Li Yazhuo, Yang Yunsheng, Lu Youyong, Herman James G, Brock Malcolm V, Zhao Po, Guo Mingzhou
Department of Pathology, Chinese PLA General Hospital, Haitangwan Town, Sanya, 572000, Hainan, China.
Gastric Cancer. 2015 Apr;18(2):280-7. doi: 10.1007/s10120-014-0370-2. Epub 2014 Apr 21.
Gastric carcinoma (GC) has one of the highest mortality rates of cancer diseases and has a high incidence rate in China. Palliative chemotherapy is the main treatment for advanced gastric cancer. It is necessary to compare the effectiveness and toxicities of different regimens. This study explores the possibility of methylation of DNA damage repair genes serving as a prognostic and chemo-sensitive marker in human gastric cancer.
The methylation status of five DNA damage repair genes (CHFR, FANCF, MGMT, MLH1, and RASSF1A) was detected by nested methylation-specific PCR in 102 paraffin-embedded gastric cancer samples. Chi-square or Fisher's exact tests were used to evaluate the association of methylation status and clinic-pathological factors. The Kaplan-Meier method and Cox proportional hazards models were employed to analyze the association of methylation status and chemo-sensitivity.
The results indicate that CHFR, MLH1, RASSF1A, MGMT, and FANCF were methylated in 34.3% (35/102), 21.6% (22/102), 12.7% (13/102), 9.8% (10/102), and 0% (0/102) of samples, respectively. No association was found between methylation of CHFR, MLH1, RASSF1A, MGMT, or FANCF with gender, age, tumor size, tumor differentiation, lymph node metastasis, and TNM stage. In docetaxel-treated gastric cancer patients, resistance to docetaxel was found in CHFR unmethylated patients by Cox proportional hazards model (HR 0.243, 95% CI, 0.069-0.859, p = 0.028), and overall survival is longer in the CHFR methylated group compared with the CHFR unmethylated group (log-rank, p = 0.036). In oxaliplatin-treated gastric cancer patients, resistance to oxaliplatin was found in MLH1 methylated patients (HR 2.988, 95% CI, 1.064-8.394, p = 0.038), and overall survival was longer in the MLH1 unmethylated group compared with the MLH1 methylated group (log-rank, p = 0.046).
CHFR is frequently methylated in human gastric cancer, and CHFR methylation may serve as a docetaxel-sensitive marker. MLH1 methylation was related to oxaliplatin resistance in gastric cancer patients.
胃癌（GC）是癌症疾病中死亡率最高的之一，在中国发病率也很高。姑息化疗是晚期胃癌的主要治疗方法。比较不同方案的有效性和毒性很有必要。本研究探讨DNA损伤修复基因甲基化作为人类胃癌预后和化疗敏感性标志物的可能性。
采用巢式甲基化特异性PCR检测102例石蜡包埋胃癌样本中5个DNA损伤修复基因（CHFR、FANCF、MGMT、MLH1和RASSF1A）的甲基化状态。采用卡方检验或Fisher精确检验评估甲基化状态与临床病理因素的相关性。采用Kaplan-Meier法和Cox比例风险模型分析甲基化状态与化疗敏感性的相关性。
结果表明，CHFR、MLH1、RASSF1A、MGMT和FANCF的甲基化率分别为34.3%（35/102）、21.6%（22/102）、12.7%（13/102）、9.8%（10/102）和0%（0/102）。未发现CHFR、MLH1、RASSF1A、MGMT或FANCF的甲基化与性别、年龄、肿瘤大小、肿瘤分化、淋巴结转移和TNM分期之间存在关联。在多西他赛治疗的胃癌患者中，通过Cox比例风险模型发现CHFR未甲基化患者对多西他赛耐药（HR 0.243，95%CI，0.069 - 0.859，p = 0.028），且CHFR甲基化组的总生存期比CHFR未甲基化组长（对数秩检验，p = 0.036）。在奥沙利铂治疗的胃癌患者中，发现MLH1甲基化患者对奥沙利铂耐药（HR 2.988，95%CI, 1.064 - 8.394，p = 0.038），且MLH1未甲基化组的总生存期比MLH1甲基化组长（对数秩检验，p = 0.046）。
CHFR在人类胃癌中经常发生甲基化，CHFR甲基化可能作为多西他赛敏感性标志物。MLH1甲基化与胃癌患者对奥沙利铂耐药有关。
