Common genetic variants and cancer risk in Mendelian cancer syndromes

Multiple lines of evidence suggest that genetic factors modify the cancer risks in carriers of mutations in Mendelian cancer syndromes. We review the latest evidence for genetic modifiers of risk for four Mendelian cancer syndromes. In general, candidate gene studies have not been very successful at identifying modifier genes and most studies have been underpowered, but recently polymorphisms identified through genome wide association studies of unselected cancer patients and controls have been shown to modify cancer risk in studies of large numbers of mutation carriers. This approach has identified two genetic variants that are associated with colorectal cancer risk in Lynch Syndrome, and five polymorphisms that are associated with the risk of breast cancer for BRCA1 and/or BRCA2 mutation carriers. As predicted from the association between these five polymorphisms and risk of estrogen-positive or estrogen-negative breast cancer in the general population, differential associations of these polymorphisms with breast cancer risk were found for BRCA1 and BRCA2 mutation carriers presumably because BRCA1 breast cancer tumors are predominantly ER-negative and are biologically distinct from BRCA2 breast cancers. These findings suggest that studies of mutation carriers may be useful for identifying genetic variants associated with different disease subtypes. The current literature underlies the need for increased international collaboration between individual studies, and the continued recruitment of mutation carriers, in order to reliably estimate and identify the genetic modifiers of risk in Mendelian cancer syndromes.