Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-22381, Lund, Sweden.
Wellcome Sanger Institute, Wellcome Genome Campus, CB10 1SA, Cambridge, UK.
Nat Commun. 2020 Jul 27;11(1):3747. doi: 10.1038/s41467-020-17537-2.
Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
同源重组缺陷（HRD）是由关键通路基因的遗传或表观遗传改变引起的 BRCA 缺陷型乳腺癌的一个决定性特征。我们使用已发表的全基因组和 RNA 测序数据，对来自基于人群的研究中的 237 例三阴性乳腺癌（TNBC）进行了 BRCA1 启动子超甲基化频率的研究，同时还分析了遗传、表观遗传、转录组和免疫浸润表型。我们证明，BRCA1 启动子超甲基化在早期 TNBC 中的发生频率是 BRCA1 致病性变异的两倍，并且超甲基化和突变病例在接受辅助化疗后具有相似的预后改善。BRCA1 超甲基化赋予 HRD、免疫细胞类型、全基因组 DNA 甲基化和转录表型，与具有 BRCA1 失活变异的 TNBC 肿瘤相似，并且可以在伴有肿瘤超甲基化的患者的匹配外周血中观察到。超甲基化可能是肿瘤发展的早期事件，沿着与 BRCA1 突变疾病相同的途径进展，代表了早期 TNBC 有前途的基于 DNA 的生物标志物。
