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

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...

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Vydané v:	Nature communications Ročník 11; číslo 1; s. 2220 - 14
Hlavní autori:	Ji, Xuemei, Mukherjee, Semanti, Landi, Maria Teresa, Bosse, Yohan, Joubert, Philippe, Zhu, Dakai, Gorlov, Ivan, Xiao, Xiangjun, Han, Younghun, Gorlova, Olga, Hung, Rayjean J., Brhane, Yonathan, Carreras-Torres, Robert, Christiani, David C., Caporaso, Neil, Johansson, Mattias, Liu, Geoffrey, Bojesen, Stig E., Le Marchand, Loic, Albanes, Demetrios, Bickeböller, Heike, Aldrich, Melinda C., Bush, William S., Tardon, Adonina, Rennert, Gad, Chen, Chu, Byun, Jinyoung, Dragnev, Konstantin H., Field, John K., Kiemeney, Lambertus FA, Lazarus, Philip, Zienolddiny, Shan, Lam, Stephen, Schabath, Matthew B., Andrew, Angeline S., Pesatori, Angela C., Diao, Nancy, Su, Li, Song, Lei, Zhang, Ruyang, Leighl, Natasha, Mellemgaard, Anders, Saliba, Walid, Haiman, Christopher, Wilkens, Lynne, Fernandez-Somoano, Ana, Heijden, Erik H. F. M. van der, Kim, Jin Hee, Davies, Michael P. A., Brunnström, Hans, Manjer, Jonas, Melander, Olle, Muller, David C., Overvad, Kim, Trichopoulou, Antonia, Tumino, Rosario, Goodman, Gary E., Cox, Angela, Taylor, Fiona, Woll, Penella, Wichmann, Erich, Muley, Thomas, Risch, Angela, Rosenberger, Albert, Grankvist, Kjell, Shepherd, Frances, Tsao, Ming-Sound, Haura, Eric B., Bolca, Ciprian, Holcatova, Ivana, Janout, Vladimir, Kontic, Milica, Lissowska, Jolanta, Mukeria, Anush, Ognjanovic, Simona, Orlowski, Tadeusz M., Scelo, Ghislaine, Swiatkowska, Beata, Bakke, Per, Butler, Lesley M., Offit, Kenneth, Srinivasan, Preethi, Bandlamudi, Chaitanya, Hellmann, Matthew D., Solit, David B., Robson, Mark E., Rudin, Charles M., Stadler, Zsofia K., Berger, Michael F., Houlston, Richard, McLaughlin, John, Stevens, Victoria, Nickle, David C., Obeidat, Ma’en, Timens, Wim, Shete, Sanjay, Brenner, Hermann, Chanock, Stephen, McKay, James D., Amos, Christopher I.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 11.05.2020 Nature Publishing Group Nature Portfolio
Predmet:	38 45/43 631/114 631/208 631/67 Adenocarcinoma Adenocarcinoma - genetics Aged Alleles Ataxia Telangiectasia Mutated Proteins - genetics Basic Medicine Databases, Genetic Female Gene expression Genetic diversity Genetic Predisposition to Disease Genetic variance Genotyping Techniques Germ-Line Mutation Health risk assessment Health risks Heterozygosity Heterozygote Humanities and Social Sciences Humans Jews - genetics Loss of heterozygosity Lung cancer Lung Neoplasms - genetics Male Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Middle Aged multidisciplinary Mutation Mutation, Missense Odds Ratio Oligonucleotide Array Sequence Analysis Pedigree Population genetics Replication Risk analysis Risk Factors RNA-Seq Science Science (multidisciplinary) Tumors White People - genetics
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-15905-6