Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Department of Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Endocr Relat Cancer. 2019 Oct;26(10):779-794. doi: 10.1530/ERC-19-0278.
Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.
男性乳腺癌（MBC）极为罕见，占所有乳腺癌恶性肿瘤的比例不足 1%。因此，MBC 的临床管理目前是基于对女性乳腺癌疾病的研究。在这项研究中，对 45 例福尔马林固定石蜡包埋（FFPE）MBC 组织和 90 例 MBC（52 例 FFPE 和 38 例新鲜冷冻）组织的 DNA 进行了靶向 1943 个癌症相关基因所有外显子的大规模平行测序。突变和拷贝数改变的图谱与公共可用的雌激素受体（ER）阳性女性乳腺癌（smFBC）进行了比较，并与预后相关。在这 135 例 MBC 中，90%为导管组织学，96%为 ER 阳性，66%为孕激素受体（PR）阳性，2%为 HER2 阳性，分别有 50%、46%和 4%为 luminal A 样、luminal B 样和基底样病例。5 例患者患有 Klinefelter 综合征（4%），11%的患者存在致病性 BRCA2 种系突变。MBC 的基因组图谱在某种程度上反映了 smFBC 的情况，存在反复出现的 PIK3CA（36%）和 GATA3（15%）体细胞突变，并且两种性别中最常扩增的基因有 40%重叠。与 smFBC 相比，MBC 中 TP53（3%）体细胞突变明显较少，而调节染色质功能和同源重组缺陷相关特征的基因中的体细胞突变更为常见。MDM2 扩增很常见（13%），与蛋白过表达相关（P = 0.001），并预测预后不良（P = 0.007）。总之，尽管 MBC 和 smFBC 之间在基因组图谱上存在相似性，但 MBC 是一种具有独特分子特征和异质性的疾病，需要开展自己的临床试验和制定治疗指南。
