Chapter 079. Cancer Genetics (Part 2) potx

Chapter 079. Cancer Genetics (Part 2) General Classes of Cancer Genes There are two major classes of cancer genes. The first class comprises genes that directly affect cell growth either positively (oncogenes) or negatively (tumor-suppressor genes). These genes exert their effects on tumor growth through their ability to control cell division (cell birth) or cell death (apoptosis). Oncogenes are tightly regulated in normal cells. In cancer cells, oncogenes acquire mutations that relieve this control and lead to increased activity of the gene product. This mutational event typically occurs in a single allele of the oncogene and acts in a dominant fashion. In contrast, the normal function of tumor- suppressor genes is to restrain cell growth, and this function is lost in cancer. Because of the diploid nature of mammalian cells, both alleles must be inactivated to completely lose the function of a tumor-suppressor gene, leading to a recessive mechanism at the cellular level. From these ideas and studies on the inherited form of retinoblastoma, Knudson and others formulated the two-hit hypothesis, which in its modern version states that both copies of a tumor-suppressor gene must be inactivated in cancer. The second class of cancer genes, the caretakers, does not directly affect cell growth but rather affects the ability of the cell to maintain the integrity of its genome. Cells with deficiency in these genes have an increased rate of mutations in all the genes, including oncogenes and tumor-suppressor genes. This "mutator" phenotype was first hypothesized by Loeb to explain how the multiple mutational events required for tumorigenesis can occur in the lifetime of an individual. A mutation phenotype has now been observed in cancer at both the nucleotide sequence and chromosomal levels. Mechanisms of Tumor-Suppressor Inactivation The two major types of somatic lesions observed in tumor-suppressor genes during tumor development are point mutations and large deletions. Point mutations in the coding region of tumor-suppressor genes will frequently lead to truncated protein products or otherwise nonfunctional proteins. Similarly, deletions lead to the loss of a functional product and sometimes encompass the entire gene or even the entire chromosome arm, leading to loss of heterozygosity (LOH) in the tumor DNA compared to the corresponding normal tissue DNA (Fig. 79-3). LOH in tumor DNA is considered a hallmark for the presence of a tumor- suppressor gene at a particular locus, and LOH studies have been useful in the positional cloning of many tumor-suppressor genes. Gene silencing, which occurs in conjunction with hypermethylation of the promoter, is another mechanism of tumor-suppressor gene inactivation. Silencing is an epigenetic change rather than a sequence alteration. Figure 79-3 Diagram of possible mechanisms for tumor formation in an individual with hereditary (familial) retinoblastoma. On the left is shown the pedigree of an affected individual who has inherited the abnormal (Rb) allele from her affected mother. The four chromosomes of her two parents are drawn to indicate their origin. Just below the retinoblastoma locus a polymorphic marker is also analyzed in this fam ily. The patient is AB at this locus, like her mother, whereas her father is AA. Thus the B allele must be on the chromosome carrying the retinoblastoma disease gene. Tumor formation results when the normal allele (N), which this patient inherited from her father, is inactivated. On the right are shown four possible ways in which this could occur. In each case, the resulting chromosome 13 arrangement is shown, as well as the results of a Southern blot comparing normal tissue with tumor tissue. Note that in the first three situations the normal allele (A) has been lost in the tumor tissue, which is referred to as loss of heterozygosity (LOH). ( From TD Gelehrter and FS Collins, in Principles of Medical Genetics, Baltimore, Williams and Wilkins, 1990, with permission.) . Chapter 079. Cancer Genetics (Part 2) General Classes of Cancer Genes There are two major classes of cancer genes. The first class comprises genes. version states that both copies of a tumor-suppressor gene must be inactivated in cancer. The second class of cancer genes, the caretakers, does not directly affect cell growth but rather affects. normal function of tumor- suppressor genes is to restrain cell growth, and this function is lost in cancer. Because of the diploid nature of mammalian cells, both alleles must be inactivated to