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.

中文翻译：

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来自ATM生殖细胞突变载体的乳腺癌体细胞遗传变异情况。

共济失调毛细血管扩张症（ATM）中的致病种系变异体（一种在DNA损伤反应和细胞周期检查点中起作用的基因）赋予患乳腺癌（BC）的风险增加。在这里，我们通过全外显子组和靶向测序研究了来自ATM种系突变携带者的24 BC中的体细胞遗传变异的表型特征和景观。ATM相关的BCs始终是激素受体阳性，并且很大程度上显示出最小的免疫浸润。尽管这些肿瘤中有79.2％表现出ATM野生型等位基因的杂合性丧失，但没有一个显示出与缺陷性同源重组DNA（HRD）修复相关的突变签名3的高活性。在与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体细胞突变是互斥的。我们的发现表明，与ATM相关的BCs经常具有ATM的双等位基因失活，在表型上不同于与BRCA1 / 2相关的BCs，缺乏与HRD相关的突变特征，并且TP53和ATM的遗传改变可能是上位性的。