Three genetic loci for lung cancer risk have been identified by genome-wide association
studies (GWAS), but inherited susceptibility to specific histologic types of lung
cancer is not well established. We conducted a GWAS of lung cancer and its major histologic
types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer
cases and 5848 controls from one population-based case-control study and three cohort
studies. Results were combined with summary data from ten additional studies, for
a total of 13,300 cases and 19,666 controls of European descent. Four studies also
provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589
squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by
histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma
(odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but
not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC,
respectively). This finding was confirmed in each replication study and overall meta-analysis
(OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48
for SQ and SC, respectively). Other previously reported association signals on 15q25
and 6p21 were also refined, but no additional loci reached genome-wide significance.
In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to
adenocarcinoma.