Chapter 079. Cancer Genetics (Part 3) ppt

Chapter 079. Cancer Genetics (Part 3) Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene or caretaker gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the Knudson hypothesis (Fig. 79-3). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled growth. The normal function of tumor suppressors is to restrain growth, to promote differentiation (gatekeeper genes), or to preserve genome integrity (caretaker genes). Roughly 100 syndromes of familial cancer have been reported, although many are rare. The majority are inherited as autosomal dominant traits, although some of those associated with DNA repair abnormalities (xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia) are autosomal recessive. Table 79-1 shows a number of cancer predisposition syndromes and the responsible genes. The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic (noninherited) tumors. The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types. This section examines the case of inherited colon cancer in detail, but the same general lessons can be applied to all the cancer syndromes listed in Table 79-1. Table 79-1 Cancer Predisposition Syndromes and Associated Genes Syndrome Gene Chromo some Inherit ance Tumors Ataxia telangiectasia ATM 11q22- q23 AR Breast cancer Autoimmun FAS 10q24 AD Lymphom e lymphoproliferativ e syndrome FASL 1q23 as Bloom syndrome BLM 15q26.1 AR Cancer of all types Cowden syndrome PTE N 10q23 AD Breast, thyroid Familial adenomatous polyposis APC 5q21 AD Intestinal adenoma, colorectal cancer Familial melanoma p16I NK4 9p21 AD Melanoma , pancreatic cancer Familial Wilms tumor WT1 11p13 AD Pediatric kidney cancer Hereditary breast/ovarian cancer BRC A1 BRC A2 17q21 13q12.3 AD Breast, ovarian, colon, prostate Hereditary diffuse gastric cancer CDH 1 16q22 AD Stomach cancers Hereditary multiple exostoses EXT1 EXT2 8q24 11p11- 12 AD Exostoses, chondrosarcoma Hereditary prostate cancer HPC 1 1q24-25 AD Prostate carcinoma Hereditary retinoblastoma RB1 13q14.2 AD Retinoblas toma, osteosarcoma Hereditary nonpolyposis colon cancer (HNPCC) MSH 2 MLH 1 MSH 6 PMS 2 2p16 3p21.3 2p16 7p22 AD Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma Hereditary papillary renal carcinoma MET 7q31 AD Papillary renal tumor Juvenile polyposis SMA D4 18q21 AD Gastrointe stinal, pancreatic cancers Li-Fraumeni TP53 17p13.1 AD Sarcoma, breast cancer Multiple endocrine neoplasia type 1 MEN 1 11q13 AD Parathyroi d, endocrine, pan creas, and pituitary Multiple endocrine neoplasia type 2a RET 10q11.2 AD Medullary thyroid carcinoma, pheochromocyto ma Neurofibro matosis type 1 NF1 17q11.2 AD Neurofibr oma, neurofibrosarcom a, brain tumor Neurofibro matosis type 2 NF2 22q12.2 AD Vestibular schwannoma, meningioma, spine Nevoid basal cell carcinoma syndrome (Gorlin's syndrome) PTC H 9q22.3 AD Basal cell carcinoma, medulloblastoma, jaw cysts Tuberous sclerosis TSC1 TSC2 9q34 16p13.3 AD Angiofibr oma, renal angiomyolipoma Von Hippel–Lindau VHL 3p25-26 AD Kidney, cerebellum, pheochromocyto ma Note: AD, autosomal dominant; AR, autosomal recessive. . Chapter 079. Cancer Genetics (Part 3) Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition colorectal cancer Familial melanoma p16I NK4 9p21 AD Melanoma , pancreatic cancer Familial Wilms tumor WT1 11p13 AD Pediatric kidney cancer Hereditary breast/ovarian cancer BRC A1 . diffuse gastric cancer CDH 1 16q22 AD Stomach cancers Hereditary multiple exostoses EXT1 EXT2 8q24 11p11- 12 AD Exostoses, chondrosarcoma Hereditary prostate cancer HPC 1 1q24-25