Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers - Journal of Internal Medicine
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Genetic variants associated with breast cancer risk for BRCA1 mutations carriers
Genetic variants associated with breast cancer risk for BRCA2 mutations carriers
Patterns of association and tumour characteristics
Genetic modifiers of ovarian cancer risk
Environmental, hormonal and reproductive modifiers of risk
Common alleles and cancer risks for mutation carriers
Future challenges "Over the past 5 years, there has been substantial progress in our understanding of genetic factors that modify breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. This was made possible to a great extent because of the availability of large numbers of mutation carriers from the CIMBA consortium and GWAS data. However, the five loci described in this review that are associated with breast cancer risk for BRCA1 mutation carriers are estimated to explain only approximately 3% of the genetic variability in breast cancer risk for BRCA1 mutation carriers. Similarly, the 11 SNPs associated with breast cancer risk for BRCA2 mutation carriers are estimated to account for approximately 6% of the genetic variability in breast cancer risk for BRCA2 mutation carriers. Therefore, the majority of the genetic variability in breast cancer risk for mutation carriers still remains unexplained. Several more breast and ovarian cancer susceptibility alleles have been identified through GWAS in the general population, but have not yet been investigated in mutation carriers [61, 63, 72, 75]. Given the observed association patterns in mutation carriers with previously identified loci, it is expected that at least a subset of these will also be associated with breast or ovarian cancer risk for mutation carriers. Additional genetic modifiers of risk may also be identified through not only the ongoing GWAS in BRCA1 and BRCA2 mutation carriers but also other GWAS from the general population or by GWAS focusing on specific cancer subtypes such as oestrogen-receptor-negative or triple-negative breast cancers, or serous ovarian cancer. However, it is likely that several of the alleles identified through population-based GWAS may be associated with modest relative risks in the range of 1.05–1.10. Despite sample sizes of approximately 15 000 BRCA1 and 10 000 BRCA2 mutation carriers, CIMBA would still be underpowered to detect modifying polymorphisms conferring such modest relative risks. Given the rarity of BRCA1 and BRCA2 mutations, increasing sample sizes is currently only possible through increased collaboration between studies and through continued recruitment of mutation carriers........
Conclusions
As more cost-effective mutation screening techniques become available, the number of identified BRCA1 and BRCA2
mutation carriers in the population is likely to increase. Therefore,
it will be important that all mutation carriers are provided with
accurate information on their risk of developing breast and ovarian
cancer, so that informed decisions on clinical management are made. Our
understanding of factors influencing cancer risk variability in mutation
carriers has increased over the last few years and is likely to improve
further in the near future. Therefore, we are getting closer to the
goal of being able to provide more individualized clinical management.
Understanding how cancer risks are modified in BRCA1 and BRCA2
mutation carriers will also provide further insights for studying the
biological mechanisms of cancer development in mutation carriers. These
may lead to the development of novel therapies and more accurate
prediction of breast and ovarian cancer progression in mutation
carriers.
Studying genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2
mutation carriers has provided useful insights in study design,
analytical methodology and applications, which could be used for
studying modifiers of disease in carriers of other high-risk mutations
such as the mismatch repair genes MSH2, MLH1, MSH6, PMS2 in colorectal cancer (Lynch Syndrome) and CDKN2A in melanoma but also other noncancer-related diseases.
