Translational Research Unit, Department of Oncology, Istituto Toscano Tumori, Prato, Italy;
Oncologist. 2013;18(10):1063-73. doi: 10.1634/theoncologist.2013-0163. Epub 2013 Sep 26.
DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n = 294) or anthracycline (n = 210). We independently assessed estrogen receptor (ER)-positive/HER2-negative, HER2-positive, and ER-negative/HER2-negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty-two genes were consistently overexpressed in ER-negative tumors, and five genes were overexpressed in ER-positive tumors, but no differences in expression were associated with HER2 status. In ER-positive/HER2-negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment-specific manner. In ER-negative/HER2-negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline-treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2-positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA-damaging agents.
DNA 修复途径可使肿瘤细胞在化疗诱导的 DNA 损伤后存活下来，从而提供预后和/或预测价值。我们评估了未经治疗的乳腺癌（BC）患者（n = 684）和接受新辅助紫杉烷/蒽环类药物（n = 294）或蒽环类药物（n = 210）治疗的 BC 患者的 145 个 DNA 修复基因的 Affymetrix 基因表达谱。我们独立评估了雌激素受体（ER）阳性/HER2 阴性、HER2 阳性和 ER 阴性/HER2 阴性亚组的差异表达、双峰分布以及 DNA 修复基因表达的预后和预测价值。22 个基因在 ER 阴性肿瘤中持续过表达，5 个基因在 ER 阳性肿瘤中过表达，但与 HER2 状态无关。在 ER 阳性/HER2 阴性肿瘤中，9 个基因（BUB1、FANCI、MNAT1、PARP2、PCNA、POLQ、RPA3、TOP2A 和 UBE2V2）的表达与预后不良相关，一个基因（ATM）的表达与预后良好相关。此外，特定基因的预后价值与增殖无关。少数基因与 BC 亚型的化疗反应和治疗特异性有关。在 ER 阴性/HER2 阴性肿瘤中，MSH2、MSH6 和 FAN1（先前称为 MTMR15）基因与紫杉烷/蒽环类药物治疗患者的病理完全缓解和残留浸润性癌相关。相反，PMS2 表达与蒽环类药物单药治疗的残留浸润性癌相关。在 HER2 阳性肿瘤中，TOP2A 与蒽环类药物的患者反应相关，但与紫杉烷/蒽环类药物方案无关。在呈双峰表达的基因中，RECQL4 与临床结果显著相关。体外研究表明，RECQL4 缺陷会损害同源重组，使 BC 细胞对 DNA 损伤剂敏感。
