Wang Yufei, McKay James D, Rafnar Thorunn, Wang Zhaoming, Timofeeva Maria N, Broderick Peter, Zong Xuchen, Laplana Marina, Wei Yongyue, Han Younghun, Lloyd Amy, Delahaye-Sourdeix Manon, Chubb Daniel, Gaborieau Valerie, Wheeler William, Chatterjee Nilanjan, Thorleifsson Gudmar, Sulem Patrick, Liu Geoffrey, Kaaks Rudolf, Henrion Marc, Kinnersley Ben, Vallée Maxime, LeCalvez-Kelm Florence, Stevens Victoria L, Gapstur Susan M, Chen Wei V, Zaridze David, Szeszenia-Dabrowska Neonilia, Lissowska Jolanta, Rudnai Peter, Fabianova Eleonora, Mates Dana, Bencko Vladimir, Foretova Lenka, Janout Vladimir, Krokan Hans E, Gabrielsen Maiken Elvestad, Skorpen Frank, Vatten Lars, Njølstad Inger, Chen Chu, Goodman Gary, Benhamou Simone, Vooder Tonu, Välk Kristjan, Nelis Mari, Metspalu Andres, Lener Marcin, Lubiński Jan, Johansson Mattias, Vineis Paolo, Agudo Antonio, Clavel-Chapelon Francoise, Bueno-de-Mesquita H Bas, Trichopoulos Dimitrios, Khaw Kay-Tee, Johansson Mikael, Weiderpass Elisabete, Tjønneland Anne, Riboli Elio, Lathrop Mark, Scelo Ghislaine, Albanes Demetrius, Caporaso Neil E, Ye Yuanqing, Gu Jian, Wu Xifeng, Spitz Margaret R, Dienemann Hendrik, Rosenberger Albert, Su Li, Matakidou Athena, Eisen Timothy, Stefansson Kari, Risch Angela, Chanock Stephen J, Christiani David C, Hung Rayjean J, Brennan Paul, Landi Maria Teresa, Houlston Richard S, Amos Christopher I
1] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK. [2].
1] International Agency for Research on Cancer (IARC, World Health Organization (WHO)), Lyon, France. [2] [3].
Nat Genet. 2014 Jul;46(7):736-41. doi: 10.1038/ng.3002. Epub 2014 Jun 1.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
我们对欧洲血统人群中四项肺癌全基因组关联研究（11348例病例和15861例对照）的数据进行了推算，推算至千人基因组计划，另外对10246例病例和38295例对照进行基因分型以作后续研究。我们发现，对于肺鳞癌，罕见变异BRCA2 p.Lys3326X（rs11571833，优势比（OR）=2.47，P=4.74×10⁻²⁰）和CHEK2 p.Ile157Thr（rs17879961，OR=0.38，P=1.27×10⁻¹³）存在全基因组范围的大效应关联。我们还发现，3q28（TP63，rs13314271，OR=1.13，P=7.22×10⁻¹⁰）的常见变异与肺腺癌之间存在关联，此前该关联仅在亚洲人中报道过。这些发现为肺癌的遗传易感性及其生物学基础提供了进一步证据。此外，我们的分析表明，推算能够从现有的全基因组关联研究数据中识别出对癌症风险有实质性影响的罕见致病变异。
