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

Wang Y1, McKay JD2, Rafnar T3, Wang Z4, Timofeeva MN5, Broderick P6, Zong X7, Laplana M8, Wei Y9, Han Y10, Lloyd A6, Delahaye-Sourdeix M5, Chubb D6,Gaborieau V5, Wheeler W11, Chatterjee N4, Thorleifsson G3, Sulem P3, Liu G12, Kaaks R13, Henrion M6, Kinnersley B6, Vallée M5, LeCalvez-Kelm F5, Stevens VL14, Gapstur SM14, Chen WV15, Zaridze D16, Szeszenia-Dabrowska N17, Lissowska J18, Rudnai P19, Fabianova E20, Mates D21, Bencko V22, Foretova L23,Janout V24, Krokan HE25, Gabrielsen ME25, Skorpen F26, Vatten L27, Njølstad I28, Chen C29, Goodman G29, Benhamou S30, Vooder T31, Välk K32, Nelis M33,Metspalu A34, Lener M35, Lubiński J35, Johansson M5, Vineis P36, Agudo A37, Clavel-Chapelon F38, Bueno-de-Mesquita HB39, Trichopoulos D40, Khaw KT41,Johansson M42, Weiderpass E43, Tjønneland A44, Riboli E45, Lathrop M46, Scelo G5, Albanes D4, Caporaso NE4, Ye Y47, Gu J47, Wu X47, Spitz MR48,Dienemann H49, Rosenberger A50, Su L9, Matakidou A51, Eisen T52, Stefansson K3, Risch A53, Chanock SJ4, Christiani DC9, Hung RJ7, Brennan P5, Landi MT54, Houlston RS55, Amos CI56.

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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.