Suh Kwang Wook, Kim Joo Hyung, Kim Do Yoon, Kim Young Bae, Lee Chulho, Choi Sungho
Department of Surgery, Ajou University School of Medicine, Suwon, 442-749, Korea.
Ann Surg Oncol. 2006 Nov;13(11):1379-85. doi: 10.1245/s10434-006-9112-y. Epub 2006 Sep 29.
Combination chemotherapy using oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX) is known to be effective in the treatment of metastatic colon cancer. Genes regulating the actions of 5-fluorouracil and oxaliplatin have been identified, but precisely which gene is dominant has not yet been determined. The aim of the investigation reported here was to identify which gene polymorphism is a dominant factor in FOLFOX chemotherapy-the methylenetetrahydrofolate reductase (MTHFR) gene for 5-fluorouracil or the X-ray cross-complementing1 (XRCC1) gene for oxaliplatin.
Paraffin-embedded tissues from 54 patients with unresectable metastases from colorectal cancer who had undergone chemotherapy with the FOLFOX regimen were analyzed for MTHFR polymorphisms in the MTHFR gene (677C-->T, Ala-->Val mutation) and XRCC1 gene (Arg-->Gln substitution in exon 10). Response rates and survivals were compared by types of polymorphism.
Analyses of the patterns of MTHFR polymorphism revealed that 29.6% of the patients showed no mutation, 51.6% showed heterozygous mutations, and 11.8% showed homozygous mutations. Analyses of the XRCC1 polymorphism revealed that 60.8% of the patients showed no mutation, 31.4% showed heterozygous mutations, and 7.8% showed homozygous mutations. After four cycles of chemotherapy, 3.7% showed a complete response, 57.4% showed a partial response (PD) or stable disease, and 38.9% showed PD. The MTHFR polymorphism was not significant in predicting response and 30-month-survival (P > .1), whereas the XRCC1 polymorphism was a significant prognostic factor for both response (P = .038) and survival (P = .011).
We found a higher rate of mutations in the MTHFR gene than in the XRCC1 gene in Korean colorectal cancer patients. Response to FOLFOX was better in the patient group with mutations for MTHFR and worse in the patient group with mutations for XRCC1. However, only the XRCC1 polymorphism was a significant prognostic factor for the response to FOLFOX chemotherapy and short-term survival.
已知使用奥沙利铂、5-氟尿嘧啶和亚叶酸（FOLFOX）的联合化疗对转移性结肠癌有效。调控5-氟尿嘧啶和奥沙利铂作用的基因已被确定，但究竟哪个基因起主导作用尚未明确。本文报道的研究目的是确定哪种基因多态性是FOLFOX化疗中的主导因素——5-氟尿嘧啶的亚甲基四氢叶酸还原酶（MTHFR）基因还是奥沙利铂的X射线修复交叉互补蛋白1（XRCC1）基因。
对54例接受FOLFOX方案化疗的不可切除结直肠癌转移患者的石蜡包埋组织进行分析，检测MTHFR基因（677C→T，丙氨酸→缬氨酸突变）和XRCC1基因（第10外显子精氨酸→谷氨酰胺替换）的多态性。根据多态性类型比较缓解率和生存率。
MTHFR多态性模式分析显示，29.6%的患者无突变，51.6%为杂合突变，11.8%为纯合突变。XRCC1多态性分析显示，60.8%的患者无突变，31.4%为杂合突变，7.8%为纯合突变。化疗四个周期后，3.7%完全缓解，57.4%部分缓解（PR）或疾病稳定，38.9%疾病进展（PD）。MTHFR多态性在预测缓解和30个月生存率方面无统计学意义（P＞0.1），而XRCC1多态性是缓解（P = 0.038）和生存（P = 0.011）的显著预后因素。
我们发现韩国结直肠癌患者中MTHFR基因的突变率高于XRCC1基因。MTHFR基因突变患者组对FOLFOX的反应较好，而XRCC1基因突变患者组较差。然而，只有XRCC1多态性是FOLFOX化疗反应和短期生存的显著预后因素。
