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

Brhane, Yonathan, Yang, Ping, Christiani, David C, Liu, Geoffrey, McLaughlin, John R, Brennan, Paul, Shete, Sanjay, Field, John K ORCID: 0000-0003-3951-6365, Tardon, Adonina, Kohno, Takashi
et al (show 5 more authors) (2020) Genetic Determinants of Lung Cancer Prognosis in Never Smokers: A Pooled Analysis in the International Lung Cancer Consortium. CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 29 (10). pp. 1983-1992.

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<h4>Background</h4>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).<h4>Methods</h4>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 (<i>N</i> = 887).<h4>Results</h4>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), <i>P</i> = 3.60 × 10<sup>-8</sup>], and altered mRNA expression of <i>LMO7DN</i> in lung tissue (GTEx, <i>P</i> = 9.40 × 10<sup>-7</sup>; Lung eQTL dataset, <i>P</i> = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level (<i>P</i> < 10<sup>-6</sup>) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including <i>CAPZB</i> at 1p36.13 and <i>UBAC1</i> at 9q34.3. One locus encoding <i>NWD2/KIAA1239</i> at 4p14 showed associations in both European [HR = 0.50 (0.38-0.66), <i>P</i> = 6.92 × 10<sup>-7</sup>] and Japanese populations [HR = 0.79 (0.67-0.94), <i>P</i> = 0.007].<h4>Conclusions</h4>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.<h4>Impact</h4>We identified one locus near <i>LMO7DN</i> at genome-wide level and several potential prognostic genes with <i>cis</i>-effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.

Item Type: Article
Uncontrolled Keywords: Humans, Lung Neoplasms, Prognosis, Middle Aged, Female, Male
Depositing User: Symplectic Admin
Date Deposited: 14 Sep 2020 12:58
Last Modified: 08 Feb 2023 10:12
DOI: 10.1158/1055-9965.EPI-20-0248
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