大规模关联分析确定了新的肺癌易感位点以及不同组织学亚型遗传易感性的异质性。
Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.
作者信息
McKay James D, Hung Rayjean J, Han Younghun, Zong Xuchen, Carreras-Torres Robert, Christiani David C, Caporaso Neil E, Johansson Mattias, Xiao Xiangjun, Li Yafang, Byun Jinyoung, Dunning Alison, Pooley Karen A, Qian David C, Ji Xuemei, Liu Geoffrey, Timofeeva Maria N, Bojesen Stig E, Wu Xifeng, Le Marchand Loic, Albanes Demetrios, Bickeböller Heike, Aldrich Melinda C, Bush William S, Tardon Adonina, Rennert Gad, Teare M Dawn, Field John K, Kiemeney Lambertus A, Lazarus Philip, Haugen Aage, Lam Stephen, Schabath Matthew B, Andrew Angeline S, Shen Hongbing, Hong Yun-Chul, Yuan Jian-Min, Bertazzi Pier Alberto, Pesatori Angela C, Ye Yuanqing, Diao Nancy, Su Li, Zhang Ruyang, Brhane Yonathan, Leighl Natasha, Johansen Jakob S, Mellemgaard Anders, Saliba Walid, Haiman Christopher A, Wilkens Lynne R, Fernandez-Somoano Ana, Fernandez-Tardon Guillermo, van der Heijden Henricus F M, Kim Jin Hee, Dai Juncheng, Hu Zhibin, Davies Michael P A, Marcus Michael W, Brunnström Hans, Manjer Jonas, Melander Olle, Muller David C, Overvad Kim, Trichopoulou Antonia, Tumino Rosario, Doherty Jennifer A, Barnett Matt P, Chen Chu, Goodman Gary E, Cox Angela, Taylor Fiona, Woll Penella, Brüske Irene, Wichmann H-Erich, Manz Judith, Muley Thomas R, Risch Angela, Rosenberger Albert, Grankvist Kjell, Johansson Mikael, Shepherd Frances A, Tsao Ming-Sound, Arnold Susanne M, Haura Eric B, Bolca Ciprian, Holcatova Ivana, Janout Vladimir, Kontic Milica, Lissowska Jolanta, Mukeria Anush, Ognjanovic Simona, Orlowski Tadeusz M, Scelo Ghislaine, Swiatkowska Beata, Zaridze David, Bakke Per, Skaug Vidar, Zienolddiny Shanbeh, Duell Eric J, Butler Lesley M, Koh Woon-Puay, Gao Yu-Tang, Houlston Richard S, McLaughlin John, Stevens Victoria L, Joubert Philippe, Lamontagne Maxime, Nickle David C, Obeidat Ma'en, Timens Wim, Zhu Bin, Song Lei, Kachuri Linda, Artigas María Soler, Tobin Martin D, Wain Louise V, Rafnar Thorunn, Thorgeirsson Thorgeir E, Reginsson Gunnar W, Stefansson Kari, Hancock Dana B, Bierut Laura J, Spitz Margaret R, Gaddis Nathan C, Lutz Sharon M, Gu Fangyi, Johnson Eric O, Kamal Ahsan, Pikielny Claudio, Zhu Dakai, Lindströem Sara, Jiang Xia, Tyndale Rachel F, Chenevix-Trench Georgia, Beesley Jonathan, Bossé Yohan, Chanock Stephen, Brennan Paul, Landi Maria Teresa, Amos Christopher I
机构信息
International Agency for Research on Cancer, World Health Organization, Lyon, France.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, Ontario, Canada.
出版信息
Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
尽管已经确定了几个肺癌易感基因座，但肺癌的大部分遗传力仍无法解释。在此，对14803例欧洲血统的病例和12262例对照进行了OncoArray基因分型，并与现有数据相结合，对29266例病例和56450例对照进行了肺癌全基因组关联研究（GWAS）汇总分析。我们确定了18个达到全基因组显著性的易感基因座，其中包括10个新基因座。这些新基因座凸显了肺癌不同组织学亚型在遗传易感性方面的显著异质性，其中4个基因座与总体肺癌相关，6个基因座与肺腺癌相关。对1425份正常肺组织样本进行的基因表达定量性状基因座（eQTL）分析表明，RNASET2、SECISBP2L和NRG1为候选基因。其他基因座包括诸如胆碱能烟碱受体CHRNA2以及端粒相关基因OFBC1和RTEL1等基因。对这些靶基因的进一步探索将继续为肺癌的病因学提供新的见解。
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