KRAS基因突变预测结直肠癌单纯肝转移肝切除术后预后的价值

Value of KRAS mutation predicting prognosis of patients with colorectal liver-only metastasis after hepa

目的：探讨KRAS基因突变预测结直肠癌单纯肝转移肝切除术后预后的价值。方法：采用回顾性病例对照研究方法。收集2010年10月至2016年10月中山大学肿瘤防治中心收治的79例结直肠癌单纯肝转移行肝切除术患者的临床病理资料。采用荧光定量聚合酶链反应仪和激光飞行质谱仪检测结直肠癌手术切除标本肿瘤组织KRAS基因突变情况。观察指标：（1）KRAS基因突变情况。（2）KRAS突变状态与结直肠癌单纯肝转移患者临床病理因素的关系。（3）随访和生存情况。采用门诊和电话方式进行随访，了解患者肿瘤无复发生存情况和总体生存情况。随访时间截至2017年6月30日。KRAS基因突变状态与结直肠癌单纯肝转移患者临床病理因素的关系分析采用x2检验或Fisher确切概率法。采用Kaplan-Meier法绘制生存曲线并计算生存时间，采用COX回归模型进行生存分析。结果：（1）KRAS基因突变情况：79例结直肠癌手术切除标本肿瘤组织中，KRAS基因野生型54例，KRAS基因突变型25例。25例KRAS基因突变型患者中，21例第2号外显子12号密码子突变，突变类型为GGT〉GAT（G12D）13例、GGT〉GTT（G12V）4例、GGT〉TGT（G12C）2例、GGT〉GCT（G12A）1例、GGT〉CGT（G12R）1例；3例第2号外显子13号密码子突变，突变类型均为GGC〉GAC（G13D）；1例第3号外显子61号密码子突变，突变类型为CAA〉CAT （Q61H）。（2）KRAS突变状态与结直肠癌单纯肝转移患者临床病理因素的关系：KRAS基因突变型结直肠癌单纯肝转移患者原发肿瘤部位分别为右半结肠11例、左半结直肠14例，KRAS基因野生型患者原发肿瘤部位为右半结肠7例、左半结直肠47例，两者比较，差异有统计学意义（χ^2=9.357，P〈0.05）。（3）随访和生存情况：79例患者均获得随访，随访时间为2.0-71.0个月，中位随访时间为29.0个月。25例KRAS基因突变型患者中位肿瘤无复发生存时间和中位总体生存时间分别为11.3个月和43.5个月，54例KRAS基因野生型患者分别为9.9个月和44.3个月，两者肿瘤无复发和总体生存情况比较，差异均无统计学意义［风险比（HR）=1.255,1.108，95%可信区间：0.741-2.126，0.521-2.355，P〉0.05］。进一步分析结果显示：美国纪念斯隆凯特琳癌症中心（MSKCC）预后风险评分（CRS） 低危患者中，17例KRAS基因突变型患者中位肿瘤无复发生存时间为11.3个月，26例KRAS基因野生型患者为23.5个月，两者肿瘤无复发生存情况比较，差异有统计学意义（HR=2.082，95%可信区间：1.006-4.307，P〈0.05）；17例KRAS基因突变型患者中位总体生存时间为44.6个月，26例KRAS基因野生型患者为49.0个月，两者总体生存情况比较，差异无统计学意义（HR=1.165，95%可信区间：0.413-3.282，P〉0.05）。MSKCC CRS高危患者中，7例KRAS基因突变型患者中位肿瘤无复发生存时间和中位总体生存时间分别为5.6个月和28.7个月，24例KRAS基因野生型患者分别为4.5个月和36.7个月，两者肿瘤无复发和总体生存情况比较，差异均无统计学意义（HR=0.402，1.197，95%可信区间：0.284-1.656，0.371-3.866，P〉0.05）。结论：KRAS基因突变多发生在右半结肠癌。KRAS基因突变MSKCC CRS低危患者肿瘤无复发生存时间显著缩短。

Objective：To explore the value of KRAS mutation predicting prognosis of patients with colorectal liver-only metastasis after hepatectomy. Methods：The retrospective case-control study was conducted. The clinicopathological data of 79 patients with colorectal liver-only metastasis who underwent hepatectomy in the Sun Yat-sen University Cancer Center between October 2010 and October 2016 were collected. KRAS mutation in colorectal cancer tissue was detected by fluorescent quantitative polymerase chain reaction （PCR） and laser flight mass spectrometer. Observation indicators： （1） KRAS mutation; （2） relationship between KRAS mutation and clinicopathological factors of patients with colorectal liver-only metastasis; （3） follow-up and survival situations. Follow-up using outpatient examination and telephone interview was performed to detect recurrence-free survival and overall survival up to June 30, 2017. The relationship between KRAS mutation and clinicopathological factors of patients with colorectal liver-only metastasis was analyzed by the chi-square test or Fisher exact probability. The survival curve and time were respectively drawn and calculated by the Kaplan-Meier method, and COX regression model was used for survival analysis. Results：（1） KRAS mutation： 79 patients received KRAS gene detection of surgical tumor tissues, including 54 in wide-type mutation and 25 in mutant-type mutation. Of 25 patients in mutant-type mutation, mutation at codon 12 of KRAS exon 2 was in 21 patients, and GGT〉GAT （G12D）, GGT〉GTT （G12V）, GGT〉TGT （G12C）, GGT〉GCT （G12A） and GGT〉CGT （G12R） of mutation types were respectively detected in 13, 4, 2 , 1 and 1 patients; mutation at codon 13 of KRAS exon 2 was in 3 patients, with a mutation type of GGC〉GAC （G13D）; mutation at codon 61 of KRAS exon 3 was in 1 patient, with a mutation type of CAA〉CAT （Q61H）. （2） Relationship between KRAS mutation and clinicopathological factors of patients with colorectal liver-only metastasis： primary tumor located in right and left hemicolon were detected in 11, 14 patients with mutant-type mutation and 7, 47 patients with wide-type mutation, respectively, with a statistically significant difference （χ^2=9.357, P〈0.05）. （3） Follow-up and survival situations： 79 patients were followed up for 2.0-71.0 months, with a median time of 29.0 months. Median recurrence-free survival time and median overall survival time were respectively 11.3 months, 43.5 months in patients with mutant-type mutation and 9.9 months, 44.3 months in patients with wide-type mutation, respectively, with no statistically significant difference in recurrence-free and overall survivals [hazard ratio （HR）=1.255, 1.108, 95% confidence interval （CI）： 0.741-2.126, 0.521-2.355, P〉0.05]. Further analysis： of patients with low clinical risk score （CRS） of Memorial Sloan Caitlin Cancer Center （MSKCC）, median recurrence-free survival time was 11.3 months in 17 patients with mutant-type mutation and 23.5 months in 26 patients with wide-type mutation, with a statistically significant difference in recurrence-free survival of patients （HR=2.082, 95%CI： 1.006-4.307, P〈0.05）. The median overall survival time was 44.6 months in 17 patients with mutant-type mutation and 49.0 months in 26 patients with wide-type mutation, with no statistically significant difference in overall survival of patients （HR= 1.165, 95%CI： 0.413-3.282, P〉0.05）. Of patients with high CRS of MSKCC, median recurrence-free survival time and median overall survival time were respectively 5.6 months, 28.7 months in 7 patients with mutant-type mutation and 4.5 months, 36.7 months in 24 patients with wide-type mutation, with no statistically significant difference in recurrence-free and overall survivals （HR=0.402, 1.197, 95%CI： 0.284-1.656, 0.371-3.866, P〉0.05）. Conclusion：KRAS mutation is often detected in patients with right colon cancer. Recurrence-free survival time is obviously reduced in patients with KRAS mutation and low CRS of MSKCC.