The Prognostic Value of BRAF Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis

BackgroundMutation of BRAF is a predominant event in cancers with poor prognosis such as melanoma and colorectal cancer. BRAF mutation leads to a constitutive activation of mitogen activated protein kinase pathway which is essential for cell proliferation and tumor progression. Despite tremendous efforts made to target BRAF for cancer treatment, the correlation between BRAF mutation and patient survival is still a matter of controversy. Methods/Principal FindingsClinical studies on the correlation between BRAF mutation and patient survival were retrieved from MEDLINE and EMBASE databases between June 2002 and December 2011. One hundred twenty relevant full text studies were categorized based on study design and cancer type. Publication bias was evaluated for each category and pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using random or fixed effect meta-analysis based on the percentage of heterogeneity. Twenty six studies on colorectal cancer (11,773 patients) and four studies on melanoma (674 patients) were included in our final meta-analysis. The average prevalence of BRAF mutation was 9.6% in colorectal cancer, and 47.8% in melanoma reports. We found that BRAF mutation increases the risk of mortality in colorectal cancer patients for more than two times; HR = 2.25 (95% CI, 1.82–2.83). In addition, we revealed that BRAF mutation also increases the risk of mortality in melanoma patients by 1.7 times (95% CI, 1.37–2.12). ConclusionsWe revealed that BRAF mutation is an absolute risk factor for patient survival in colorectal cancer and melanoma.

BRAF基因突变是黑色素瘤、结直肠癌等预后不良癌症的主要驱动事件。BRAF突变可导致丝裂原活化蛋白激酶（mitogen activated protein kinase）通路持续激活，而该通路对细胞增殖与肿瘤进展至关重要。尽管学界已在BRAF靶向癌症治疗领域投入大量研究，但BRAF突变与患者生存预后的相关性仍存在争议。

研究方法与主要结果 本研究于2002年6月至2011年12月期间，从MEDLINE与EMBASE数据库中检索有关BRAF突变与患者生存预后相关性的临床研究。最终筛选得到120篇符合纳入标准的全文文献，并根据研究设计与癌症类型进行分类。针对每一类研究评估发表偏倚，并基于异质性百分比采用随机效应模型或固定效应模型进行荟萃分析，计算合并风险比（hazard ratio, HR）及95%置信区间（confidence interval, CI）。本研究最终纳入26项结直肠癌相关研究（共11773例患者）与4项黑色素瘤相关研究（共674例患者）。结直肠癌样本中BRAF突变的平均检出率为9.6%，黑色素瘤样本中则为47.8%。分析结果显示，BRAF突变可使结直肠癌患者的死亡风险升高两倍以上，合并HR=2.25（95%CI：1.82~2.83）；此外，BRAF突变也可使黑色素瘤患者的死亡风险升高1.7倍（95%CI：1.37~2.12）。

研究结论 本研究证实，BRAF突变是结直肠癌与黑色素瘤患者生存预后的独立危险因素。