Publication Title
Nat Commun
Document Type
Article
Publication Date
5-11-2020
Keywords
Adenocarcinoma; Aged; Alleles; Ataxia Telangiectasia Mutated Proteins; Databases, Genetic; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genotyping Techniques; Germ-Line Mutation; Heterozygote; Humans; Jews; Lung Neoplasms; Male; Middle Aged; Mutation, Missense; Odds Ratio; Oligonucleotide Array Sequence Analysis; Pedigree; RNA-Seq; Risk Factors
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.
Area of Special Interest
Cancer
Specialty/Research Institute
Oncology
