Posted September 28, 2016
Fergus Couch, Ph.D., Mayo Clinic Rochester, Minnesota

Women who carry a genetic mutation in the BRCA1 gene have a substantially increased risk of developing ovarian cancer in comparison with women who do not have mutations; however, only 39% of those who have the mutation develop ovarian cancer. This indicates that although the BRCA1 mutation correlates with the development of this disease, there are other genetic and environmental factors that modify the risk of ovarian cancer for BRCA1 mutation carriers. For example, inheriting several common genetic factors along with a BRCA1 mutation may play an important role in determining if and when a carrier develops ovarian cancer. 

Dr. Fergus Couch was awarded a Fiscal Year 2009 Ovarian Cancer Research Program Idea Development Award to conduct a genome-wide association study (GWAS) to search for additional genetic factors that alter a BRCA1 carrier's susceptibility to developing ovarian cancer. The funding from this award led Dr. Couch and the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) to identify a total of 27 genetic modifications (single nucleotide polymorphisms, [SNPs]) that increase ovarian cancer risk among BRCA1 carriers. These findings have been featured in several high-profile publications. Interestingly, one of the genetic regions (locus) identified, 4q32, is exclusively linked to the development of ovarian cancer in BRCA1 carriers. The SNP rs4691139 at 4q32.3, along with BRCA1 mutation, is associated with an approximately 20% increased risk for developing ovarian cancer. In addition, Dr. Couch and his colleagues also observed that SNP rs17631303 in locus 17q21.31 is associated with a 27% increased risk of ovarian cancer in BRCA1 mutation carriers; this alteration was also significantly associated with ovarian cancer in BRCA2 mutation carriers and the general population. Most recently, the consortia identified multiple SNPs at the 19p13.1 locus associated with ovarian cancer in BRCA1 and BRCA2 mutation carriers. These SNPs affect the expression of the genes ABHD8 and ANKLE; aberrant regulation of these genes, along with a mutation in BRCA1/2, correlates with the development of both ovarian and breast cancers.

Overall, the findings from this study established that the 5% of BRCA1 mutation carriers that carry the smallest number of these additional genetic modifications have a lifetime risk of developing ovarian cancer of 28% or lower, whereas, the 5% with the highest number of risk-associated common alterations have a lifetime risk of 63% or higher. Thus, Dr. Couch and his team have been able to identify key genetic factors that, when inherited together with BRCA1, affect the risk associated with developing ovarian cancer. Identification of these additional genetic risk factors that correlate with BRCA1 in the development of ovarian cancer is increasingly useful for predicting an individual's risk for developing this disease. Furthermore, with improved risk assessment, women at highest, or lowest, risk of ovarian cancer can be identified and critical changes made to their clinical care. Overall, the results will contribute to the development of personalized risk-assessment diagnostics that can be used for screening BRCA1 carrier's for their susceptibility of developing ovarian cancer and allow women with the highest risk of developing this disease to be offered enhanced screening or certain prevention measures.

Publications:

Cheng TH, Thompson DJ, O'Mara TA, et al. 2016. Five endometrial cancer risk loci identified through genome-wide association analysis. Nat Genet 48(6):667-674. PMC4907351. 

Kuchenbaecker KB, Ramus SJ, Tyrer J, et al. 2015. Consortium of Investigators of modifiers of BRCA1 and BRCA2. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet 47(2):164-171. PMC4445140.  

Peterlongo P, Chang-Claude J, Moysich KB, et al. 2015. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Epidemiol Biomarkers Prev 24(1):308-316. PMC4294951.  

Rebbeck TR, Mitra N, Wan F, et al. 2015. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313(13):1347-1361. 

Couch FJ, Nathanson KL, and Offit K. 2014. Two decades after BRCA: Setting paradigms in personalized cancer care and prevention. Science 343(6178):1466-1470. PMC4074902. 

Couch FJ, Wang X, McGuffog L, et al. 2013. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. Genet 9(3):e1003212. PMC3609646. 

Permuth-Wey J, Lawrenson K, Shen HC, et al. 2013. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nat Commun 4:1627. PMC3709460. 

Couch FJ, Gaudet MM, Antoniou AC, et al. 2012. Common variants at the 19p13.1 and ZNF365 Loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 21(4):645-657. PMC3319317. 

Ramus SJ, Antoniou AC, Kuchenbaecker KB, et al. 2012. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Hum Mutat 33(4):690-702. PMC3458423. 

Links:

Public and Technical Abstracts: Genetic Modifiers of Ovarian Cancer

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