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

作者：Jaclyn LoPiccolo, Ryan L. Collins, Noah Fields, Carter Nakagawa, Kodi Taraszka, Xinan Wang, S Li, Diane R. Koeller, Alison Levine Schwartz, Alicia Charleston Pollaci, Sarah M. Young, Victoria G. Williamson, José A. Ávila, Emma Voligny, T L Nguyen, Andy Pangilinan, R. Erwin, Barbara J. Glitz, Silvia Novello, Geoffrey R. Oxford, Ugonma N. Chukwueke, Priscilla K. Brastianos, Ayal A. Aizer, Mizuki Nishino Hatabu, Narjust Florez, Kevin Haigis, Eliezer M. Van Allen, J. Nieva, Judy Garber, D C Christiani, Pasi A. Janne, Alexander Gusev · 发表于：medRxiv · 年份：2026 · DOI：10.64898/2026.06.30.26356693 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Genomics and Diagnostics、Cancer-related Molecular Pathways

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.