论文总字数：28104字

摘 要

目的：KRAS基因及BRAF基因突变与结直肠癌患者预后的相关性一直是近十几年研究的热点，由于不同的研究其检测样本、检测方法、样本量等的差异，结论之间存在较大的差异，KRAS基因突变及BRAF基因突变对结直肠癌患者预后的影响尚无定论。本文通过运用Meta分析对以往中国人群的研究结果进行综合定量分析，评价KRAS基因和BRAS基因突变在中国结直肠癌患者预后中的作用。方法：本文通过检索电子数据库PubMed、Web of Science核心合集、Cochrane Library、万方数据库以及中国知网，搜集从建库时间至2015年4月公开发表的相关文献并筛选符合入选要求的临床研究，对入选临床研究的数据进行提取和评估。纳入文献为研究KRAS基因突变或BRAF基因突变与结直肠癌预后相关性的病例对照研究或队列研究，结局指标包括总生存期（Overall Survival, OS）以及无进展生存期（Progression Free Survival, PFS）。本文应用风险比(Hazard Ratio，HR)来评价结局指标，并计算其95%可信区间。采用Stata 12.0进行Meta分析，同时进行发表偏倚分析以及敏感性分析。结果：本篇系统评价共纳入19项研究，共计2938例患者。19篇文献均包含KRAS基因突变相关分析；包含BRAF基因突变分析的文献6篇，共计包含1552例患者。结果显示，KRAS突变型患者有较短的总生存期（HR=1.709，95%CI 1.279-2.285）和无进展生存期（HR=2.363，95%CI 1.242-4.496）。BRAF突变型患者有较短的总生存期（HR=1.900，95%CI 1.536-2.351），BRAF基因突变与结直肠癌患者PFS之间的相关性无统计学意义（HR=1.885，95%CI 0.598-5.942）。结论：KRAS基因和BRAF基因均可能是中国结直肠癌患者预后的危险因素。KRAS基因能增加中国结直肠癌患者的死亡风险和疾病进展风险，BRAF基因能增加中国结直肠癌患者的死亡风险。本研究结论需更多的临床研究加以验证。本系统评价的结论仅供临床研究与实践参考。

关键词：结直肠癌；预后；KRAS；BRAF；Meta分析

THE PROGNOSTIC VALUE Of KRAS MUTATION AND BRAF MUTATION IN COLORECTAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Jiaxuan Liu(41111106)

Supervisor: Bei Wang

Abstract

Objective: The correlation between KRAS mutation as well as BRAF mutation and the prognosis of colorectal cancer patients has been one of the hot research topics. However, due to the differences in research population, testing method and sample size between studies, there has no verdict on this disputable problem. This article derive a more precise estimation of the prognostic significance of KRAS mutation and BRAF mutation by means of meta-analysis. Methods: Clinical studies on the correlation between KRAS mutation or BRAF mutation and the prognosis of colorectal cancer patients were retrieved from PubMed, Web of Science, Cochrane Library, Wan Fang database, CNKI. The latest searching was done at April, 2015. Both case control studies and cohort studies are included. Each study was reviewed and data extracted. Outcome indicators include the overall survival(OS) and progression free survival(PFS). Hazard ration(HR) and 95% credible interval(CI) were used to evaluate the outcomes. The meta-analysis was done by Stata 12.0. Publication bias was assessed with Begg’s test and sensitivity analysis was also done. Results: A total of 19 clinical studies with 2938 patients were qualified to this meta-analysis. All of them were eligible for the analysis of KRAS mutation and 6 of them describing 1552 patients were available for the analysis of BRAF mutation. Patients with KRAS mutation was associated with shorter OS(HR=1.709, 95%CI 1.279-2.285) and PFS(HR=2.363, 95%CI 1.242-4.496). Patients with BRAF mutation was associated with shorter OS(HR=1.900, 95%CI 1.536-2.351). But no significant correlation was found between BRAF mutation and the PFS of colorectal cancer patients. Conclusion: We revealed that both KRAS mutation and BRAF mutation are possible risk factors for patient prognosis in colorectal caner. Patients with KRAS mutation showed increased risks of mortality and patients with BRAF mutation showed increased risks of mortality. More clinical studies need to be performed to prove the conclusion. The conclusion of this systematic review only provides some references for clinical research and practice.

Keywords: Colorectal Cancer; Prognosis; KRAS; BRAF; Meta-analysis

目 录

摘要 ……………………………………………………………………………………Ⅰ

Abstract …………………………………………………………………………… Ⅱ

1. 绪论 ………………………………………………………………………1

1.1 引言 …………………………………………………………………1

1.2 结直肠癌的治疗与EGFR信号通路 ………………………………………1

1.3 KRAS基因突变与结直肠癌的预后 ………………………………………1

1.4 BRAF基因突变与结直肠癌的预后 ………………………………………2

1.5 本文的研究目的和主要研究内容 ………………………………………3

1. 资料与方法 …………………………………………………………………3

2.1 检索策略 …………………………………………………………………3

2.2 文献检索的纳入及排除标准 ………………………………………………3

2.2.1 文献的纳入标准 ……………………………………………………3

2.2.2 文献的排除标准 ……………………………………………………3

2.3 文献筛选及资料提取 ………………………………………………………4

2.4 质量评价 ……………………………………………………………………5

2.5 统计学方法 …………………………………………………………………5

1. 结果 ………………………………………………………………6

3.1 文献检索结果 ………………………………………………………………6

3.2 纳入研究的基本特征 ………………………………………………………7

3.3 KRAS基因突变的预后意义 ……………………………………………10

3.3.1 KRAS基因突变对结直肠癌患者OS的影响 ………………………10

3.3.1.1 异质性分析 ………………………………………………11

3.3.1.2 发表偏倚分析 ………………………………………………12

3.3.1.3 敏感性分析 ………………………………………………13

3.3.2 KRAS基因突变对结直肠癌患者PFS的影响 ………………………14

3.3.2.1 异质性分析 ……………………………………………15

3.3.2.2 发表偏倚分析 ……………………………………………15

3.3.2.3 敏感性分析 ……………………………………………15

3.3.3 KRAS基因第12、13号密码子突变的预后意义 …………………16

3.3.3.1 异质性分析 ……………………………………………17

3.3.3.2 发表偏倚分析 ………………………………………18

3.3.3.3 敏感性分析 ………………………………………………18

3.4 BRAF基因突变的预后意义 …………………………………………19

3.4.1 BRAF基因突变对结直肠癌患者OS的影响 ……………………19

3.4.1.1 异质性分析 ………………………………………………20

3.4.1.2 发表偏倚分析 ……………………………………………20

3.4.1.3 敏感性分析 ……………………………………………20

3.4.2 BRAF基因突变对结直肠癌患者PFS的影响 ………………………21

1. 讨论 …………………………………………………………………………22
2. 结论 …………………………………………………………………………25

参考文献（References） ……………………………………………………………26

致谢 …………………………………………………………………………………29

1. 绪 论

1.1 引言

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