中文摘要：

目的：探索EGFR单抗治疗转移性结直肠癌患者耐药性相关基因。方法：选取2012年3月至2013年8月在北京肿瘤医院接受EGFR单抗治疗的31例转移性结直肠癌患者,利用二代测序技术检测肿瘤组织中与肿瘤发生、发展和EGFR信号传导通路相关的21个基因,分析其与EGFR单抗疗效的关系。结果：Kras基因外显子2为野生型的晚期结直肠癌的患者31例,接受EGFR单抗单药三线治疗。全组患者中位PFS为89 d,OS为311 d,ORR为16.1%。5例存在Kras第3、4外显子或者Nras第2、3外显子突变,均出现首次疗效评估PD（中位PFS 31d）。其他突变包括1例PIK3CA突变,PFS为35 d。1例m TOR突变,PFS为91 d。2例患者存在SMAD4突变,PFS分别是58d及59d。1例FBXW7突变,PFS为93d。在26例全Ras基因野生型患者中MLL3、TP53、APC是突变频率最高的3个基因。MLL3突变比例为92.3%（24/26）,TP53为53.8%（14/26）,APC为42.3%（11/26）。结论：进行EGFR单抗治疗前必须进行Kras及Nras第2、3、4外显子的检测,EGFR通路下游信号分子,如PI3KCA、mTOR等可能在EGFR单抗疗效上起一定预测作用,针对EGFR外的其他信号通路分子如SMAD4、FBXW7等,需要进一步关注。

英文摘要：

Objective： To explore genes associated with sensitivity to anti-EGFR therapy. Methods： From March 2012 to August 2013,31 metastatic colorectal cancer patients in Peking University Cancer Hospital Institute were treated with anti-EGFR mono-therapy. A total of 21 genes associated with oncogenesis, metastasis, and EGFR signaling pathway were profiled in these 31 patients by using targeted next-generation sequencing technology. Results： A total of 31 patients with Kras exon 2 wild-type received anti-EGFR therapy as third-line treatment. Among these patients, the median progression-free survival（PFS） was 89 days, overall survival was 311 days, and objective response rate was 16.1%. Five cases harbored Kras exons 3/4 or Nras exons 2/3 mutations. These five Ras mutation patients showed disease progression during the first evaluation with 31-day PFS. One PIK3 CA mutation case exhibited disease progression during the first evaluation（PFS 35 days）, and one case showed m TOR mutation with 91-day PFS. The PFS of two cases with SMAD4 mutation were 58 and 59 days, whereas that of the case containing FBXW7 mutation was 93 days. Among the 26 Ras wild- type patients,MLL3, TP53, and APC were the three genes with the highest mutation frequencies of 92.3%（24/26）, 53.8%（14/26）, and 42.3%（11/26）, respectively. Conclusion： Extended Ras analysis（including Kras and Nras exons 2/3/4） is recommended for patients who are candidates for anti-EGFR therapy. Mutations in the downstream effectors of the EGFR signaling pathway, such as PI3 KCA and m TOR, may also have a predictive role in anti- EGFR therapy. Mutations beyond the EGFR pathway such as FBXW7 and SMAD4 may be associated with anti-EGFR efficacy and deserve further attention.