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

Background: 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).

Methods: 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).

Results: 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].

Conclusions: 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.

Impact: 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.