Background: Mutations in BRCA1 and BRCA2 cause deficiencies in homologous recombination repair (HR), resulting in repair of DNA double-strand breaks by the alternative non-homologous end-joining pathway, which is more error prone. HR deficiency of breast tumors is important because it is associated with better responses to platinum salt therapies and PARP inhibitors. Among other consequences of HR deficiency are characteristic somatic-mutation signatures and gene-expression patterns. The term "BRCAness" describes tumors that harbor an HR defect but have no detectable germline mutation in BRCA1 or BRCA2. A better understanding of the genes and molecular events associated with BRCAness could provide mechanistic insights and guide development of targeted treatments. Methods: Using data from The Cancer Genome Atlas (TCGA) for 1101 breast-cancer patients, we identified individuals with a germline mutation, somatic mutation, homozygous deletion, and/or hypermethylation event in BRCA1, BRCA2, and 59 other cancer-predisposition genes. Based on the assumption that BRCAness events would have similar downstream effects on tumor biology as BRCA1/BRCA2 germline mutations, we quantified these effects based on somatic-mutation signatures and gene-expression profiles. We reduced the dimensionality of the somatic-mutation signatures and expression data and used a statistical resampling approach to quantify similarities between patients who had a BRCA1/BRCA2 germline mutation, another type of aberration in BRCA1 or BRCA2, or any type of aberration in one of the other genes. Results: Somatic-mutation signatures of tumors having a somatic mutation, homozygous deletion, or hypermethylation event in BRCA1/BRCA2 (n = 80) were generally similar to each other and to tumors from BRCA1/BRCA2 germline carriers (n = 44). Additionally, somatic-mutation signatures of tumors with germline or somatic events in ATR (n = 16) and BARD1 (n = 8) showed high similarity to tumors from BRCA1/BRCA2 carriers. Other genes also showed high similarity but only for a small number of events or for a single event type. Tumors with germline mutations or hypermethylation of BRCA1 had relatively similar gene-expression profiles and overlapped considerably with the Basal-like subtype; but the transcriptional effects of the other events lacked consistency. Conclusions: Our findings confirm previously known relationships between molecular signatures and germline or somatic events in BRCA1/BRCA2 and suggest additional genes that may be considered for inclusion in the definition of BRCAness.

中文翻译：

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候选BRCAness基因的种系和体细胞事件对乳腺肿瘤特征的影响

背景：BRCA1和BRCA2中的突变会导致同源重组修复（HR）不足，从而导致DNA双链断裂通过另一种非同源末端连接途径修复，这更容易出错。乳腺肿瘤的HR缺乏很重要，因为它与对铂盐疗法和PARP抑制剂的更好反应有关。HR缺乏的其他后果包括特征性的体细胞突变特征和基因表达模式。术语“ BRCAness”描述了具有HR缺陷但在BRCA1或BRCA2中没有可检测的种系突变的肿瘤。对与BRCAness相关的基因和分子事件的更好理解可以提供机械方面的见解，并指导靶向治疗的发展。方法：使用来自1101例乳腺癌患者的癌症基因组图谱（TCGA）的数据，我们确定了在BRCA1，BRCA2和59个其他癌症易感基因中发生种系突变，体细胞突变，纯合缺失和/或甲基化过度事件的个体。基于BRCAness事件对肿瘤生物学的下游影响与BRCA1 / BRCA2种系突变相似的假设，我们根据体细胞突变特征和基因表达谱对这些影响进行了量化。我们减少了体细胞突变签名和表达数据的维度，并使用统计重采样方法来量化患有BRCA1 / BRCA2种系突变，BRCA1或BRCA2的另一种畸变，或其中一种的任何畸变的患者之间的相似性其他基因。结果：在BRCA1 / BRCA2中具有体细胞突变，纯合缺失或甲基化过度事件的肿瘤（n = 80）的体细胞突变特征通常彼此相似，并且与来自BRCA1 / BRCA2种系携带者的肿瘤（n = 44）相似。此外，ATR（n = 16）和BARD1（n = 8）中具有种系或体细胞事件的肿瘤的体细胞突变特征显示出与BRCA1 / BRCA2携带者的肿瘤高度相似。其他基因也显示出高度相似性，但仅针对少量事件或单个事件类型。具有种系突变或BRCA1甲基化的肿瘤具有相对相似的基因表达谱，并且与基底样亚型有相当多的重叠。但是其他事件的转录作用缺乏一致性。结论：