Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium

Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO). Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression-based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study ( = 887). One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41-2.07), = 3.60 × 10 ], and altered mRNA expression of in lung tissue (GTEx, = 9.40 × 10 ; Lung eQTL dataset, = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level ( < 10 ) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including at 1p36.13 and at 9q34.3. One locus encoding at 4p14 showed associations in both European [HR = 0.50 (0.38-0.66), = 6.92 × 10 ] and Japanese populations [HR = 0.79 (0.67-0.94), = 0.007]. Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants. We identified one locus near at genome-wide level and several potential prognostic genes with -effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.