Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Sci Rep. 2017 Dec 19;7(1):17814. doi: 10.1038/s41598-017-18165-5.
EGFR-TKIs show dramatic treatment benefits for advanced lung adenocarcinoma patients with activating EGFR mutations. Considering the essential role of autophagy in EGFR-TKIs treatments, we hypothesized that genetic variants in autophagy core genes might contribute to outcomes of advanced lung adenocarcinoma treated with gefitinib. We systematically examined 27 potentially functional genetic polymorphisms in 11 autophagy core genes among 108 gefitinib-treated advanced lung adenocarcinoma patients. We found that ATG10 rs10036653, ATG12 rs26538, ATG16L1 rs2241880 and ATG16L2 rs11235604 were significantly associated with survival of lung adenocarcinoma patients (all P < 0.05). Among EGFR-mutant patients, ATG5 rs688810, ATG5 rs510432, ATG7 rs8154, ATG10 rs10036653, ATG12 rs26538, ATG16L1 rs2241880 and ATG16L2 rs11235604 significantly contributed to disease prognosis. We also found that ATG5 rs510432, ATG5 rs688810, ATG10 rs10036653 and ATG10 rs1864182 were associated with primary or acquired resistance to gefitinib. Functional analyses of ATG10 rs10036653 polymorphism suggested that ATG10 A allele might increase transcription factor OCT4 binding affinity compared to the T allele in lung cancer cells. Our results indicate that autophagy core genetic variants show potential clinical implications in gefitinib treatment, especially among advanced lung adenocarcinoma patients, highlighting the possibility of patient-tailored decisions during EGFR-TKIs based on both germline and somatic variation detection.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）为携带 EGFR 激活突变的晚期肺腺癌患者带来了显著的治疗获益。鉴于自噬在 EGFR-TKIs 治疗中的重要作用，我们假设自噬核心基因中的遗传变异可能会影响吉非替尼治疗晚期肺腺癌的疗效。我们系统地检测了 108 例接受吉非替尼治疗的晚期肺腺癌患者中 11 个自噬核心基因中的 27 个潜在功能遗传多态性。我们发现 ATG10 rs10036653、ATG12 rs26538、ATG16L1 rs2241880 和 ATG16L2 rs11235604 与肺腺癌患者的生存显著相关（均 P<0.05）。在 EGFR 突变型患者中，ATG5 rs688810、ATG5 rs510432、ATG7 rs8154、ATG10 rs10036653、ATG12 rs26538、ATG16L1 rs2241880 和 ATG16L2 rs11235604 对疾病预后有显著影响。我们还发现 ATG5 rs510432、ATG5 rs688810、ATG10 rs10036653 和 ATG10 rs1864182 与吉非替尼的原发性或获得性耐药相关。ATG10 rs10036653 多态性的功能分析表明，与 T 等位基因相比，肺癌细胞中 ATG10 A 等位基因可能增加转录因子 OCT4 的结合亲和力。我们的研究结果表明，自噬核心遗传变异在吉非替尼治疗中具有潜在的临床意义，特别是在晚期肺腺癌患者中，这突出了基于种系和体细胞变异检测在 EGFR-TKIs 治疗中为患者量身定制决策的可能性。
