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


Authors: 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. A.; 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.; Kim, J. H.; Davies, M. P. A.; Marcus, M. W.; Brunnström, H.; Manjer, J.; Melander, O.; Muller, D. C.; Overvad, K.; Trichopoulou, A.; Tumino, R.; Goodman, G. E.; Cox, A.; Taylor, F.; Woll, P.; 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.; Swiatkowska, 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.; McLaughlin, J.; Stevens, V.; Nickle, D. C.; Obeidat, M.; Timens, W.; Artigas, M. S.; Shete, S.; Brenner, H.; Chanock, S.; Brennan, P.; McKay, J. D.; Amos, C. I.
Article Title: Protein-altering germline mutations implicate novel genes related to lung cancer development
Abstract: 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. © 2020, The Author(s).
Keywords: mutation; genetic analysis; allele; gene expression; heterozygosity; tumor; health risk; cancer
Journal Title: Nature Communications
Volume: 11
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2020-05-11
Start Page: 2220
Language: English
DOI: 10.1038/s41467-020-15905-6
PUBMED: 32393777
PROVIDER: scopus
PMCID: PMC7214407
DOI/URL:
Notes: Article -- Export Date: 1 June 2020 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    610 Offit
  2. Mark E Robson
    456 Robson
  3. David Solit
    546 Solit
  4. Zsofia Kinga Stadler
    202 Stadler
  5. Michael Forman Berger
    497 Berger
  6. Matthew David Hellmann
    256 Hellmann
  7. Barry Stephen Taylor
    191 Taylor
  8. Charles Rudin
    230 Rudin