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.
- MeSH
- adenokarcinom genetika MeSH
- alely MeSH
- ATM protein genetika MeSH
- běloši genetika MeSH
- databáze genetické MeSH
- genetická predispozice k nemoci MeSH
- genotypizační techniky MeSH
- heterozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- missense mutace MeSH
- nádory plic genetika MeSH
- odds ratio MeSH
- rizikové faktory MeSH
- rodokmen MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- sekvenování transkriptomu MeSH
- senioři MeSH
- zárodečné mutace MeSH
- židé genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH