the general population J Natl Cancer Inst 85:1483–​1492 PMID: 8360931 Blot WJ 1994 Esophageal cancer trends and risk factors Semin Oncol 21:403–​ 410 PMID: 8042037 Blot WJ, Devesa SS, Kneller RW, Fraumeni JFF Jr 1991 Rising incidence of adenocarcinoma of the esophagus and gastric cardia JAMA 265:1287–​ 1289 PMID: 1995976 Blot WJ, McLaughlin JK, Fraumeni JF Jr 2006 Esophageal cancer In: Schottenfeld D, Fraumeni JFJr (eds.), Cancer epidemiology and prevention, 3rd ed New York: Oxford University Press, pp 697–​706 Bosetti C, Levi F, Ferlay J, Garavello W, Lucchini F, Bertuccio P, et al 2008 Trends in oesophageal cancer incidence and mortality in Europe Int J Cancer 122:1118–​1129 PMID: 17990321 Brennan P, Lewis S, Hashibe M, Bell DA, Boffetta P, Bouchardy C, et al 2004 Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review Am J Epidemiol 159:1–​16 PMID: 14693654 Buas MF, Levine DM, Makar KW, Utsugi H, Onstad L, Li X, et  al 2014 Integrative post-​genome-​wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma Carcinogenesis 35:2740–​ 2747 PMCID: PMC4247522 Buas MF, Onstad L, Levine DM, Risch HA, Chow WH, Liu G, et  al 2015 MiRNA-​ related SNPs and risk of esophageal adenocarcinoma and Barrett’s esophagus:  post genome-​ wide association analysis in the BEACON consortium PLoS One 10(6):e0128617 doi: 10.1371/​journal pone.0128617 PMCID: PMC4454432 Carter BD, Abnet CC, Feskanich D, Freedman ND, Hartge P, Lewis CE, et al 2015 Smoking and mortality: beyond established causes N Engl J Med 372:631–​640 PMID: 25671255 Chandar AK, Iyer PG 2015 Role of obesity in the pathogenesis and progression of Barrett’s esophagus Gastroenterol Clin N Am 44:249–​264 PMID: 26021193 Chang CM, Corey CG, Rostron BL, Apelberg BJ 2015 Systematic review of cigar smoking and all cause and smoking related mortality BMC Public Health Apr 24;15:390 doi:  10.1186/​s12889-​015-​1617-​5 PMCID: PMC4408600 Chang JS, Straif K, Guha N 2012 The role of alcohol dehydrogenase genes in head and neck cancers: a systematic review and meta-​analysis of ADH1B and ADH1C Mutagenesis 27:275–​286 PMID: 22042713 Chang P, Friedenberg F 2014 Obesity and GERD Gastroenterol Clin N Am 43:161–​173 PMCID: PMC3920303 Chen H, Ward MH, Graubard BJ, Heineman EF, Markin RM, Potischman NA, et al 2002 Dietary patterns and adenocarcinoma of the esophagus and distal stomach Am J Clin Nutr 75:137–​144 PMID: 11756071 Chen X, Yang C 2001 Esophageal adenocarcinoma:  a review and perspectives on the mechanism of carcinogenesis and chemoprevention Carcinogenesis 22:1119–​1129 PMID: 11470739 Chen Y, Tong Y, Yang C, Gan Y, Sun H, Bi H, et  al 2015 Consumption of hot beverages and foods and risk of esophageal cancer: meta-​analysis of observational studies BMC Cancer 15:449 PMCID: PMC4457273 Chow WH, Blot WJ, Vaughn TL, Risch HA, Gammon MD, Stanford JL, et al 1998 Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia J Natl Cancer Inst 90:150–​155 PMID: 9450576 Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni JF Jr 1995 The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia JAMA 274:474–​ 477 PMID: 7629956 Chung CC, Lee YC, Wu MS 2015 Prevention strategies for esophageal cáncer:  perspective of the East vs West Best Practices Res Clin Gastroenterol 29:869–​883 PMID: 26651249 Conio M, Blanchi S, Lapertosa G, Ferraris R, Sablich R, Marchi S, et al 2003 Long-​term endoscopic surveillance of patients with Barrett’s esophagus Incidence of dysplasia and adenocarcinoma:  a prospective study Am J Gastroenterol 98:1931-​1939 PMID:14499768 Cook MB, Corley DA, Murray LJ, Liao LM, Kamangar F, Ye W, et al 2014 Gastroesophageal reflux in relation to adenocarcinomas of the esophagus: a pooled analysis from the Barrett’s and Esophageal Adenocarcinoma consortium PLoS One 9:e103508 PMCID: PMC4116205 Cook MB, Kamangar F, Whiteman DC, Freedman ND, Gammon M, Bernstein L, et  al 2010 Cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction:  a pooled analysis from the international BEACON consortium J Natl Cancer Inst 102:1344–​1353 PMCID: PMC2935475 Cook MB, Shaheen NJ, Anderson LA, Giffen C, Chow WH, Vaughan TL, et al 2012 Cigarette smoking increases risk of Barrett’s esophagus: an analysis of the Barrett’s and Esophageal Adenocarcinoma Consortium Gastroenterol 142:744–​753 PMCID: PMC3321098 Corley DA, Kubo A, Zhao W 2007 Abdominal obesity, ethnicity and gastro-​ oesophageal reflux symptoms Gut 56:756–​762 PMCID: PMC1954862 Corley DA, Kubo A, Zhao W 2008 Abdominal obesity and the risk of esophageal and gastric cardia carcinomas Cancer Epidemiol Biomarkers Prev 17:352–​358 PMCID: PMC2670999 Cross AJ, Freedman ND, Ren J, Ward MH, Hollenbeck AR, Schatzkin A, et  al 2011 Meat consumption and risk of esophageal and gastric cancer in a large prospective study Am J Gastroenterol 106:432–​442 PMCID: PMC3039705 Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, Kawaguchi T, et  al 2009 Functional variants in ADH1B and ALDH2 coupled with alcohol and  589 Esophageal Cancer smoking synergistically enhance esophageal cancer risk Gastroenterol 137:1768–​1775 PMID: 19698717 Davis FG, Krestinina LY, Preston D, Epifanova S, Degteva M, Akleyev AV 2015 Solid cancer incidence in the Techna River Incidence Cohort Radiation Res 184:56–​65 PMID: 26121228 Drahos J, Xiao Q, Risch HA, Freedman ND, Abnet CC, Anderson LA, et al 2016 Age-​specific risk factor profiles of adenocarcinomas of the esophagus: a pooled analysis from the international BEACON consortium Int J Cancer 138:55–​64 PMCID: PMC4607633 Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C, et al 2013 Exome and whole-​genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity Nature Genet 45:478–​486 PMCID: PMC3678719 Dunbar KB, Souza RF, Spechler SJ 2015 The effect of proton pump inhibitors on Barrett’s esophagus Gastroenterol Clin N Am 44:415–​424 PMID: 26021202 Dura P, van Veen EM, Salomon J, te Morsche RHM, Roelofs HMJ, Kristinsson JO, et  al 2013a Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk Int J Cancer 133:1751–​1756 PMID: 23504527 Dura P, Bregitha CVV, te Morsche RHM, Roelofs HMJ, Kristinsson JO, Wobbes T, et  al 2013b GWAS-​uncovered SNPs in PLCE1 and RFT2 genes are not implicated in Dutch esophageal adenocarcinoma and squamous cell carcinoma etiology Eur J Cancer Prev 22:417–​419 PMID: 23222411 Eckardt AJ, Eckardt VF 2010 Cancer surveillance in achalasia: better late than never? Am J Gastroenterol 105:2150–​2152 PMID: 20927062 Ek WE, Levine DM, D’Amato M, Pedersen NL, Magnusson PKE, Bresso F, et  al 2013 Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett’s esophagus, and gastroesophageal reflux J Natl Cancer Inst 105:1711–​1718 PMCID: PMC3833931 El-​Serag HB, Hollier JM, Gravitt P, Alsarraj A, Younes M 2013 Human papillomavirus and the risk of Barrett’s esophagus Dis Esophagus 26:517–​ 521 PMCID: PMC4412355 Falk GW 2015 Barrett’s oesophagus:  frequency and prediction of dysplasia and cancer Best Pract Res Clin Gastroenterol 29:125–​138 PMCID: PMC4352690 Fishbach LA, Nordenstedt H, Kramer JR, Gandhi S, Dick-​Onuoha S, Lewis A, El-​Serag HB 2012 The association between Barrett’s esophagus and Helicobacter pylori infection: a meta-​analysis Helicobacter 17:163–​175 PMCID: PMC3335759 Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et  al 2013 GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide:  IARC CancerBase No 11 Lyon, France:  International Agency for Research on Cancer Available from: http://​globocan.iarc.fr, accessed August 27, 2015 Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et  al 2015 Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 136:E359–​E386 PMID: 25220842 Freedman ND, Abnet CC, Leitzmann MF, Mouw T, Subar AF, Hollenbeck AR, Schatzkin A 2007 A prospective study of tobacco, alcohol, and the risk of esophageal and gastric cancer subtypes Am J Epidemiol 165:1424–​ 1433 PMID: 17420181 Freedman ND, Murray LJ, Kamangar F, Abnet CC, Cook MB, Nyrén O, et  al 2011 Alcohol intake and risk of oesophageal adenocarcinoma:  a pooled analysis from the BEACON consortium Gut 60:1029–​1037 PMCID: PMC3439838 Friedenberg FK, Xanthopoulos M, Foster GD, Richter JE 2008 The association between gastroesophageal reflux disease and obesity Am J Gastroenterol 103:2111–​2122 PMID: 18796104 Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD, et al 2007 NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma PLoS Med 4:e67 PMCID: PMC1808095 Gao Y, Hu N, Han XY, Giffen C, Ding T, Goldstein A, Taylor P 2009 Family history of cancer and risk for esophageal and gastric cancer in Shanxi, China BMC Cancer 9:269 PMCID: PMC2729777 Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, et al 2014 Genetic landscape of esophageal squamous cell carcinoma Nature Genet 46:1097–​ 1102 PMID: 25151357 Gatenby P, Caygill C, Wall C, Bhatacharjee S, Ramus J, Watson A, Winslet M 2014 Lifetime risk of esophageal adenocarcinoma in patients with Barrett’s esophagus World J Gastroenterol 20:9611–​9617 PMCID: PMC4110596 Goodman M, Morgan RW, Ray R, Malloy CD, Zhao K 1999 Cancer in asbestos-​exposed occupational cohorts: a meta-​analysis Cancer Causes Control 10:453–​465 PMID: 10530617 589 Grantzau T, Overgaard J 2015 Risk of second non-​breast cancer after radiotherapy for breast cancer:  a systematic review and meta-​ analysis of 762,468 patients Radiother Oncol 114:56–​65 PMID: 25454172 Hardefeldt HA, Cox MR, Eslick GD 2014 Association between human papillomavirus (HPV) and oesophageal squamous cell carcinoma:  a meta-​ analysis Epidemiol Infect 142:1119–​1137 PMID: 24721187 Hoyo C, Cook MB, Kamangar F, Freedman ND, Whiteman DC, Bernstein L, et  al 2012 Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas:  a pooled analysis from the international BEACON consortium Int J Epidemiol 41:1706–​1718 PMCID: PMC3535758 Hur C, Miller M, Kong CY, Dowling EC, Nattinger KJ, Dunn M, Feuer EJ 2013 Trends in esophageal adenocarcinoma incidence and mortality Cancer 119:1149–​1158 PMCID: PMC3744155 International Agency for Research on Cancer (IARC) 1986 Tobacco smoking IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 38 Lyon, France: IARC PMID: 3460963 International Agency for Research on Cancer (IARC) 1988 Alcohol drinking IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 44 Lyon, France: IARC PMID: 3236394 International Agency for Research on Cancer (IARC) 2004 Tobacco smoke and involuntary smoking IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 83 Lyon, France:  IARC PMCID: PMC4781536 International Agency for Research on Cancer (IARC) 2012a Biologic agents IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 100B Lyon, France: IARC PMCID: PMC4781184 International Agency for Research on Cancer (IARC) 2012b Personal habits and indoor combustions IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 100E Lyon, France:  IARC PMCID: PMC4781577 International Agency for Research on Cancer (IARC) 2014 Trichloroethylene, tetrachloroethylene, and some other chlorinated agents IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol 106 Lyon, France: IARC PMCID: PMC4781308 Islami F, Boffetta P, Ren JS, Pedoeim L, Khatib D, Kamangar F 2009 High-​ temperature beverages and foods and esophageal cancer risk: a systematic review Int J Cancer 125:491–​524 PMCID: PMC2773211 Islami F, Fedirko V, Tramacere I, Bagnardi V, Jenab M, Scotti L, et al 2011 Alcohol drinking and esophageal squamous cell carcinoma with focus on light-​drinkers and never-​smokers: a systematic review and meta-​analysis Int J Cancer 129:2473–​2484 PMID: 21190191 Islami F, Kamangar F 2008 Helicobacter pylori and esophageal cancer risk: a meta-​analysis Cancer Prev Res 1:329–​338 PMCID: PMC3501739 Jiang X, Tseng CC, Bernstein L, Wu AH 2014 Family history of cancer and gastroesophageal disorders and risk of esophageal and gastric adenocarcinomas:  a case-​ control study BMC Cancer 14:60 PMCID: PMC3915076 Kaakoush NO, Casto-​ Rodríguez N, Man SM, Mitchell HM 2015 Is Campylobacter to esophageal adenocarcinoma as Helicobacter is to gastric adenocarcinoma? Trends Microbiol 23:455–​462 PMID: 25937501 Kamiya K, Ozasa K, Akiba S, Niwa O, Kodama K, Takamura N, et al 2015 From Hiroshima and Nagasaki to Fukushima 1: long-​term effects of radiation exposure on health Lancet 386:469–​478 PMID: 26251392 Kong CY, Kroep S, Curtius K, Hazleton WD, Jeon J, Meza R, et  al 2014 Exploring the recent trend in esophageal adenocarcinoma incidence and mortality using comparative simulation modeling Cancer Epidemiol Biomarkers Prev 23:997–​1006 PMCID: PMC4048738 Koshiol J, Wei WQ, Kreimer AR, Chen W, Gravitt P, Ren JS 2010 No role for human papillomavirus in esophageal squamous cell carcinoma in China Int J Cancer 127:93–​100 PMCID: PMC3069961 Krishnamoorthi R, Borah B, Heien H, Das A, Chak A, Iyer P 2016 Rates and predictors of progression to esophageal carcinoma in a large population-​ based esophagus cohort Gastrointest Endosc 84:40–​46 PMID: 26772891 Kroep S, Lansdorp-​Vogelaar I, Rubenstein JH, Lemmens VEPP, van Heijningen EB, Aragonés N, et al 2014 Comparing trends in esophageal adenocarcinoma incidence and lifestyle factors between the United States, Spain, and The Netherlands Am J Gastroenterol 109:336–​343 PMID: 24343546 Kubo A, Corley DA, Jensen CD, Kaur R 2010 Dietary factors and the risks of oesophageal adenocarcinoma and Barrett’s esophagus Nutr Res Rev 23:230–​246 PMCID: PMC3062915 Kubo A, Corley DA 2006 Body mass index and adenocarcinomas of the esophagus or gastric cardia:  a systematic review and meta-​ analysis Cancer Epidemiol Biomarkers Prev 15:872–​878 PMID: 16702363 Lada MJ, Nieman DR, Han M, Timratana P, Alsalahi O, Peyre CG, et al 2013 Gastroesophageal reflux disease, proton-​pump inhibitor use and Barrett’s 590 590 PART IV:  Cancers by Tissue of Origin esophagus in oesophageal adenocarcinoma:  trends revisited Surgery 154:856–​866 PMID: 24074425 Lagergren J Influence of obesity on the risk of esophageal disorders 2011 Nat Rev Gastroenterol Hepatol 8:340–​347 PMID: 21643038 Lagergren J, Bergström R, Lindgren A, Nyrén O 2000 The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia Int J Cancer 85:340–​346 PMID: 10652424 Lagergren J, Bergström R, Nyrén O 1999 Association between body mass index and adenocarcinoma of the esophagus and gastric cardia Ann Intern Med 130:883–​890 PMID: 10375336 Lagergren J, Lagergren P 2013 Recent developments in esophageal adenocarcinoma CA Cancer J Clin 63:232–​248 PMID: 23818335 Lam TK, Freedman ND, Fan JH, Qiao YL, Dawsey SM, Taylor PR, Abnet CC 2013 Prediagnostic plasma vitamin C and risk of gastric adenocarcinoma and esophageal squamous cell carcinoma in a Chinese population Am J Clin Nutr 98:1289–​1297 PMCID: PMC3798080 Lambert JD, Yang CS 2003 Mechanisms of cancer prevention by tea constituents J Nutr 133:3262s–​3267s PMID: 14519824 Lee PN, Hamling J 2009 Systematic review of the relation between smokeless tobacco and cancer in Europe and North America BMC Medicine 7:36 PMCID: PMC2744672 Leeuwenburgh I, Scholten P, Caljé TJ, Vaessen RJ, Tilanus HW, Hansen BE, Kuipers EJ 2013 Barrett’s esophagus and esophageal adenocarcinoma are common after treatment for achalasia Dig Dis Sci 58:244–​252 PMID: 23179142 Levine DM, Ek WE, Zhang R, Liu X, Onstad L, Sather C, et al 2013 A genome-​ wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus Nature Genet 45:1487–​1493 PMCID: PMC3840115 Li X, Gao C, Yang Y, Zhou F, Li M, Jin Q, Gao L 2014 Systematic review with meta-​analysis: the association between human papillomavirus infection and oesophageal cancer Aliment Pharmacol Ther 39:270–​281 PMID: 24308856 Li WQ, Hu N, Hyland PL, Gao Y, Wang ZM, Yu K, et al 2013a Genetic variations in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population Carcinogenesis 34:1536–​1542 PMCID: PMC3697889 Li WQ, Hu N, Wang Z, Yu K, Su H, Wang L, et al 2013b Genetic variants in epidermal growth factor receptor pathway genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population PLoS One 8:e68999 PMCID: PMC3715462 Li WQ, Park Y, Wu JW, Ren JS, Goldstein AM, Taylor PR, et  al 2013c Index-​based dietary patterns and risk of esophageal and gastric cancer in a large cohort study Clin Gastroenterol Hepatol 11:1130–​1136 PMCID: PMC3758458 Liao LM, Vaughan TL, Corley DA, Cook MB, Casson AG, Kamangar F, et al 2012 Nonsteroidal anti-​inflammatory drug use reduces the risk of adenocarcinomas of the esophagus and esophagogastric junction in a pooled analysis Gastroenterol 142:442–​452 PMCID: PMC3488768 Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, et  al 2014 Genomic and molecular characterization of esophageal squamous cell carcinoma Nature Genet 46:467–​473 PMCID: PMC4070589 Liu X, Wang X, Lin S, Yuan J, Yu ITS 2014 Dietary patterns and oesophageal squamous cell carcinoma:  a systematic review and meta-​analysis Br J Cancer 110:2785–​2795 PMCID: PMC4037820 Liyanage SS, Rahman B, Ridda I, Newall AT, Tabrizi SN, Garland SM, et  al 2013 The aetiological role of human papillomavirus in oesophageal squamous cell carcinoma:  a meta-​analysis PLoS One 8:e69238 PMCID: PMC3722293 Lubin JH, Cook MB, Pandeya N, Vaughan TL, Abnet CC, Giffen C, et  al 2012 The importance of exposure rate on odds ratios by cigarette smoking and alcohol consumption for esophageal adenocarcinoma and squamous cell carcinoma in the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium Cancer Epidemiol 36:306–​316 PMCID: PMC3489030 Ludmir EB, Stephens SJ, Palta M, Willett CG, Czito BG 2015 Human papillomavirus tumor infection in esophageal squamous cell carcinoma J Gastrointest Oncol 6:287–​295 PMCID: PMC4397257 Mohammed ME, Abuidris DO, Elgaili EM, Gasmelseed N 2012 Predominance of females with oesophageal cancer in Gezira, Central Sudan Arab J Gastroenterol 13:174–​177 PMID: 23432985 Morton LM, Gilbert ES, Hall P, Andersson M, Joensuu H, Vaalavirta L, et al 2012 Risk of treatment-​related esophageal cancer among breast cancer survivors Ann Oncol 23:3081–​3091 PMCID: PMC3501231 Morton LM, Gilbert ES, Stovall M, van Leeuwen FE, Dores GM, Lynch CF, et al 2014 Risk of esophageal cancer following radiotherapy for Hodgkin lymphoma Haematologica 99:e193 PMCID: PMC4181268 Muñoz N, Day NE 1996 Esophageal cancer In: Schottenfeld D, Fraumeni JFJr (eds.), Cancer epidemiology and prevention, 2nd ed New York: Oxford University Press, pp 681–​706 Myung SK, Yang HJ 2013 Efficacy of vitamin and antioxidant supplements in prevention of esophageal cancer: meta-​analysis of randomized controlled trials J Cancer Prev 18:135–​143 PMCID: PMC4189455 National Academies of Science 2006 Asbestos: selected cancers Washington, DC: The National Academies Press National Cancer Institute (NCI) 1998 Cigars:  health effects and trends Smoking and Tobacco Control Mongraph 9.  NIH Publication no.  98–​ 4302 Bethesda, MD: NCI National Cancer Institute (NCI) 2015 DCCPS, Surveillance Research Program, Cancer Statistics Branch SEER Program Public Use Data Tapes 1973–​2012, released April 2015, based on the November 2014 submission Neto AG, Whitaker A, Pei Z 2016 Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma Semin Oncol 43:86–​96 PMC4789168 Nguyen TH, Thrift AP, Ramsey D, Green L, Shaib YH, Graham DY, El-​Serag HB 2014 Risk factors for Barrett’s esophagus compared between African Americans and non-​ Hispanic whites Am J Gastroenterol 109:1870–​ 1880 PMID: 25420546 Nie S, Chen T, Yang X, Huai P, Lu M 2014 Association of Helicobacter pylori infection with esophageal adenocarcinoma and squamous cell carcinoma: a meta-​analysis Dis Esophagus 27:645–​653 PMID: 24635571 O’Doherty MG, Cantwell MM, Murray LJ, Anderson LA, Abnet CC; on behalf of the FINBAR study group 2011 Dietary fat and meat intakes and risk of reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma Int J Cancer 129:1493–​1502 PMCID: PMC3144995 O’Doherty MG, Freedman ND, Hollenbeck AR, Schatzkin A, Abnet CC 2012 A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH–​AARP Diet and Health Study Gut 61:1261–​ 1268 PMCID: PMC3504700 Ogden CL, Carroll MD, Kit BK, Flegal KM 2014 Prevalence of childhood and adult obesity in the United States, 2011–​2012 JAMA 311:806–​814 PMCID: PMC4770258 Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al 1996 Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease N Engl J Med 334:1150–​1155 PMID: 8602180 Orloff M, Peterson C, He X, Ganapathi S, Heald B, Yang YR, et  al 2011 Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma JAMA 306:410–​419 PMCID: PMC3574553 Palles C, Chegwidden L, Li X, Findlay JM, Farnham G, Giner FC, et  al 2015 Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett’s esophagus Gastroenterol 148:367–​378 PMCID: PMC4315134 Peixoto GD, Hsin LS, Snijders P, Wilmotte R, Herrero R, Lenoir G, et al 2001 Absence of association between HPV DNA, TP53 codon 72 polymorphism, and risk of oesophageal cancer in high-​risk area of China Cancer Lett 162:231–​235 PMID: 11146230 Petrick JL, Li N, McClain KM, Steck SE, Gammon MD 2015 Dietary risk reduction factors for Barrett’s esophagus-​ esophageal adenocarcinoma continuum:  a review or the recent literature Curr Nutr Rep 4:47–​65 PMCID: PMC4349493 Petrick JL, Wyss AB, Butler AM, Cummings C, Sun X, Poole C, et al 2014 Prevalence of human papillomavirus among oesophageal squamous cell carcinoma cases:  systematic review and meta-​ analysis Br J Cancer 110:2369–​2377 PMCID: PMC4007246 Prabhu A, Obi KO, Rubenstein JH 2014 The synergistic effects of alcohol and tobacco consumption on the risk of esophageal squamous cell carcinoma: a meta-​analysis Am J Gastroenterol 109:822–​827 PMID: 24751582 Qiao YL, Dawsey SM, Kamangar F, Fan JH, Abnet CC, Sun XD, et al 2009 Total and cancer mortality after supplementation with vitamins and minerals: follow-​up of the Linxian General Population Nutrition Intervention Trial J Natl Cancer Inst 101:507–​518 PMCID: PMC2664089 Robertson EV, Jankowski JA 2008 Genetics of gastroesophageal cancer: paradigms, paradoxes, and prognostic utility Am J Gastroenterol 103:443–​ 449 PMID: 17925001 Rokkas T, Pistiolas D, Sechopoulos P, Robotis I, Margantinis G 2007 Relationship between Helicobacter pylori infection and esophageal neoplasia:  a meta-​analysis Clin Gastroenterol Hepatol 5:1413–​1417 PMID: 17997357 Rosekrans SL, Baan B, Muncan V, van den Brink GR 2015a Esophageal development and epithelial homeostasis Am J Physiol Gastronintest Liver Physiol 309:G216–​G228 PMID: 26138464  591 Esophageal Cancer Rosekrans SL, Heijmans J, Büller NVJA, Westerlund J, Lee AS, Muncan V, van den Brink GR 2015b ER stress induces epithelial differentiation in the mouse esophagus Gut 64:195–​202 PMID: 24789843 Ross-​Innes CS, Becq J, Warren A, Cheetham RK, Northern H, O’Donovan M, et  al 2015 Whole-​genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma Nature Genet 47:1038–​1046 PMCID: PMC4556068 Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TW 2011 Effect of daily aspirin on long-​term risk of death due to cancer:  analysis of individual patient data from randomized trials Lancet 377:31–​41 PMID: 21144578 Rothwell PM, Price JF, Fowkes FGR, Zanchetti A, Roncaglioni MC, Tognoni G, et  al 2012 Short-​term effects of daily aspirin on cancer incidence, mortality and non-​vascular death:  analysis of the time course of risks and benefits in 51 randomized controlled trials Lancet 379:1602–​1612 PMID: 22440946 Rubenstein JH, Inadomi JM, Scheiman J, Schoenfeld P, Appelman H, Zhang M, et  al 2014 Association between Helicobacter pylori and Barrett’s esophagus, erosive esophagitis, and gastroesophageal reflux symptoms Clin Gastroenterol Hepatol 12:239–​245 PMCID: PMC3947027 Rubenstein JH, Scheiman JM, Sadeghi S, Whiteman D, Inadomi JM 2011 Esophageal adenocarcinoma incidence in individuals with gastroesophageal reflux:  synthesis and estimates from population studies Am J Gastroenterol 106:254–​260 PMCID: PMC3901355 Runge TM, Abrams JA, Shaheen NJ 2015 Epidemiology of Barrett’s esophagus and esophageal adenocarcinoma Gastroenterol Clin N Am 44:203–​ 231 PMCID: PMC4449458 Rustgi AK, El-​Serag HB 2014 Esophageal carcinoma N Eng J Med 371:2499–​ 2509 PMID: 25539106 Ryan AM, Duoung M, Healy L, Ryan SA, Parekh N, Reynolds JV, Power DG 2011 Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets Cancer Epidemiol 35:309–​319 PMID: 21470937 Saraggi D, Fassan M, Bornschein J, Farinati F, Realdon S, Valeri N, Rugge M 2016 From Barrett metaplasia to esophageal adenocarcinoma:  the molecular background Histol Histopathol 31:25–​32 PMID: 26334343 Sawada G, Niida A, Uchi R, Hirata H, Shimamura T, Suzuki Y, et  al 2016 Genomic landscape of esophageal squamous cell carcinoma in a Japanese population Gastroenterol 150:1171–​1182 PMID: 26873401 Schneider JL, Corley DA 2015 A review of the epidemiology of Barrett’s oesophagus and oesophageal adenocarcinoma Best Pract Res Clin Gastroenterol 29:29–​39 PMID: 25743454 Schneider JL, Zhao WK, Corley DA 2015 Aspirin and Nonsteroidal anti-​ inflmmatory drug use and the risk of Barrett’s esophagus Dig Dis Sci 60:436–​443 PMCID: PMC4304909 Shen FF, Zhou FY, Xue QS, Pan Y, Zheng L, Zhang H, et al 2013 Association between CYP1A1 polymorphisms and esophageal cancer:  a meta-​ analysis Mol Biol Rep 40:6035–​6042 PMID: 24065535 Siddiqi K, Shah S, Abbas SM, Vidyasagaran A, Jawad M, Dogar O, Sheikh A 2015 Global burden of disease due to smokeless tobacco consumption in adults:  analysis of data from 113 countries BMC Med 13:194 PMCID: PMC4538761 Simard EP, Ward EM, Siegel R, Jemal A 2012 Cancers with increasing incidence trends in the United States: 1999 through 2008 CA Cancer J Clin 62:118–​128 PMID: 22281605 Singh S, Garg SK, Singh PP, Iyer PG, El-​Serag HB 2014 Acid-​suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett’s oesophagus:  a systematic review and meta-​ analysis Gut 63:1229–​1237 PMCID: PMC4199831 Singh S, Goyal A, Singh PP, Murad MH, Iyer PG 2013a Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett’s esophagus:  a systematic review and meta-​analysis Clin Gastroenterol Hepatol 11:620–​629 PMCID: PMC3660516 Singh S, Sharma AN, Murad MH, Buttar NS, El-​Serag HB, Katzka DA, Iyer PG 2013b Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-​analysis Clin Gastroenterol Hepatol 11:1399–​1412 PMCID: PMC3873801 Sinha DN, Abdulkader RS, Gupta PC 2016 Smokeless tobacco-​associated cancers:  a systematic review and meta-​analysis of Indian studies Int J Cancer 138:1368–​1379 PMID: 26443187 Sitas F, Egger S, Urban MI, Taylor PR, Abnet CC, Boffetta P, et  al 2012 InterSCOPE study: associations between esophageal squamous cell carcinoma and human papillomavirus serologic markers J Natl Cancer Inst 104:147–​158 PMCID: PMC3260131 591 Song Y, Li L, Ou Y, Gao Z, Li E, Li X, et al 2014 Identification of genomic alterations in oesophageal squamous cell cancer Nature 509:91–​95 PMID: 24670651 Spechler SJ 2013 Barrett esophagus and risk of esophageal cancer: a clinical review JAMA 310:627–​636 PMID: 23942681 Spechler SJ 2014 Does Barrett’s esophagus regress after surgery (or proton pump inhibitors)? Dig Dis 32:156–​163 PMID: 24603402 Stachler MD, Taylor-​Weiner A, Peng S, McKenna A, Agoston AT, Odze RD, et al 2015 Paired exome analysis of Barrett’s esophagus and adenocarcinoma Nature Genet 47:1047–​1055 PMCID: PMC4552571 Steevens J, Schouten LJ, Goldbohm RA, van den Brandt PA 2011 Vegetables and fruits consumption and risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study Int J Cancer 129:2681–​2693 PMID: 21960262 Steffen A, Huerta JM, Weiderpass E, Bueno-​ de-​ Mesquita HB, May AM, Siersema PD, et  al 2015 General and abdominal obesity and risk of esophageal and gastric adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition Int J Cancer 137:646–​657 PMID: 25598323 Streppel MM, Lata S, DelaBastide M, Montgomery EA, Wang JS, Canto MI, et al 2014 Next-​generation sequencing of endoscopic biopsies identifies ARID1A as a tumor-​suppressor gene in Barrett’s esophagus Oncogene 33:347–​357 PMCID: PMC3805724 Streppel MM, Montgomery EA, Maitra A 2014 New advances in the pathogenesis and progression of Barrett’s esophagus Curr Mol Med 14:58–​68 PMID: 23865431 Su Z, Gay LJ, Strange A, Palles C, Band G, Whiteman DC, et  al 2012 Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus Nature Genet 44:1131–​1136 PMCID: PMC3459818 Sun L, Yu S 2011 Meta-​analysis:  non-​steroidal anti-​inflammatory drug use and the risk of esophageal squamous cell carcinoma Dis Esophagus 24:544–​549 PMID: 21539676 Tanaka F, Yamamoto K, Suzuki S, Inoue H, Tsurumaru M, Kajiyama Y, et al 2010 Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/​or ALDH2 risk alleles Gut 59:1457–​1464 PMID: 20833657 Tang L, Xu, F, Zhang T, Lei J, Binns CW, Lee AHW 2013 High temperature food and beverage intake increases the risk of oesophageal cancer in Xinjiang, China Asian Pac J Cancer Prev 14:5085–​5088 PMID: 24175780 Taylor PR, Abnet CC, Dawsey SM 2013 Squamous dysplasia:  the precursor lesion for esophageal squamous cell carcinoma Cancer Epidemiol Biomarkers Prev 22:540–​552 PMCID: PMC3681095 Teng H, Li X, Liu X, Wu J, Zhang J 2014 The absence of human papillomavirus in esophageal squamous cell carcinoma in East China Int J Exp Pathol 7:4184–​4193 PMCID: PMC4129033 Thrift AP 2015 Esophageal adenocarcinoma:  the influence of medications used to treat comorbidities on cancer prognosis Clin Gastroenterol Hepatol 13:2225–​2232 PMID: 25835331 Thrift AP, Cook MB, Vaughan TL, Anderson LA, Murray LJ, Whiteman DC, et al 2014a Alcohol and the risk of Barrett’s esophagus: a pooled analysis from the international BEACON consortium Am J Gastroenterol 109:1586–​1594 PMCID: PMC4189971 Thrift AP, Risch HA, Onstad L, Shaheen NJ, Casson AG, Bernstein L, et al 2014b Risk of esophageal adenocarcinoma decreases with height, based on consortium analysis and confirmed by Mendelian randomization Clin Gastroenterol Hepatol 12:1667–​1676 PMCID: PMC4130803 Thrift AP, Shaheen NJ, Gammon MD, Bernstein L, Reid BJ, Onstat L, et al 2014c Obesity and risk of esophageal adenocarcinoma and Barrett’s esophagus:  a Mendelian randomization study J Natl Cancer Inst 106:dju252 doi: 10.1093/​jnci/​dju252 PMCID: PMC4200028 Tramacere I, La Vecchia C, Negri E 2011 Tobacco smoking and esophageal and gastric cardia adenocarcinoma: a meta-​analysis Epidemiology 22:344–​349 PMID: 21330928 Tramacere I, Pelucchi C, Bagnardi V, Rota M, Scotti L, Islami F, et al 2012 A meta-​analysis on alcohol drinking and esophageal and gastric cardia adenocarcinoma risk Ann Oncol 23:287–​297 PMID: 21551004 Turati F, Tramacere, I, La Vecchia C, Negri E 2013 A meta-​analysis of body mass index and esophageal and gastric cardia adenocarcinoma Ann Oncol 24:609–​617 PMID: 22898040 Tuyns AJ, Pequignot G, Jensen OM 1977 [Esophageal cancer in Ille-​et-​ Vilaine in relation to levels of alcohol and tobacco consumption Risks are multiplying] Bull Cancer 64:45–​60 PMID: 861389 Verbeek RE, Leenders M, ten Kate FJW, van Hillegersberg R, Vleggaar FP, van Baal JWPM, et  al 2014 Surveillance of Barrett’s esophagus and 592 592 PART IV:  Cancers by Tissue of Origin mortality from esophageal adenocarcinoma:  a population-​based cohort study Am J Gastroenterol 109:1215–​1222 PMID: 24980881 Vineis P, Alavanja M, Buffler P, Fontham E, Franceschi S, Gao YT, et al 2004 Tobacco and cancer:  recent epidemiologic findings J Natl Cancer Inst 96:99–​106 PMID: 14734699 Wang D, Su M, Tian D, Liang S, Zhang J 2012 Associations between CYP1A1 and CYP2E1 polymorphisms and susceptibility to esophageal cancer in Chaoshan and Taihang areas of China Cancer Epidemiol 36:276–​282 PMID: 22088806 Wang F, Lv ZS, Fu YK 2011 Nonsteroidal anti-​inflammatory drugs and esophageal inflammation–​ Barrett’s esophagus–​ adenocarcinoma sequence:  a meta-​analysis Dis Esophagus 24:318–​324 PMID: 21166737 Wang FR, Fang QQ, Tang WM, Xu XS, Mahapatra T, Liu YF, et al 2015 Nested case-​ control study of occupational radiation exposure and breast and esophagus cancer risk among medical diagnostic X ray workers in Jiangsu of China Asian Pac J Cancer Prev 16:4699–​4704 PMID: 26107226 Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, et al 2010 Genome-​wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies a susceptibility locus at PLCE1 Nature Genet 9:759–​763 PMID: 20729853 WCRF/​AICR 2007 Food, nutrition, physical activity, and prevention of cancer: a global perspective Washington, DC: AICR http://​www.aicr.org/​ assets/​docs/​pdf/​reports/​Second_​Expert_​Report.pdf Weaver JM, Ross-​Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M, et al 2014 Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis Nature Genet 46:837–​843 PMCID: PMC4116294 Wild CP, Hardie LJ 2003 Reflux, Barrett’s oesophagus and adenocarcinoma: burning questions Nat Rev Cancer 3:676–​684 PMID: 12951586 Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y, et al 2011 Genome-​wide association study identifies three new susceptibility loci for esophageal squamous cell carcinoma in Chinese populations Nature Genet 43: 679–​684 PMID: 21642993 Wu C, Kraft P, Zhai K, Chang J, Wang Z, Li Y, et  al 2012 Genome-​wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-​environment interactions Nature Genet 44:1090–​1096 PMCID: PMC3513832 Wu C, Li D, Jia W, Hu Z, Zhou Y, Yu D, et al 2013 Genome-​wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-​cell carcinoma Nature Genet 45:632–​ 638 PMID: 23644492 Wu C, Wang Z, Song X, Feng XS, Abnet CC, He J, et  al 2014 Joint analysis of three genome-​wide association studies of esophageal squamous cell carcinoma in Chinese populations Nature Genet 46:1001–​1006 PMCID: PMC4212832 Wu M, Liu AM, Kampman E, Zhang ZF, van’t Veer P, Wu DL, et  al 2009 Green tea drinking, high tea temperature and esophageal cancer in high-​and low-​risk areas of Jiangsu Province, China: a population-​based case-​control study Int J Cancer 124:1907–​1913 PMID: 19123468 Xie FJ, ZhangYP, Zheng QQ, Jin HC, Wang FL, Chen M, et al 2013 Helicobacter pylori infection and esophageal cancer risk: and updated meta-​analysis World J Gastroenterol 19:6098–​6107 PMCID: PMC3785633 Xie SH, Lagergren J 2016 The male predominance in esophageal adenocarcinoma Clin Gastroenterol Hepatol 14:338–​347 PMID: 26484704 Xu X, Wang J, Zhu SM, Yang M, Fang Y, Zhao A, et al 2015 Impact of alcohol dehydrogenase gene polymorphisms on esophageal squamous cell carcinoma risk in a Chinese population PLoS One 10:e0127304 doi: 10.1371/​journal.pone.0127304 PMCID: PMC4454665 Yokoyama A, Kato H, Yokoyama T, Tsujinaka T, Muto M, Omori T, et al 2002 Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-​transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma Carcinogenesis 23:1851–​ 1859 PMID: 12419833 Yousef F, Cardwell C, Cantwell MM, Galway K, Johnston BT, Murray L 2008 The incidence of esophageal cancer and high-​grade dysplasia in Barrett’s esophagus:  a systematic review and meta-​ analysis Am J Epidemiol 168:237–​249 PMID: 18550563 Zandberg DP, Bhargava R, Badin S, Cullen KJ 2013 The role of human papillomavirus in nongenital cancers CA Cancer J Clin 63:57–​81 PMID: 23258613 Zendehdel K, Nyrén O, Edberg A, Ye W 2011 Risk of esophageal adenocarcinoma in achalasia patients, a retrospective cohort study in Sweden Am J Gastroenterol 106:57–​61 PMID: 21212754 Zhang GH, Mai RQ, Huang B 2010 Meta-​ analysis of ADH1B and ALDH2 polymorphisms and esophageal cancer risk in China World J Gastroenterol 16:6020–​6025 PMCID: PMC3007115 Zhang L, Zhou Y, Cheng C, Cui H, Cheng L, Kong P, et al 2015 Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma Am J Hum Genet 96:597–​611 PMCID: PMC4385186 Zheng JS, Yang J, Fu YQ, Huang T, Li D 2013 Effects of green tea, black tea, and coffee consumption on the risk of esophageal cancer:  a systematic review and meta-​analysis of observational studies Nutr Cancer 65:1–​16 PMID: 23368908 Zhu HC, Yang X, Xu LP, Zhao LJ, Tao GZ, Zhang C, et al 2014 Meat consumption is associated with esophageal cancer risk in a meat-​and cancer-​histological-​type dependent manner Dig Dis Sci 59:664–​673 PMID: 24395380 Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, Boffetta P 2003 Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men Int J Cancer 105:681–​686 PMID: 12740918 ... health and social sciences Soc Sci Med, 35 (11 ), 13 43– 13 57 Schottenfeld D, and Fraumeni JF 19 82 Cancer Epidemiology and Prevention 1st ed Philadelphia: Saunders Schottenfeld D, and Fraumeni JF 19 96... Banegas, and Donatus U Ekwueme 16 9 vi vi Contents III  THE CAUSES OF CANCER 11 Tobacco  Michael J Thun and Neal D Freedman 18 5 12 Alcohol and Cancer Risk  Susan M Gapstur and Philip John Brooks 213 13 ... Primary Cancers  Lindsay M Morton, Sharon A Savage, and Smita Bhatia 11 55 V  CANCER PREVENTION AND CONTROL 61 Framework for Understanding Cancer Prevention Michael J Thun, Christopher P Wild, and