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

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.

More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles

“…BRCA1 and BRCA2 are tumor suppressor genes that are responsible for DNA repair, regulation of cell division, and maintenance of chromosomal stability ( Scully and Livingston, 2000 ). There are several polymorphisms of BRCA1 and BRCA2 associated with increased risk of sex-specific cancers such as breast cancer ( Valentini et al, 2024 ), ovarian cancer ( Risch et al, 2001 ; Horackova et al, 2023 ), and endometrial cancer ( Sorouri et al, 2023 )in women and prostate cancer in men ( Kalampokis et al, 2024 ). Both men and women with BRCA2 mutations also appear to have increased risks of gastric cancer ( Buckley et al, 2022 ), pancreatic cancer ( McGarry et al, 2022 ) and melanoma ( Toussi et al, 2020 ).…”

BRCA1, BRCA2 and PALB2 mRNA Expression as Prognostic Markers in Patients with Early Breast Cancer

“…Given the heterogeneous biology of BC, the different responses to therapy, and the high cost of treatments, there is an increasing interest in identifying the role of prognostic and treatment-predictive factors [ 21 ]. Inherited monoallelic mutations in PALB2 , just like BRCA1/2 , cause a high risk of breast cancer and also increase the risks of other cancers [ 4 ]. However, the role of messenger ribonucleic acid (mRNA) expression of different genes in the prognosis of BC is incompletely understood [ 22 ].…”

“…Multiple studies have explored the specific roles of inherited high-penetrance pathogenic variants of genes such as breast cancer gene type 1 ( BRCA1 ) and breast cancer gene type 2 ( BRCA2 ) and of moderate-penetrance BC risk variants, particularly partner and localizer of BRCA2 ( PALB2 ), checkpoint kinase 2 ( CHEK2 ), and ataxia teleangiectasia mutated ( ATM ) in the pathogenesis of BC [ 4 ]. BRCA tumor-suppressor genes have been shown to be associated with an increased risk of breast cancer [ 5 ].…”

Cancer as an Individual Risk Factor for Heart Failure: A Review of Literature

“…Key molecules and receptors of the innate immune system are expressed in both cardiomyocytes and fibroblasts within the heart. Additionally, activation of the adaptive immune system, which depends on specific interactions between antigen-presenting cells and distinct antigen-specific receptors on T cells, significantly contributes to infarct healing and cardiac remodeling [ 22 ].…”