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Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

2014; Nature Portfolio; Volume: 46; Issue: 7 Linguagem: Inglês

10.1038/ng.3002

1546-1718

Yufei Wang, James McKay, Þórunn Rafnar, Zhaoming Wang, Maria Timofeeva, Peter Broderick, Xuchen Zong, Marina Laplana, Yongyue Wei, Younghun Han, Amy Lloyd, Manon Delahaye-Sourdeix, Daniel Chubb, Valérie Gaborieau, William Wheeler, Nilanjan Chatterjee, Guðmar Þorleifsson, Patrick Sulem, Geoffrey Liu, Rudolf Kaaks, Marc Henrion, Ben Kinnersley, Maxime Vallée, Florence Le Calvez‐Kelm, Victoria L. Stevens, Susan M. Gapstur, Wei V. Chen, Давид Заридзе, Neonilia Szeszenia‐Dabrowska, Jolanta Lissowska, Péter Rudnai, Eleonóra Fabiánová, Dana Mateș, Vladimír Bencko, Lenka Foretová, Vladimí­r Janout, Hans E. Krokan, Maiken E. Gabrielsen, Frank Skorpen, Lars J. Vatten, Inger Njølstad, Chu Chen, Gary E. Goodman, Simone Benhamou, Tõnu Vooder, Kristjan Välk, Mari Nelis, Andres Metspalu, Marcin Lener, Jan Lubiński, Mattias Johansson, Paolo Vineis, Antonio Agudo, Françoise Clavel‐Chapelon, H. Bas Bueno‐de‐Mesquita, Dimitrios Trichopoulos, Kay‐Tee Khaw, Mikael Johansson, Elisabete Weiderpass, Anne Tjønneland, Elio Ríboli, Mark Lathrop, Ghislaine Scélo, Demetrius Albanes, Neil E. Caporaso, Yuanqing Ye, Jian Gu, Xifeng Wu, Margaret R. Spitz, Hendrik Dienemann, Albert Rosenberger, Li Su, Athena Matakidou, Timothy Eisen, Kāri Stefánsson, Angela Risch, Stephen J. Chanock, David C. Christiani, Rayjean J. Hung, Paul Brennan, Maria Teresa Landi, Richard S. Houlston, Christopher I. Amos,

Genetic factors in colorectal cancer

Richard Houlston, Maria Teresa Landi and colleagues report the identification of large-effect associations for squamous lung cancer with rare variants in BRCA2 and CHEK2. 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.