Germline determinants of risk and molecular subtype in young-onset lung cancer

Le résumé fourni par la source

A bstract Young-onset lung cancer is enriched for never-smoking and oncogene-driven tumors, yet its inherited genetic basis remains poorly defined. We performed germline whole-genome sequencing in 251 young-onset lung cancer cases (median age 37), which we jointly analyzed with never-smoking cases (n=196; median age 68) and cancer-free controls (n=1,883). We identified enrichments of rare deleterious coding variants across 55 cancer-related gene sets, including EGFR/ERBB2 signaling and genes implicated by prior lung cancer GWAS. Exome-wide analyses of rare coding variants affirmed TP53 as a penetrant lung cancer predisposition gene (odds ratio [OR]=36.1, p=1.02×10 -7 ) and discovered two novel exome-wide significant tumor subtype-dependent associations: IREB2 in cases with fusion-driven tumors (p=1.39×10 -6 ) and SMAD6 in fusion-negative tumors (p=2.05×10 -6 ). Structural variants contributed distinct risk, with enrichment in constrained, lung-expressed genes (OR=5.79, p=5.8×10 -5 ) and very large germline deletions being markedly enriched in cases with fusion-driven tumors. Polygenic risk scores for lung cancer were inversely correlated with rare variant burden, consistent with additive risk from rare and common variants. Collectively, these findings delineate a complex germline architecture underlying susceptibility and molecular subtype in young-onset lung cancer.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.