Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Ann Surg Oncol. 2011 Sep;18(9):2688-98. doi: 10.1245/s10434-011-1601-y. Epub 2011 Feb 24.
DNA repair plays an important role in chemoresistance to platinum-based therapy, and therefore polymorphisms in the genes may modulate therapeutic response. We assessed 12 polymorphisms in 7 DNA repair genes and 2 polymorphisms in the MTHFR gene for association with disease response and prognosis.
A total of 258 patients included in the study had adenocarcinoma of the esophagus (n = 114) or gastric cancer (n = 144), at stage cT3/4 and cM0, and had been treated with platinum-based neoadjuvant polychemotherapy. The patients were genotyped for polymorphisms in the XPC, XPD, XPG, APEX, XRCC1, NBS1, XRCC3, and MTHFR genes by the allelic discrimination method and the data correlated with various clinical parameters.
None of the investigated polymorphisms was associated with histopathological response. XRCC3 polymorphisms rs861539 (P = 0.02) and rs861530 (P = 0.05) showed association with clinical response in gastric cancer. The variants in XRCC3 (rs861539, P = 0.05; rs1799794, P = 0.03) and MTHFR (rs1801131, P = 0.02) were associated with survival in esophageal and gastric cancer, respectively. In R0 resected patients, XRCC3 variants (rs861539, P = 0.04; rs861530, P = 0.02) in esophageal cancer, and XRCC3 (rs1799794, P = 0.02) and MTHFR (rs1801131, P = 0.005) in gastric cancer predicted survival. Cox regression revealed ypT category (P = 0.001) and lymphatic vessel invasion (P = 0.03) to be independent prognostic factors for esophageal cancer, and histopathological response (P = 0.01), MTHFR variant (rs1801131, P = 0.002), and ypN category (P = 0.02) to be prognostic factors for gastric cancer.
In gastric cancer patients, MTHFR variant (rs1801131) could serve as a potential prognostic marker. In esophageal cancer patients, none of the polymorphisms studied had conclusive results in multivariate analysis, although XRCC3 variant (rs861539) showed an effect on survival in Kaplan-Meier univariate analysis.
DNA 修复在铂类药物化疗耐药中起着重要作用，因此基因中的多态性可能调节治疗反应。我们评估了 7 个 DNA 修复基因中的 12 个多态性和 MTHFR 基因中的 2 个多态性与疾病反应和预后的关系。
本研究共纳入 258 例患者，包括食管腺癌（n=114）或胃癌（n=144），分期为 cT3/4 和 cM0，并接受了铂类新辅助化疗。通过等位基因鉴别方法对 XPC、XPD、XPG、APEX、XRCC1、NBS1、XRCC3 和 MTHFR 基因中的多态性进行基因分型，并将数据与各种临床参数相关联。
未发现研究的多态性与组织病理学反应相关。XRCC3 多态性 rs861539（P=0.02）和 rs861530（P=0.05）与胃癌的临床反应相关。XRCC3（rs861539，P=0.05；rs1799794，P=0.03）和 MTHFR（rs1801131，P=0.02）中的变体与食管癌和胃癌的生存相关。在 R0 切除的患者中，XRCC3 变体（rs861539，P=0.04；rs861530，P=0.02）在食管癌中，以及 XRCC3（rs1799794，P=0.02）和 MTHFR（rs1801131，P=0.005）在胃癌中与生存相关。Cox 回归显示 ypT 分期（P=0.001）和淋巴管侵犯（P=0.03）是食管癌的独立预后因素，组织病理学反应（P=0.01）、MTHFR 变体（rs1801131，P=0.002）和 ypN 分期（P=0.02）是胃癌的预后因素。
在胃癌患者中，MTHFR 变体（rs1801131）可能是一个潜在的预后标志物。在食管癌患者中，尽管 XRCC3 变体（rs861539）在单因素 Kaplan-Meier 分析中显示对生存有影响，但在多因素分析中没有得出明确的结果。
