Evidence for the role of DNA repair genes in the origin of cancer also comes from the study of hereditary breast cancer. Germ line mutations in two genes, BRCA1 and BRCA2, account for 50% of cases of familial breast cancer. In addition to breast cancer, women with BRCA1 mutations have a substantially higher risk for developing epithelial ovarian cancers, and men have a slightly higher risk for developing prostate cancer. Likewise, germ line mutations in the BRCA2 gene increase the risk for developing breast cancer in both men and women, as well as cancers originating from the ovary, prostate, pancreas, bile ducts, stomach, melanocytes, and B lymphocytes. Although the functions of BRCA1 and BRCA2 have not been elucidated fully, cells with a defective version of these genes develop chromosomal breaks and severe aneuploidy. Indeed, both genes seem to function, at least in part, in the homologous recombination DNA repair pathway. For example, BRCA1 forms a complex with other proteins in the homologous recombination pathway and also is linked to the ATM kinase pathway. BRCA2 was identified as one of several genes mutated in Fanconi anemia, and the BRCA2 protein has been shown to bind to RAD51, a protein required for homologous recombination. Similar to other tumor suppressor genes, both copies of BRCA1 and BRCA2 must be inactivated for cancer to develop. Although linkage of BRCA1 and BRCA2 to familial breast cancers is well established, these genes are rarely inactivated in sporadic cases of breast cancer. In this regard, BRCA1 and BRCA2 are different from other tumor suppressor genes, such as APC and TP53, which are frequently inactivated in sporadic cancers.
Cancers Resulting From Mutations Induced by Regulated Genomic Instability: Lymphoid Neoplasms
A special type of DNA damage plays a central role in the pathogenesis of tumors of B cells and T lymphocytes. As discussed earlier, adaptive immunity relies on the ability of B cells and T cells to diversify their antigen receptor genes. Immature B cells and T progenitors both express a pair of gene products, RAG1 and RAG2, that carry out V(D)J segment recombination, permitting the assembly of functional immunoglobulin and T-cell receptor genes. In addition, after encountering antigen, mature B cells express a specialized enzyme called activation-induced cytosine deaminase (AID), which catalyzes both immunoglobulin gene class switch recombination and immunoglobulin diversification through somatic hypermutation. Errors that occur during antigen receptor gene assembly and immunoglobulin gene class switching and diversification provide fertile soil for many of the mutations that cause lymphoid neoplasms, discussed in detail in Chapter 12.
•IndividualswithinheritedmutationsofgenesinvolvedinDNArepairsystemsareatgreatlyincreasedriskforthedevelopmentofcancer.
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PatientswithHNPCCsyndromehavedefectsinthemismatchrepairsystem,leadingtodevelopmentofcarcinomasofthecolon.Thesepatients’genomesshowmicrosatelliteinstability(MSI),characterizedbychangesinlengthofshorttandemrepeatingsequencesthroughoutthegenome.
Patientswithxerodermapigmentosumhaveadefectinthenucleotideexcisionrepairpathway.TheyareatincreasedriskforthedevelopmentofskincancersinsitesexposedtosunlightbecauseofaninabilitytorepairpyrimidinedimersinducedbyUVlight.