Poor-prognosis breast cancers are treated with cytotoxic chemotherapy, but often without any guidance from therapy predictive markers because universally accepted markers are not currently available. Treatment failure, in the form of recurrences, is relatively common. We aimed to identify chemotherapy predictive markers and resistance pathways in breast cancer. Our hypothesis was that tumor cells remaining after neoadjuvant chemotherapy (NAC) contain somatic variants causing therapy resistance, while variants present pre-NAC but lost post-NAC cause sensitivity. Whole-exome sequencing was performed on matched pre- and post-NAC cancer cells, which were isolated by laser microdissection, from 6 cancer cases, and somatic variants selected for or against by NAC were identified. Somatic variant diversity was significantly reduced after therapy (P < 0.05). MUC17 variants were identified in 3 tumors and were selected against by NAC in each case, while PCNX1 variants were identified in 2 tumors and were selected for in both cases, implicating the function of these genes in defining chemoresponse. In vitro knockdown of MUC17 or PCNX1 was associated with significantly increased or decreased chemotherapy sensitivity, respectively (P < 0.05), further supporting their roles in chemotherapy response. Expression was tested for predictive value in two independent cohorts of chemotherapy-treated breast cancers (n = 53, n = 303). Kaplan–Meier analyses revealed that low MUC17 expression was significantly associated with longer survival after chemotherapy, whereas low PCNX1 was significantly associated with reduced survival. We concluded that therapy-driven selection of somatic variants allows identification of chemotherapy response genes. With respect to MUC17 and PCNX1, therapy-driven selection acting on somatic variants, in vitro knockdown data concerning drug sensitivity, and survival analysis of expression levels in patient cohorts all define the genes as mediators of and predictive markers for chemotherapy response in breast cancer.

中文翻译：

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基因组和表达分析将 MUC17 和 PCNX1 定义为乳腺癌化疗反应的预测因子

预后不良的乳腺癌采用细胞毒性化疗进行治疗，但通常没有来自治疗预测标志物的任何指导，因为目前还没有普遍接受的标志物。以复发形式出现的治疗失败相对常见。我们旨在确定乳腺癌的化疗预测标志物和耐药途径。我们的假设是，新辅助化疗 (NAC) 后残留的肿瘤细胞含有导致治疗抵抗的体细胞变异，而变异存在 NAC 前但失去 NAC 后引起的敏感性。对通过激光显微切割从 6 个癌症病例中分离的匹配的 NAC 前和 NAC 后癌细胞进行全外显子组测序，并确定了 NAC 选择的体细胞变异体。治疗后体细胞变异多样性显着降低（P < 0. 05）。在 3 个肿瘤中鉴定出 MUC17 变体，并在每种情况下都被 NAC 选择，而 PCNX1 变体在 2 个肿瘤中被鉴定，并且在两种情况下都被选择，暗示这些基因在定义化学反应中的功能。MUC17 或 PCNX1 的体外敲低分别与化疗敏感性显着增加或降低相关（P < 0.05），进一步支持它们在化疗反应中的作用。在两个独立的化疗治疗乳腺癌队列（n = 53，n = 303）中测试了表达的预测价值。Kaplan-Meier 分析显示，低 MUC17 表达与化疗后更长的生存期显着相关，而低 PCNX1 与降低的生存率显着相关。我们得出结论，治疗驱动的体细胞变异选择允许鉴定化疗反应基因。关于 MUC17 和 PCNX1，作用于体细胞变异的治疗驱动选择、关于药物敏感性的体外敲低数据以及患者队列中表达水平的生存分析都将这些基因定义为乳腺癌化疗反应的介质和预测标志物。