K-ras基因突变与结直肠癌肝转移及其预后关系的研究

目的探讨结直肠癌肿瘤原发灶中K-ras基因突变情况与肝转移及其预后的关系。方法回顾性选取2003年1月至2008年12月间经复旦大学附属中山医院普通外科手术治疗的结直肠癌病例，根据术时诊断和术后随访肝转移情况分为同时性肝转移、异时性肝脏转移和未发生肝脏转移的患者3组，每组各100例。运用PCR及Pyrosequencing法检测石蜡标本中肿瘤原发灶K-ras第2外显子突变情况．分析其与结直肠癌肝转移的发生及其预后的关系。结果300例样本中肿瘤原发灶K-1-as突变者120例（40．0％），其中K-ras第2外显子G13D突变32例，而异时性肝转移组中K-ras的第2外显子G13D突变较同时性肝转移组多（17．0％比8．0％，P=0．041）。多因素回归模型提示，K-ras第2外显子的G13D突变是结直肠癌异时性肝转移的独立危险因素（P=0．048，HR=1．108．95％CI：1．032-5．062）。结直肠癌无肝转移组中K-ras基因突变者较无突变者总体生存期短（中位生存时间65比72个月，P=0．039），而在结直肠癌肝转移切除的患者中，K-ras基因突变者无复发生存期短（中位时间18比24个月，P=0．048），多因素分析提示，K-ras基因突变（HR=1．561，95％CI：1．022-6．422，P=0．045）是影响结直肠癌无肝转移组总体生存的独立危险因素。结论检测结直肠癌原发灶中的K-ras基因状态可以为预测肝脏的转移和预后情况提供参考。

Study on relationship of the K-ras mutation with the occurrence of colorectal liver metastasis and survival outcomes

Objective To analyze the relationship of K-ras mutation with the development of liver metastasis in colorectal cancer patients and the survival outcomes. Methods From 2003 to 2008, 300 patients who underwent colorectal cancer surgery in the Department of General Surgery of Zhongshan Hospital, Fudan University were assigned to different groups, according to the diagnosis and follow-up results. The mutation of exon 2 of K-ras was detected in primary paraffin-embedded lesions by PCR and Pyrosequencing. The association of gene mutation with the development of liver metastasis and its prognosis was studied. Results Among 300 cases, the mutations of exon 2 were present in 120 cases （40%）. The G13D mutation was more common in metachronous metastasis group than that in synchronous group （17.0% vs. 8.0%, P=0.041）. Muhivariable regression analysis showed that G13D mutation was an independent risk factor （HR=1.108, 95%CI： 1.032-5.062, P=0.048） for metaehronous metastasis. Patients with mutated K-ras had a poorer overall survival compared to those without mutated K-ras for patients without liver metastasis （median overall, 65 vs. 72 months, P=0.039）, and for patients who received metastasis resection （median disease-free survival 18 vs. 24 months, P=0.048）. Muhivariable analysis showed that K-ras mutation was an independent risk factors of overall survival （HR =1.561, 95% CI：1.022-6.422, P=0.045） in patients without liver metastasis. Conculsion Detection of K-ras mutation may predict the development of liver metastasis and prognosis.