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Common cancers, including breast cancer, exhibit familial aggregation, consistent with substantial variation in inherited susceptibility. Over the past 25 years, the underlying genetic basis for this susceptibility has been increasingly understood. Three important classes of genetic loci have been identified: (1) Highpenetrance genes, principally BRCA1 and BRCA2. Mutations in these genes confer a high lifetime risk of breast, ovarian and other cancers. However, mutations in these genes are rare and explain less than 20% of the familial risk of breast cancer. (2) Intermediate-penetrance? genes currently include ATM, CHEK2, BRIP1 and PALB2. Mutations in these genes confer a 2-3 fold increased risk of breast cancer. (3) Common low-penetrance alleles, principally identified through genome-wide association studies (GWAS). There are currently approximately 20 such loci.
The most significant such loci, in FGFR2 and TOX3, confer relative risks of 1.2 to 1.3 fold. Altogether, the known loci probably explain 25-30% of the familial aggregation of breast cancer, implying that many additional loci remain to be found. It is unlikely that there any further important high-penetrance loci, but many more lower penetrance loci should be identifiable, through GWAS, large-scale replication studies and resequencing. The mutations in BRCA1 and BRCA2 (and, so far, those in the intermediate risk genes) involve inactivating coding alterations. In contrast, the low-penetrance loci are occur in non-coding regions (including gene deserts?) and are presumably regulatory. Most ofthese regions have not previously been related to carcinogenesis and point to novel mechanisms. While the risks associated with the common low-penetrance alleles are modest, these risks combine multiplicatively with each other and with BRCA1 and BRCA2. This raises the possibility that common genetic variation may become important in risk prediction, particularly in women with a family history of the disease.
There are also important differences in susceptibility by tumor subtype: BRCA1 mutations predispose predominately to ER-negative Basal? breast cancer, whereasmany of the low-penetrance loci are specific to ER-positive disease. These pathological differences may have implications both for risk prediction and prevention. |
