BRCA1 and BRCA2 - genetic and non-genetic influencing factors for risk of disease

Background. The lifelong risk for breast cancer and ovarian cancer differs among carriers of mutations in the BRCA1 and BRCA2 genes. Cancer risk is modulated by a multitude of genetic and non-genetic factors. For the decision on intensified surveillance or prophylactic mastectomy no risk modifiers are so far taken into account. Aims. This article examines whether genetic and non-genetic factors modify the risk of breast cancer for BRCA1 and BRCA2 gene mutation carriers and which are integrated into currently used risk calculation programs. Results and discussion. A number of genetic low risk variants have been identified and validated in genome-wide association studies. Several of these modify the risk of sporadic and BRCA-associated breast cancer and others are specific for each type. The results of initial studies suggest that lifestyle factors and reproductive history can also modify the risk of breast cancer for BRCA-associated tumors. Current risk calculation programs estimate the individual cancer risk based on assumptions on major genes with high penetrance and on the family pedigree over three generations. Some of these also take clinical data, such as previous operations, histopathological features of tumors, reproductive factors and body mass index into account but no explicit low risk variants. Ongoing research on modifying genetic and nongenetic risk factors aims to establish a more differentiated and comprehensive risk prediction model in order to prevent overtreatment with respect to preventive strategies. Additionally, knowledge on individual trigger mechanisms of potential breast or ovarian cancer might lead to targeted prevention by medicinal therapy and lifestyle interventions.