Tumors with a pathogenicBRCA1/2mutation are homologous recombination (HR)-deficient (HRD) and consequently sensitive to platinum-based chemotherapy and Poly-[ADP-Ribose]-Polymerase inhibitors (PARPi). We hypothesized that functional HR status better reflects real-time HR status thanBRCA1/2mutation status. Therefore, we determined the functional HR status of 53 breast cancer (BC) and 38 ovarian cancer (OC) cell lines by measuring the formation of RAD51 foci after irradiation. Discrepancies between functional HR andBRCA1/2mutation status were investigated using exome sequencing, methylation and gene expression data from 50 HR-related genes. A pathogenicBRCA1/2mutation was found in 10/53 (18.9%) of BC and 7/38 (18.4%) of OC cell lines. AmongBRCA1/2-mutant cell lines, 14/17 (82.4%) were HR-proficient (HRP), while 1/74 (1.4%) wild-type cell lines was HRD. For most (80%) cell lines, we explained the discrepancy between functional HR andBRCA1/2mutation status. Importantly, 12/14 (85.7%)BRCA1/2-mutant HRP cell lines were explained by mechanisms directly acting on BRCA1/2. Finally, functional HR status was strongly associated with COSMIC single base substitution signature 3, but notBRCA1/2mutation status. Thus, the majority ofBRCA1/2-mutant cell lines do not represent a suitable model for HRD. Moreover, exclusively determiningBRCA1/2mutation status may not suffice for platinum-based chemotherapy or PARPi patient selection.
携带致病性BRCA1/2突变的肿瘤存在同源重组（HR）缺陷（HRD），因此对铂类化疗和聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）敏感。我们假设功能性HR状态比BRCA1/2突变状态更能反映实时的HR状态。为此，我们通过检测辐照后RAD51灶的形成情况，测定了53个乳腺癌（BC）和38个卵巢癌（OC）细胞系的功能性HR状态。利用来自50个HR相关基因的外显子组测序、甲基化和基因表达数据，研究了功能性HR状态与BRCA1/2突变状态之间的差异。在53个BC细胞系中，有10个（18.9%）发现了致病性BRCA1/2突变；在38个OC细胞系中，有7个（18.4%）发现了致病性BRCA1/2突变。在BRCA1/2突变细胞系中，14/17（82.4%）具有HR功能（HRP），而1/74（1.4%）的野生型细胞系存在HRD。对于大多数（80%）细胞系，我们解释了功能性HR状态与BRCA1/2突变状态之间的差异。重要的是，12/14（85.7%）的BRCA1/2突变HRP细胞系的差异可以通过直接作用于BRCA1/2的机制来解释。最后，功能性HR状态与COSMIC单碱基替换特征3密切相关，但与BRCA1/2突变状态无关。因此，大多数BRCA1/2突变细胞系并不适合作为HRD的研究模型。此外，仅确定BRCA1/2突变状态可能不足以用于铂类化疗或PARPi的患者选择。
肿瘤(癌症)患者之家