Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China.
Cancer Metastasis Rev. 2018 Mar;37(1):173-187. doi: 10.1007/s10555-017-9726-5.
The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05-1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13-1.47), p53 mutation (combined OR 1.35, 95% CI 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18-1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20-1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.
许多研究已经探讨了关键驱动基因的突变与结直肠癌（CRC）转移之间的关联。然而，这些研究的结果存在矛盾。在这里，我们从 TCGA 数据库中进行了全面的分析，以筛选关键的驱动基因，并验证这些突变在 CRC 转移中的作用。通过生物信息学分析，我们确定了六个关键的驱动基因，即 APC、KRAS、BRAF、PIK3CA、SMAD4 和 p53。通过系统搜索，我们纳入了截至 2017 年 11 月 30 日发表的 120 篇文章，这些文章均表明这些基因突变在 CRC 转移中发挥作用。荟萃分析显示，KRAS 突变（合并 OR 1.18，95%CI 1.05-1.33）和 p53 突变（合并 OR 1.49，95%CI 1.23-1.80）与 CRC 转移相关，包括淋巴转移和远处转移。此外，CRC 患者中 KRAS 突变（合并 OR 1.29，95%CI 1.13-1.47）、p53 突变（合并 OR 1.35，95%CI 1.06-1.72）或 SMAD4 突变（合并 OR 2.04，95%CI 1.41-2.95）发生远处转移的风险更高。按种族人群进行的亚组分析表明，BRAF 突变与 CRC 转移（合并 OR 1.42，95%CI 1.18-1.71）和远处转移（合并 OR 1.51，95%CI 1.20-1.91）相关亚洲人群。APC 或 PIK3CA 突变与 CRC 转移之间无显著相关性。总之，KRAS、p53、SMAD4 和 BRAF 的突变在 CRC 转移中发挥重要作用，它们可能是 CRC 转移的潜在生物标志物和治疗靶点。
