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) inBRCA1andBRCA2genes are the strongest BC genetic risk factor.BRCA1andBRCA2PVs 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 inPALB2,CHEK2,andATMgenes, 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 inBRCA1/2PV 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.
在肿瘤性疾病中，乳腺癌是最受性别因素影响的疾病之一。尽管普遍存在将乳腺癌视为女性专属疾病的误解，但男性同样可能罹患乳腺癌。此外，跨性别群体也存在乳腺癌发病风险。遗传风险因素在乳腺癌易感性中起着重要作用，对精准预防和治疗具有重要影响。女性和男性的乳腺癌易感遗传结构具有相似性，均包含高、中、低外显率的风险变异，但也呈现出某些性别特异性特征。BRCA1和BRCA2基因的遗传性高外显率致病性变异是最强的乳腺癌遗传风险因素，其中BRCA1和BRCA2致病性变异分别与女性和男性乳腺癌风险增加的相关性更为显著。值得注意的是，BRCA相关乳腺癌具有性别特异性的病理学特征。近年来，新一代测序技术为中外显率乳腺癌风险变异（特别是PALB2、CHEK2和ATM基因）的研究提供了新见解，而国际协作的全基因组关联研究则为常见低外显率风险变异、多基因模型中的联合效应及其在BRCA1/2致病性变异携带者中的风险调节作用提供了证据。总体而言，这些研究表明男性乳腺癌的遗传基础虽与女性相似，但仍存在差异。将男性乳腺癌的遗传组分作为独立于女性乳腺癌的实体进行评估，是改善两性个体化风险评估和治疗选择、实现乳腺癌诊疗性别平等的首要步骤。本综述总结了乳腺癌遗传易感性领域的最新研究进展，重点探讨了男女性乳腺癌的异同，并讨论了建立性别导向的乳腺癌临床管理模式所涉及的意义、挑战及待解决问题。
Gender-Specific Genetic Predisposition to Breast Cancer:BRCAGenes and Beyond
肿瘤(癌症)患者之家