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

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

doi:10.1038/ng.3002

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

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

Research output: Contribution to journal › Article › peer-review

367 Citations (Scopus)

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 â ̂'20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10 â ̂'13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10 â ̂'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.

Original language	English
Pages (from-to)	736-741
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	7
DOIs	https://doi.org/10.1038/ng.3002
Publication status	Published - 1 Jan 2014
Externally published	Yes

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10.1038/ng.3002

367 Citations
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Corrigendum: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer
Wang, Y., McKay, J. D., Rafnar, T., Wang, Z., Timofeeva, M. N., Broderick, P., Zong, X., Laplana, M., Wei, Y., Han, Y., Lloyd, A., Delahaye-Sourdeix, M., Chubb, D., Gaborieau, V., Wheeler, W., Chatterjee, N., Thorleifsson, G., Sulem, P., Liu, G. & Kaaks, R. & 63 others, Henrion, M., Kinnersley, B., Vallée, M., Le Calvez-Kelm, F., Stevens, V. L., Gapstur, S. M., Chen, W. V., Zaridze, D., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Krokan, H. E., Gabrielsen, M. E., Skorpen, F., Vatten, L., Njølstad, I., Chen, C., Goodman, G., Benhamou, S., Vooder, T., Välk, K., Nelis, M., Metspalu, A., Lener, M., Lubiński, J., Johansson, M., Vineis, P., Agudo, A., Clavel-Chapelon, F., Bueno-De-Mesquita, H. B., Trichopoulos, D., Khaw, K. T., Johansson, M., Weiderpass, E., Tjønneland, A., Riboli, E., Lathrop, M., Scelo, G., Albanes, D., Caporaso, N. E., Ye, Y., Gu, J., Wu, X., Spitz, M. R., Dienemann, H., Rosenberger, A., Su, L., Matakidou, A., Eisen, T., Stefansson, K., Risch, A., Chanock, S. J., Christiani, D. C., Hung, R. J., Brennan, P., Landi, M. T., Houlston, R. S. & Amos, C. I., 30 Mar 2017, 1 p.
Research output: Other contribution

Open Access
8 Citations (Scopus)

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Wang, Y., McKay, J. D., Rafnar, T., Wang, Z., Timofeeva, M. N., Broderick, P., Zong, X., Laplana, M., Wei, Y., Han, Y., Lloyd, A., Delahaye-Sourdeix, M., Chubb, D., Gaborieau, V., Wheeler, W., Chatterjee, N., Thorleifsson, G., Sulem, P., Liu, G., ... Amos, C. I. (2014). Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nature Genetics, 46(7), 736-741. https://doi.org/10.1038/ng.3002

@article{e5f55c28a3164305888f751ed383c86a,

title = "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 {\^a}{\^ }'20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10 {\^a}{\^ }'13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10 {\^a}{\^ }'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.",

author = "Yufei Wang and McKay, \{James D.\} and Thorunn Rafnar and Zhaoming Wang and Timofeeva, \{Maria N.\} and Peter Broderick and Xuchen Zong and Marina Laplana and Yongyue Wei and Younghun Han and Amy Lloyd and Manon Delahaye-Sourdeix and Daniel Chubb and Valerie Gaborieau and William Wheeler and Nilanjan Chatterjee and Gudmar Thorleifsson and Patrick Sulem and Geoffrey Liu and Rudolf Kaaks and Marc Henrion and Ben Kinnersley and Maxime Vall{\'e}e and Florence Lecalvez-Kelm and Stevens, \{Victoria L.\} and Gapstur, \{Susan M.\} and Chen, \{Wei V.\} and David Zaridze and Neonilia Szeszenia-Dabrowska and Jolanta Lissowska and Peter Rudnai and Eleonora Fabianova and Dana Mates and Vladimir Bencko and Lenka Foretova and Vladimir Janout and Krokan, \{Hans E.\} and Gabrielsen, \{Maiken Elvestad\} and Frank Skorpen and Lars Vatten and Inger Nj{\o}lstad and Chu Chen and Gary Goodman and Simone Benhamou and Tonu Vooder and Kristjan V{\"a}lk and Mari Nelis and Andres Metspalu and Marcin Lener and Jan Lubi{\'n}ski and Mattias Johansson and Paolo Vineis and Antonio Agudo and Francoise Clavel-Chapelon and Bueno-De-Mesquita, \{H. Bas\} and Dimitrios Trichopoulos and Khaw, \{Kay Tee\} and Mikael Johansson and Elisabete Weiderpass and Anne Tj{\o}nneland and Elio Riboli and Mark Lathrop and Ghislaine Scelo and Demetrius Albanes and Caporaso, \{Neil E.\} and Yuanqing Ye and Jian Gu and Xifeng Wu and Spitz, \{Margaret R.\} and Hendrik Dienemann and Albert Rosenberger and Li Su and Athena Matakidou and Timothy Eisen and Kari Stefansson and Angela Risch and Chanock, \{Stephen J.\} and Christiani, \{David C.\} and Hung, \{Rayjean J.\} and Paul Brennan and Landi, \{Maria Teresa\} and Houlston, \{Richard S.\} and Amos, \{Christopher I.\}",

year = "2014",

month = jan,

day = "1",

doi = "10.1038/ng.3002",

language = "English",

volume = "46",

pages = "736--741",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "7",

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Wang, Y, McKay, JD, Rafnar, T, Wang, Z, Timofeeva, MN, Broderick, P, Zong, X, Laplana, M, Wei, Y, Han, Y, Lloyd, A, Delahaye-Sourdeix, M, Chubb, D, Gaborieau, V, Wheeler, W, Chatterjee, N, Thorleifsson, G, Sulem, P, Liu, G, Kaaks, R, Henrion, M, Kinnersley, B, Vallée, M, Lecalvez-Kelm, F, Stevens, VL, Gapstur, SM, Chen, WV, Zaridze, D, Szeszenia-Dabrowska, N, Lissowska, J, Rudnai, P, Fabianova, E, Mates, D, Bencko, V, Foretova, L, Janout, V, Krokan, HE, Gabrielsen, ME, Skorpen, F, Vatten, L, Njølstad, I, Chen, C, Goodman, G, Benhamou, S, Vooder, T, Välk, K, Nelis, M, Metspalu, A, Lener, M, Lubiński, J, Johansson, M, Vineis, P, Agudo, A, Clavel-Chapelon, F, Bueno-De-Mesquita, HB, Trichopoulos, D, Khaw, KT, Johansson, M, Weiderpass, E, Tjønneland, A, Riboli, E, Lathrop, M, Scelo, G, Albanes, D, Caporaso, NE, Ye, Y, Gu, J, Wu, X, Spitz, MR, Dienemann, H, Rosenberger, A, Su, L, Matakidou, A, Eisen, T, Stefansson, K, Risch, A, Chanock, SJ, Christiani, DC, Hung, RJ, Brennan, P, Landi, MT, Houlston, RS & Amos, CI 2014, 'Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer', Nature Genetics, vol. 46, no. 7, pp. 736-741. https://doi.org/10.1038/ng.3002

TY - JOUR

T1 - Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

AU - Wang, Yufei

AU - McKay, James D.

AU - Rafnar, Thorunn

AU - Wang, Zhaoming

AU - Timofeeva, Maria N.

AU - Broderick, Peter

AU - Zong, Xuchen

AU - Laplana, Marina

AU - Wei, Yongyue

AU - Han, Younghun

AU - Lloyd, Amy

AU - Delahaye-Sourdeix, Manon

AU - Chubb, Daniel

AU - Gaborieau, Valerie

AU - Wheeler, William

AU - Chatterjee, Nilanjan

AU - Thorleifsson, Gudmar

AU - Sulem, Patrick

AU - Liu, Geoffrey

AU - Kaaks, Rudolf

AU - Henrion, Marc

AU - Kinnersley, Ben

AU - Vallée, Maxime

AU - Lecalvez-Kelm, Florence

AU - Stevens, Victoria L.

AU - Gapstur, Susan M.

AU - Chen, Wei V.

AU - Zaridze, David

AU - Szeszenia-Dabrowska, Neonilia

AU - Lissowska, Jolanta

AU - Rudnai, Peter

AU - Fabianova, Eleonora

AU - Mates, Dana

AU - Bencko, Vladimir

AU - Foretova, Lenka

AU - Janout, Vladimir

AU - Krokan, Hans E.

AU - Gabrielsen, Maiken Elvestad

AU - Skorpen, Frank

AU - Vatten, Lars

AU - Njølstad, Inger

AU - Chen, Chu

AU - Goodman, Gary

AU - Benhamou, Simone

AU - Vooder, Tonu

AU - Välk, Kristjan

AU - Nelis, Mari

AU - Metspalu, Andres

AU - Lener, Marcin

AU - Lubiński, Jan

AU - Johansson, Mattias

AU - Vineis, Paolo

AU - Agudo, Antonio

AU - Clavel-Chapelon, Francoise

AU - Bueno-De-Mesquita, H. Bas

AU - Trichopoulos, Dimitrios

AU - Khaw, Kay Tee

AU - Johansson, Mikael

AU - Weiderpass, Elisabete

AU - Tjønneland, Anne

AU - Riboli, Elio

AU - Lathrop, Mark

AU - Scelo, Ghislaine

AU - Albanes, Demetrius

AU - Caporaso, Neil E.

AU - Ye, Yuanqing

AU - Gu, Jian

AU - Wu, Xifeng

AU - Spitz, Margaret R.

AU - Dienemann, Hendrik

AU - Rosenberger, Albert

AU - Su, Li

AU - Matakidou, Athena

AU - Eisen, Timothy

AU - Stefansson, Kari

AU - Risch, Angela

AU - Chanock, Stephen J.

AU - Christiani, David C.

AU - Hung, Rayjean J.

AU - Brennan, Paul

AU - Landi, Maria Teresa

AU - Houlston, Richard S.

AU - Amos, Christopher I.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 â ̂'20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10 â ̂'13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10 â ̂'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.

AB - 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 â ̂'20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10 â ̂'13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10 â ̂'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.

U2 - 10.1038/ng.3002

DO - 10.1038/ng.3002

M3 - Article

SN - 1061-4036

VL - 46

SP - 736

EP - 741

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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

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