Posted September 25, 2013
Fergus Couch, Ph.D., Mayo Clinic and Foundation, Rochester
Due to the heterogeneity of ovarian cancer onset, it is currently not possible to definitively identify BRCA1 mutation carriers who will go on to develop ovarian cancer in their lifetime and those who will not. Dr. Couch was awarded a Fiscal Year 2009 Department of Defense Ovarian Cancer Research Program Idea Development Award to conduct a genome-wide association study to search for genetic modifiers that alter a BRCA1 carrier's susceptibility for developing ovarian cancer. Each so-called genetic modifier of risk probably confers only a small to moderate increase in the lifetime ovarian cancer risk. However, when several modifiers are inherited together, along with a BRCA1 mutation, the modifiers may have an important role in determining if and when a carrier develops ovarian cancer. So far, the team has identified several novel modifiers of ovarian cancer risk for BRCA1 mutation carriers that can potentially be used for individualized ovarian cancer risk assessment. Dr. Couch and the Consortium of Investigators of Modifiers of BRCA1/2 recently published their findings, linking two new genetic risk modifiers with increased risk of ovarian cancer. A change to the genetic code (single nucleotide polymorphism, or SNP) rs4691139 at the genetic location (locus) 4q32.3 appeared to be BRCA1-specific, with BRCA1 mutation carriers experiencing an approximately 20% increased risk over baseline when they had this additional mutation. A mutation in locus 17q21.31 at SNP rs17631303 increased the risk of ovarian cancer in BRCA1 mutation carriers by approximately 27% and was also significantly associated with ovarian cancer in BRCA2 mutation carriers and the general population. Based on these and other genetic modifiers of ovarian cancer risk in BRCA1 carriers, the 5% of BRCA1 mutation carriers at the lowest risk are predicted to have a lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at the highest risk will have a lifetime risk of 63% or higher. With improved risk assessment, women at the highest and lowest risk of ovarian cancer can be identified and critical changes made to their clinical care.
Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, et al. 2013. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk. PLoS Genetics 9(3): e1003212. doi:10.1371/journal.pgen.1003212