Protein-altering germline mutations implicate novel genes related to lung cancer development.
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Date
2020-05-11ICR Author
Author
Ji, X
Mukherjee, S
Landi, MT
Bosse, Y
Joubert, P
Zhu, D
Gorlov, I
Xiao, X
Han, Y
Gorlova, O
Hung, RJ
Brhane, Y
Carreras-Torres, R
Christiani, DC
Caporaso, N
Johansson, M
Liu, G
Bojesen, SE
Le Marchand, L
Albanes, D
Bickeböller, H
Aldrich, MC
Bush, WS
Tardon, A
Rennert, G
Chen, C
Byun, J
Dragnev, KH
Field, JK
Kiemeney, LF
Lazarus, P
Zienolddiny, S
Lam, S
Schabath, MB
Andrew, AS
Bertazzi, PA
Pesatori, AC
Diao, N
Su, L
Song, L
Zhang, R
Leighl, N
Johansen, JS
Mellemgaard, A
Saliba, W
Haiman, C
Wilkens, L
Fernandez-Somoano, A
Fernandez-Tardon, G
Heijden, EHFMVD
Kim, JH
Davies, MPA
Marcus, MW
Brunnström, H
Manjer, J
Melander, O
Muller, DC
Overvad, K
Trichopoulou, A
Tumino, R
Goodman, GE
Cox, A
Taylor, F
Woll, P
Wichmann, E
Muley, T
Risch, A
Rosenberger, A
Grankvist, K
Johansson, M
Shepherd, F
Tsao, M-S
Arnold, SM
Haura, EB
Bolca, C
Holcatova, I
Janout, V
Kontic, M
Lissowska, J
Mukeria, A
Ognjanovic, S
Orlowski, TM
Scelo, G
Swiatkowska, B
Zaridze, D
Bakke, P
Skaug, V
Butler, LM
Offit, K
Srinivasan, P
Bandlamudi, C
Hellmann, MD
Solit, DB
Robson, ME
Rudin, CM
Stadler, ZK
Taylor, BS
Berger, MF
Houlston, R
McLaughlin, J
Stevens, V
Nickle, DC
Obeidat, M
Timens, W
Artigas, MS
Shete, S
Brenner, H
Chanock, S
Brennan, P
McKay, JD
Amos, CI
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Adenocarcinoma
Lung Neoplasms
Genetic Predisposition to Disease
Oligonucleotide Array Sequence Analysis
Odds Ratio
Risk Factors
Pedigree
Heterozygote
Germ-Line Mutation
Mutation, Missense
Alleles
Databases, Genetic
Aged
Middle Aged
European Continental Ancestry Group
Jews
Female
Male
Genotyping Techniques
Ataxia Telangiectasia Mutated Proteins
RNA-Seq
Research team
Cancer Genomics
Language
eng
Date accepted
2020-03-25
License start date
2020-05-11
Citation
Nature communications, 2020, 11 (1), pp. 2220 - ?
Publisher
NATURE PORTFOLIO