Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Pathology, Fudan University Cancer Center, Shanghai, China (RB, AL).
J Natl Cancer Inst. 2018 Sep 1;110(9):1030-1034. doi: 10.1093/jnci/djy028.
Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.
在参与 DNA 损伤反应和细胞周期检查点的 ATM 基因（ataxia-telangiectasia mutated 的缩写）中存在致病变异体时，会增加乳腺癌（BC）的风险。在这里，我们通过全外显子组和靶向测序，研究了 24 例 ATM 种系突变携带者的 BC 中体细胞遗传改变的表型特征和全景。与 ATM 相关的 BC 一致为激素受体阳性，且主要表现为免疫浸润程度低。尽管这些肿瘤中有 79.2%显示 ATM 野生型等位基因的杂合性丢失，但没有一种表现出与同源重组 DNA（HRD）修复缺陷相关的高活性突变特征 3。在 ATM 相关的 BC 中未发现 TP53 突变。对独立数据集的分析证实，种系 ATM 变体和 TP53 体细胞突变是相互排斥的。我们的研究结果表明，与 ATM 相关的 BC 通常具有 ATM 的双等位基因失活，与 BRCA1/2 相关的 BC 在表型上不同，缺乏 HRD 相关的突变特征，并且 TP53 和 ATM 遗传改变可能是上位性的。
