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

ABSTRACT: 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.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC4074058 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Wang Yufei Y   McKay James D JD   Rafnar Thorunn T   Wang Zhaoming Z   Timofeeva Maria N MN   Broderick Peter P   Zong Xuchen X   Laplana Marina M   Wei Yongyue Y   Han Younghun Y   Lloyd Amy A   Delahaye-Sourdeix Manon M   Chubb Daniel D   Gaborieau Valerie V   Wheeler William W   Chatterjee Nilanjan N   Thorleifsson Gudmar G   Sulem Patrick P   Liu Geoffrey G   Kaaks Rudolf R   Henrion Marc M   Kinnersley Ben B   Vallée Maxime M   LeCalvez-Kelm Florence F   Stevens Victoria L VL   Gapstur Susan M SM   Chen Wei V WV   Zaridze David D   Szeszenia-Dabrowska Neonilia N   Lissowska Jolanta J   Rudnai Peter P   Fabianova Eleonora E   Mates Dana D   Bencko Vladimir V   Foretova Lenka L   Janout Vladimir V   Krokan Hans E HE   Gabrielsen Maiken Elvestad ME   Skorpen Frank F   Vatten Lars L   Njølstad Inger I   Chen Chu C   Goodman Gary G   Benhamou Simone S   Vooder Tonu T   Välk Kristjan K   Nelis Mari M   Metspalu Andres A   Lener Marcin M   Lubiński Jan J   Johansson Mattias M   Vineis Paolo P   Agudo Antonio A   Clavel-Chapelon Francoise F   Bueno-de-Mesquita H Bas HB   Trichopoulos Dimitrios D   Khaw Kay-Tee KT   Johansson Mikael M   Weiderpass Elisabete E   Tjønneland Anne A   Riboli Elio E   Lathrop Mark M   Scelo Ghislaine G   Albanes Demetrius D   Caporaso Neil E NE   Ye Yuanqing Y   Gu Jian J   Wu Xifeng X   Spitz Margaret R MR   Dienemann Hendrik H   Rosenberger Albert A   Su Li L   Matakidou Athena A   Eisen Timothy T   Stefansson Kari K   Risch Angela A   Chanock Stephen J SJ   Christiani David C DC   Hung Rayjean J RJ   Brennan Paul P   Landi Maria Teresa MT   Houlston Richard S RS   Amos Christopher I CI  

Nature genetics 20140601 7

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 al  ...[more]

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