Targeted deep sequencing reveals <i>APC</i> mutations as predictors of overall survival in Chinese colorectal patients receiving adjuvant chemotherapy

<b>Objective:</b> Targeted deep sequencing was used to characterize the mutational spectrum of <i>APC</i> in Chinese colorectal tumors in comparison to that in Caucasians from The Cancer Genome Atlas (TCGA) and to investigate whether <i>APC</i> mutations can predict overall survival in CRC patients receiving adjuvant chemotherapy. <b>Methods:</b> A total of 315 Chinese CRC patients including 241 stage II/III patients receiving fluorouracil-based adjuvant chemotherapy were included in this study. Next generation sequencing was carried out to detect somatic mutations on all <i>APC</i> exons. The associations between <i>APC</i> mutations and overall survival were determined by the Cox proportional hazards model. <b>Results:</b><i>APC</i> was mutated in 221 of 315 colorectal tumors (70.2%). Chinese CRC had a much higher frequency of missense mutations (16.2% vs. 2.4%), but a lower frequency of nonsense (41.0% vs. 54.2%) and frameshift mutations (10.5% vs. 18.4%) than Caucasian CRC. Among stage II/III patients receiving fluorouracil-based adjuvant chemotherapy, <i>APC</i> mutations showed a significant association with worse survival (HR = 1.69; 95% CI, 1.10-2.62; <i>p</i> = .0179). Of the mutation types, frameshift mutations conferred the highest risk of death (HR = 2.88; 95% CI, 1.54-5.37; <i>p</i> =.0009). Among individual mutation sites, Arg232Ter, the most frequent mutation in Chinese CRC, exhibited the strongest negative impact on survival (HR = 2.65; 95% CI, 1.16-6.03; <i>p</i> =.0202). <b>Conclusion:</b><i>APC</i> overall mutation was an independent predictor for overall survival of stage II/III CRC patients receiving fluorouracil-based chemotherapy.**研究目的**：采用靶向深度测序技术，对中国人群结直肠肿瘤中<i>APC</i>基因的突变谱进行特征分析，并与癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中高加索人群的结直肠肿瘤突变谱进行对比；同时探讨<i>APC</i>突变能否预测接受辅助化疗的结直肠癌（Colorectal Cancer, CRC）患者的总生存期。 **研究方法**：本研究共纳入315例中国CRC患者，其中241例为接受基于氟尿嘧啶辅助化疗的II/III期患者。采用下一代测序技术检测<i>APC</i>基因所有外显子区域的体细胞突变。通过Cox比例风险模型分析<i>APC</i>突变与总生存期之间的关联。 **研究结果**：315例结直肠肿瘤中，221例检出<i>APC</i>突变（检出率70.2%）。与高加索人群CRC相比，中国CRC患者的错义突变频率显著更高（16.2% vs. 2.4%），而无义突变（41.0% vs. 54.2%）与移码突变（10.5% vs. 18.4%）的频率更低。在接受基于氟尿嘧啶辅助化疗的II/III期患者中，<i>APC</i>突变与较差的总生存期显著相关（风险比HR=1.69；95%置信区间CI：1.10~2.62；P=0.0179）。在各类突变亚型中，移码突变对应的死亡风险最高（HR=2.88；95%CI：1.54~5.37；P=0.0009）。在单个突变位点中，中国CRC患者中最常见的Arg232Ter突变对生存期的负面影响最强（HR=2.65；95%CI：1.16~6.03；P=0.0202）。 **研究结论**：<i>APC</i>整体突变可作为接受基于氟尿嘧啶化疗的II/III期CRC患者总生存期的独立预测因子。