遗传 ›› 2017, Vol. 39 ›› Issue (3): 250-262.doi: 10.16288/j.yczz.16-294

• 研究报告 • 上一篇    

自噬通路基因多态性与晚期非小细胞肺癌含铂化疗疗效的相关性分析

王诗铭1, 宋晓1,2, 赵雪莹1,3, 陈红岩1, 王久存1, 吴俊杰1,6, 高志强4, 钱吉1, 白春学5, 李强6, 韩宝惠4, 卢大儒1   

  1. 1. 复旦大学生命科学学院,遗传工程国家重点实验室,上海 200438;
    2. 同济大学附属肺科医院,上海200433;
    3. 上海市刑事科学技术研究院,上海 200063;
    4. 上海交通大学附属胸科医院,上海 200030;
    5. 复旦大学附属中山医院,上海 200032;
    6. 第二军医大学附属长海医院,上海 200433
  • 收稿日期:2016-08-29 修回日期:2016-09-06 出版日期:2017-03-20 发布日期:2016-11-15
  • 通讯作者: 卢大儒,博士,教授,研究方向：人类与医学分子遗传学。E-mail: drlu@fudan.edu.cn
  • 作者简介:王诗铭,博士研究生,专业方向：人类与医学分子遗传学。E-mail: wangshiming@fudan.edu.cn
  • 基金资助:
    国家自然科学基金项目(编号：81372235,31571371)和国家高技术研究发展计划(863计划)项目(编号：2012AA02A518) 资助

Association between polymorphisms of autophagy pathway and responses in non-small cell lung cancer patients treated with platinum-based chemotherapy

Wang Shiming1, Song Xiao1,2, Zhao Xueying1,3, Chen Hongyan1, Wang Jiucun1, Wu Junjie1, 6, Gao Zhiqiang4, Qian Ji1, Bai Chunxue5, Li Qiang6, Han Baohui4, Lu Daru1   

  1. 1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438, China;
    2. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China;
    3. Shanghai Key Laboratory of Crime Scene Evidence, Shanghai Research Institute of Criminal Science and Technology, Shanghai 200063, China;
    4. Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China;
    5. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
    6. Department of Pneumology, Changhai Hospital of Shanghai, Second Military Medical University, Shanghai 200433, China
  • Received:2016-08-29 Revised:2016-09-06 Online:2017-03-20 Published:2016-11-15
  • Supported by:
    Supported by the National Natural Science Foundation of China (Nos; 81372235, 31571371), and the National High Technology Research and Development Program( 863 Program) of China (No; 2012AA02A518)

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摘要： 对晚期非小细胞肺癌患者采用含铂化疗是肺癌临床治疗中非常重要的方法,然而不同患者对含铂化疗的敏感性却存在着明显的个体差异,这提示发现潜在的分子标志物对预测临床中含铂化疗疗效具有关键作用。本研究旨在探索自噬通路基因多态性与晚期非小细胞肺癌含铂化疗疗效之间的相关性,以期寻找可能影响含铂化疗药物敏感性的分子标记。本研究纳入了1004例接受含铂化疗的晚期非小细胞肺癌患者,分析了自噬通路中13个基因上的99个SNP位点与含铂化疗临床获益、无疾病进展时间及总生存时间之间的相关性。研究发现,位于ULK1基因的位点rs7953348(G>A) (P=0.017, OR:0.67, 95%CI:0.49~0.93)和rs12303764(A>C) (P=0.009, OR:0.63, 95%CI:0.45-0.89)及位于ATG14基因上的位点rs17742719(C>A) (P=0.002, OR:1.83, 95%CI:1.26~2.66)、rs8003279(A>G) (P=0.006, OR:1.65, 95%CI:1.16~2.35)和rs1009647(G>A) (P=0.002, OR:1.70, 95%CI:1.22~2.37)与临床获益存在显著关联,位于DRAM基因上的位点rs7955890(G>A) (P=0.004, HR:0.63; 95%CI:0.46~0.86)和rs17032060(G>A) (P=0.006, HR:0.65, 95%CI:0.48~0.88)及位于ATG3基因上的位点rs13082005(G>A) (P=0.012, HR:1.27,95%CI:1.05~1.53)与含铂化疗的无疾病进展时间显著相关,位于ULK1基因的位点rs7953348(G>A) (P=0.011, HR:0.74, 95%CI:0.58~0.93)和位于ATG10基因上的位点rs1864183(G>A) (P=0.016, HR:0.42, 95%CI:0.21~0.85)对含铂化疗的总生存时间有着显著影响。研究结果提示自噬通路在含铂化疗敏感性中发挥着重要作用,自噬通路基因多态性可能是预测含铂化疗疗效的潜在分子标志物,这可能为临床上肺癌的个体化医疗提供一定的理论基础。

关键词: 自噬, 基因多态性, 含铂化疗, 非小细胞肺癌

Abstract: Platinum-based chemotherapy is an important treatment for non-small cell lung cancer. However, the effectiveness of the treatment varies among the patients. We investigated the association between DNA polymorphisms of the autophagy pathway and responses of such treatment among 1004 Chinese patients. Ninety-nine SNPs located on 13 genes of the autophagy pathway were genotyped and assessed for their association with clinical benefit, progression-free survival (PFS) and overall survival (OS). The results showed that rs7953348 (G>A) (P=0.017, OR: 0.67, 95%CI: 0.49-0.93) and rs12303764 (A>C) (P=0.009, OR: 0.63, 95%CI: 0.45-0.89) at the ULK1 gene, and rs17742719 (C>A) (P=0.002, OR: 1.83, 95%CI: 1.26-2.66), rs8003279 (A>G) (P=0.006, OR: 1.65, 95%CI: 1.16~2.35) and rs1009647 (G>A) (P=0.002, OR: 1.70, 95%CI: 1.22-2.37) at the ATG14 gene were associated with clinical benefit. Polymorphisms at rs7955890 (G>A) (P=0.004, HR: 0.63; 95%CI: 0.46-0.86) and rs17032060 (G>A) (P=0.006, HR: 0.65, 95%CI: 0.48-0.88) at the DRAM gene, and rs13082005 (G>A) (P=0.012, HR: 1.27, 95%CI: 1.05-1.53) at the ATG3 gene were significantly associated with PFS. We also found that rs7953348 (G>A) (P=0.011, HR: 0.74, 95%CI: 0.58-0.93) at the ULK1 gene and rs1864183 (G>A) (P=0.016, HR: 0.42, 95%CI: 0.21-0.85) at the ATG10 gene were associated with OS. Thus, the study demonstrated that the autophagy pathway might play important role(s) in platinum-based chemotherapy. DNA polymorphisms in its component genes can potentially be predictors for clinical responses of platinum-based chemotherapy among the patients with non-small lung cancer.

Key words: autophagy, polymorphism, platinum-based chemotherapy, non-small cell lung cancer

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