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 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.