Genetic Modifiers

As discussed at the start of this chapter, the variation in the risk of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers between different studies, and according to the phenotype of the proband, is consistent with the presence of either environmental or genetic modifiers. Genetic modifiers are probably more likely than shared environment to account for familial clustering of cancer sites in Ashkenazi Jewish mutation carriers, for example, since intrafamilial differences in environment are large in such families with recent immigration histories (4). Although there has also been considerable interest in finding genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers, the number of published studies is still fairly modest. The underlying reason for this may be that there is still a paucity of validated "low-risk common alleles" for breast or ovarian cancer in the general population, and until such alleles are identified, testing candidate single nucleotide polymorphisms (SNPs) as modifiers of BRCA1 and BRCA2 remains a fairly high-risk endeavor. Candidate modifier genes include those involved in detoxification of environmental carcinogens, in DNA repair, and in steroidogenesis.

Most studies of genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers have focused on SNPs for which there has been some evidence for modification of breast cancer risk in the general population. Given the apparent relationship between the cancer site in the proband and risk in relatives, it is likely that at least some genetic modifiers influence the risk of breast or ovarian cancer, but not both (4). Thus, a viable strategy would also be to examine polymorphisms that affect ovarian cancer risk in the general population, once they have been convincingly identified. However, given the lower penetrance for ovarian cancer in BRCA1 and BRCA2 carriers, extremely large studies will be necessary to identify genes that modify ovarian cancer risk in these carriers.

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