KRAS基因突变与结直肠癌患者临床病理特征及预后的关系

Association between KRAS gene mutations and clinicopathological characteristics and prognosis of colorectal cancer patients

    摘要
  • 摘要: 目的:探讨KRAS基因突变与结直肠癌患者临床病理特征及预后的关系。
    方法:采用回顾性病例对照研究方法。收集2007年1月至2011年7月同济大学附属杨浦医院收治的315例行结直肠癌手术患者的临床病理资料。采用高通量测序技术检测结直肠癌手术切除标本石蜡切片KRAS基因突变情况。分析指标：(1)KRAS基因检测情况。(2)KRAS基因突变状态与结直肠癌患者临床病理因素的关系。(3)随访和生存情况。(4)结直肠癌患者预后的KRAS基因突变情况多因素分析。采用门诊和电话方式进行随访，了解患者术后总体生存情况。随访时间截至2016年8月。计数资料比较采用X2检验。偏态分布的计量资料采用M(四分位距)表示，两者比较采用非参数检验。采用Kaplan-Meier法计算患者生存率，采用Logrank检验比较患者生存情况。多因素分析采用COX比例风险回归模型。
    结果:(1)KRAS基因检测情况：315例患者手术切除标本均成功完成检测，其中KRAS基因野生型172例，KRAS基因突变型143例(第2号外显子12号密码子突变患者80例、第2号外显子13号密码子突变患者24例、其余位点突变患者40例，其中第2号外显子12号和13号密码子同时突变患者1例；错义突变141例、无义突变2例)。KRAS基因突变位点中，点突变以p.G12D和p.G13D为主。(2)KRAS基因突变状态与结直肠癌患者临床病理因素的关系：KRAS基因野生型结直肠癌患者肿瘤部位分别为：近端结肠34例、远端结肠48例、直肠90例，KRAS基因突变型结直肠癌患者肿瘤部位分别为：近端结肠44例、远端结肠27例、直肠72例，两者上述指标比较，差异有统计学意义(X2=0.038，P<0.05)。(3)随访和生存情况：315例结直肠癌患者均获得术后随访，随访时间为3～115个月，中位随访时间为78个月。172例KRAS基因野生型、80例KRAS基因第2号外显子12号密码子突变、24例KRAS基因第2号外显子13号密码子突变、40例KRAS基因其余位点突变患者术后总体生存率分别为41.0%、27.4%、26.3%、48.2%，4者总体生存情况比较，差异有统计学意义(X2=0.040，P<0.05)。(4)结直肠癌患者预后的KRAS基因突变情况多因素分析结果显示：KRAS基因第2号外显子12号密码子突变是结直肠癌患者预后不良的独立影响因素(风险比＝1.543，95%可信区间：1.050～2.265，P<0.05)。
    结论:我国结直肠癌患者KRAS基因突变位点主要在第2号外显子12号和13号密码子，其中点突变以p.G12D和p.G13D为主；KRAS基因突变情况可能与肿瘤部位有关；KRAS基因第2号外显子12号密码子突变是结直肠癌患者预后不良的独立影响因素。

     

    Abstract: Objective:To investigate the association between KRAS gene mutations and clinicopathological characteristics and prognosis of colorectal cancer (CRC) patients.
    Methods:The retrospective casecontrol study was conducted. The clinicophathological data of 315 patients who underwent radical resection of CRC in the Yangpu Hospital Affiliated to Tongji University between January 2007 and July 2011 were collected. Nextgeneration sequencing was performed to identify KRAS gene mutations from surgical specimens. Observation indicators: (1) detection of KRAS gene; (2) association between KRAS gene mutations and clinicopathological characteristics of CRC patients; (3) followup and survival situations; (4) multivariate analysis of KRAS gene mutations in the prognosis of CRC patients. Follow-up using outpatient examination and telephone interview was performed to detect postoperative overall survival up to August 2016. Comparisons of count data were analyzed using the chisquare test. Measurement data with skewed distribution were described as M (interquartile range), and comparison between groups was analyzed using the nonparametric test. The survival rate was calculated using the Kaplan-Meier method, and survival was compared using the Logrank test. The multivariate analysis was done using the COX regression model.
    Results:(1) Detection of KRAS gene: all the 315 patients finished gene detection of surgical specimens, including 172 in widetype mutations and 143 in mutanttype mutations (mutations at codon 12 and 13 of KRAS exon 2 and other mutant points were respectively detected in 80, 24 and 40 patients, and 1 patient had simultaneous mutations at codon 12 and 13 of KRAS exon 2; missense and nonsense mutations were respectively detected in 141 and 2 patients). The major point mutations were at p.G12D and p.G13D. (2) Association between KRAS gene mutations and clinicophathological characteristics of CRC patients: tumors located in the proximal colon, distal colon and rectum were respectively detected in 34, 48, 90 patients with wildtype mutation and in 44, 27, 72 patients with mutanttype mutation, with a statistically significant difference (X2=0.038, P<0.05). (3) Followup and survival situation: 315 patients were followed up for 3- 115 months, with a median time of 78 months. The postoperative overall survival rate was 41.0% in 172 patients with wildtype KRAS mutations, 27.4% in 80 patients with KRAS codon 12 mutations, 26.3% in 24 patients with KRAS codon 13 mutations and 48.2% in 40 patients with other KRAS mutations, showing a statistically significant difference (X2=0.040, P<0.05). (4) Multivariate analysis of KRAS gene mutations in the prognosis of CRC patients: the results of multivariate analysis showed that mutations at codon 12 of KRAS exon 2 was an independent factor affecting poor prognosis of CRC patients (Hazard ratio=1.543, 95% confidence interval: 1.050-2.265, P<0.05).
    Conclusions:Most KRAS mutations of CRC patients are at codon 12 and 13 of KRAS exon 2, and the major point mutations are at p.G12D and p.G13D. KRAS gene mutations may be associated with tumor location. Mutations at codon 12 of KRAS exon 2 is an independent factor affecting poor prognosis of CRC patients.

     

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