Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Simple Summary The role of gender in oncology is an issue that is starting to be recognized as being of extreme importance in the last few years. While breast cancer is commonly perceived as a female-only disease, it does also occur in men, although rarely, thus opening relevant gender issues. Breast cancer in men is much less studied, with most knowledge coming from research on female breast cancer; however, several crucial differences have begun to be discovered between male and female patients. For example, the gender-specific impact and magnitude of risks conferred by breast cancer genetic risk factors are emerging, and they should be taken into consideration for a proper personalized clinical management. Overall, addressing all the challenges and the open issues regarding breast cancer genetic predisposition, including gender, will have an important clinical impact on the management of patients of both sexes. Abstract Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, BC can also occur in men. Additionally, transgender individuals may also experience BC. Genetic risk factors play a relevant role in BC predisposition, with important implications in precision prevention and treatment. The genetic architecture of BC susceptibility is similar in women and men, with high-, moderate-, and low-penetrance risk variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) in BRCA1 and BRCA2 genes are the strongest BC genetic risk factor. BRCA1 and BRCA2 PVs are more commonly associated with increased risk of female and male BC, respectively. Notably, BRCA-associated BCs are characterized by sex-specific pathologic features. Recently, next-generation sequencing technologies have helped to provide more insights on the role of moderate-penetrance BC risk variants, particularly in PALB2, CHEK2, and ATM genes, while international collaborative genome-wide association studies have contributed evidence on common low-penetrance BC risk variants, on their combined effect in polygenic models, and on their role as risk modulators in BRCA1/2 PV carriers. Overall, all these studies suggested that the genetic basis of male BC, although similar, may differ from female BC. Evaluating the genetic component of male BC as a distinct entity from female BC is the first step to improve both personalized risk assessment and therapeutic choices of patients of both sexes in order to reach gender equality in BC care. In this review, we summarize the latest research in the field of BC genetic predisposition with a particular focus on similarities and differences in male and female BC, and we also discuss the implications, challenges, and open issues that surround the establishment of a gender-oriented clinical management for BC.