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

Ji, Xuemei ; Brunnström, Hans LU orcid ; Manjer, Jonas LU ; Melander, Olle LU orcid ; Overvad, Kim and Amos, Christopher I. (2020) In Nature Communications 11(1).
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 ×... (More)
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). (Less)
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type
Contribution to journal
publication status
published
subject
keywords
allele, cancer, gene expression, genetic analysis, health risk, heterozygosity, mutation, tumor
in
Nature Communications
volume
11
issue
1
article number
2220
publisher
Nature Publishing Group
external identifiers
  • scopus:85084474621
  • pmid:32393777
ISSN
2041-1723
DOI
10.1038/s41467-020-15905-6
language
English
LU publication?
yes
id
ed914309-9a0e-4d33-a474-3d89ae193fb6
date added to LUP
2020-06-01 11:44:31
date last changed
2024-01-17 03:03:02
@article{ed914309-9a0e-4d33-a474-3d89ae193fb6,
  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).}},
  author       = {{Ji, Xuemei and Brunnström, Hans and Manjer, Jonas and Melander, Olle and Overvad, Kim and Amos, Christopher I.}},
  issn         = {{2041-1723}},
  keywords     = {{allele; cancer; gene expression; genetic analysis; health risk; heterozygosity; mutation; tumor}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Protein-altering germline mutations implicate novel genes related to lung cancer development}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-15905-6}},
  doi          = {{10.1038/s41467-020-15905-6}},
  volume       = {{11}},
  year         = {{2020}},
}