Publication

Protein-altering germline mutations implicate novel genes related to lung cancer development

International COPD Genetics Consortium, Lung eQTL Consortium, Lung Health Study, Ji, X., Mukherjee, S., Landi, M. T., Bosse, Y., Joubert, P., Zhu, D., Gorlov, I., Xiao, X., Han, Y., Gorlova, O., Hung, R. J., Brhane, Y., Carreras-Torres, R., Christiani, D. C., Caporaso, N., Johansson, M., Liu, G., Bojesen, S. E., Le Marchand, L., Albanes, D., Bickeböller, H., Aldrich, M. C., Bush, W. S., Tardon, A., Rennert, G., Chen, C., Byun, J., Dragnev, K. H., Field, J. K., Kiemeney, L. F., Lazarus, P., Zienolddiny, S., Lam, S., Schabath, M. B., Andrew, A. S., Bertazzi, P. A., Pesatori, A. C., Diao, N., Su, L., Song, L., Zhang, R., Leighl, N., Johansen, J. S., Mellemgaard, A., Saliba, W., Haiman, C., Wilkens, L., Fernandez-Somoano, A., Fernandez-Tardon, G., van der Heijden, E. H. F. M., Hee Kim, J., Davies, M. P. A., Marcus, M. W., Brunnstrom, H., Manjer, J., Melander, O., Muller, D. C., Overvad, K., Trichopoulou, A., Tumino, R., Goodman, G., Cox, A., Taylor, F., Woll, P. J., Wichmann, E., Muley, T., Risch, A., Rosenberger, A., Grankvist, K., Johansson, M., Shepherd, F., Tsao, M-S., Arnold, S. M., Haura, E. B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T. M., Scelo, G., Świątkowska, B., Zaridze, D., Bakke, P., Skaug, V., Butler, L. M., Offit, K., Srinivasan, P., Bandlamudi, C., Hellmann, M. D., Solit, D. B., Robson, M. E., Rudin, C. M., Stadler, Z. K., Taylor, B. S., Berger, M. F., Houlston, R. S., McLaughlin, J., Stevens, V. L., Nickle, D. C., Obeidat, M., Timens, W., Soler Artigas, M., Shete, S., Brenner, H., Chanock, S. J., Brennan, P., Mckay, J. D. & Amos, C. I., 11-May-2020, In : Nature Communications. 11, 1, 14 p., 2220.

Research output: Contribution to journalArticleAcademicpeer-review

  • International COPD Genetics Consortium, Lung eQTL Consortium, Lung Health Study
  • Xuemei Ji
  • Semanti Mukherjee
  • Maria Teresa Landi
  • Yohan Bosse
  • Philippe Joubert
  • Dakai Zhu
  • Ivan Gorlov
  • Xiangjun Xiao
  • Younghun Han
  • Olga Gorlova
  • Rayjean J Hung
  • Yonathan Brhane
  • Robert Carreras-Torres
  • David C Christiani
  • Neil Caporaso
  • Mattias Johansson
  • Geoffrey Liu
  • Stig E Bojesen
  • Loic Le Marchand
  • Demetrios Albanes
  • Heike Bickeböller
  • Melinda C Aldrich
  • William S Bush
  • Adonina Tardon
  • Gad Rennert
  • Chu Chen
  • Jinyoung Byun
  • Konstantin H Dragnev
  • John K Field
  • Lambertus Fa Kiemeney
  • Philip Lazarus
  • Shan Zienolddiny
  • Stephen Lam
  • Matthew B Schabath
  • Angeline S Andrew
  • Pier A Bertazzi
  • Angela C Pesatori
  • Nancy Diao
  • Li Su
  • Lei Song
  • Ruyang Zhang
  • Natasha Leighl
  • Jakob S Johansen
  • Anders Mellemgaard
  • Walid Saliba
  • Christopher Haiman
  • Lynne Wilkens
  • Ana Fernandez-Somoano
  • Guillermo Fernandez-Tardon
  • Erik H. F. M. van der Heijden
  • Jin Hee Kim
  • Michael P. A. Davies
  • Michael W Marcus
  • Hans Brunnstrom
  • Jonas Manjer
  • Olle Melander
  • David C. Muller
  • Kim Overvad
  • Antonia Trichopoulou
  • Rosario Tumino
  • Gary Goodman
  • Angela Cox
  • Fiona Taylor
  • Penella J. Woll
  • Erich Wichmann
  • Thomas Muley
  • Angela Risch
  • Albert Rosenberger
  • Kjell Grankvist
  • Mikael Johansson
  • Frances Shepherd
  • Ming-Sound Tsao
  • Susanne M. Arnold
  • Eric B. Haura
  • Ciprian Bolca
  • Ivana Holcatova
  • Vladimir Janout
  • Milica Kontic
  • Jolanta Lissowska
  • Anush Mukeria
  • Simona Ognjanovic
  • Tadeusz M. Orlowski
  • Ghislaine Scelo
  • Beata Świątkowska
  • David Zaridze
  • Per Bakke
  • Vidar Skaug
  • Lesley M. Butler
  • Kenneth Offit
  • Preethi Srinivasan
  • Chaitanya Bandlamudi
  • Matthew D. Hellmann
  • David B. Solit
  • Mark E. Robson
  • Charles M. Rudin
  • Zsofia K. Stadler
  • Barry S. Taylor
  • Michael F. Berger
  • Richard S. Houlston
  • John McLaughlin
  • Victoria L. Stevens
  • David C Nickle
  • Ma'en Obeidat
  • Wim Timens
  • María Soler Artigas
  • Sanjay Shete
  • Hermann Brenner
  • Stephen J. Chanock
  • Paul Brennan
  • James D. Mckay
  • Christopher I. Amos

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Original languageEnglish
Article number2220
Number of pages14
JournalNature Communications
Volume11
Issue number1
Publication statusPublished - 11-May-2020

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