Mandelker Diana, Kumar Rahul, Pei Xin, Selenica Pier, Setton Jeremy, Arunachalam Sasi, Ceyhan-Birsoy Ozge, Brown David N, Norton Larry, Robson Mark E, Wen Hannah Y, Powell Simon, Riaz Nadeem, Weigelt Britta, Reis-Filho Jorge S
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
JNCI Cancer Spectr. 2019 Apr 27;3(2):pkz027. doi: 10.1093/jncics/pkz027. eCollection 2019 Jun.
Pathogenic germline variants in checkpoint kinase 2 (), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). -associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the wild-type allele. Conversely, -associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. -associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that -associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of -associated BCs. Specific germline variants may have a distinct impact on tumor biology.
在DNA损伤应答和细胞周期调控中起关键作用的检查点激酶2（CHEK2）的致病性种系变异会增加患乳腺癌（BC）的风险。在此，我们研究了33例来自种系突变携带者（16例高风险变异和17例低风险p.Ile157Thr变异）的乳腺癌的表型和基因组特征。携带高风险种系变异患者的CHEK2相关乳腺癌大多为激素受体阳性（87%，13/15），并且81%（13/16）表现出野生型等位基因杂合性缺失（LOH）。相反，携带低风险p.Ile157Thr变异患者的CHEK2相关乳腺癌显示出较低频率的杂合性缺失（5/17，29%），并且与携带高风险种系变异的乳腺癌相比，CHEK2蛋白表达水平更高。CHEK2相关乳腺癌缺乏主要的突变特征3，这是同源重组DNA修复缺陷（HRD）的一种基因组特征。我们的研究结果表明，CHEK2相关乳腺癌通常为激素受体阳性且缺乏与HRD相关的突变特征，概括了CHEK2相关乳腺癌的特征。特定的种系变异可能对肿瘤生物学有不同的影响。
