Peer-Reviewed Publication
medRxiv2026July 10, 2026Journal Article
Germline determinants of risk and molecular subtype in young-onset lung cancer.
Jaclyn LoPiccolo1,2,3, Ryan L Collins1,2,4, Noah Fields1,4, Carter Nakagawa1,3,4, Kodi Taraszka1,2,4, Xinan Wang2,5, Li Su2,5,6, Diane R Koeller1,2,7, Alison Levine Schwartz1,2,7, Alicia Charleston Pollaci1,2,7, Sarah M Young8, Victoria G Williamson1,2,3, Jose A Avila1,2,3, Emma Voligny1,2,3, Tom Nguyen1,2,3, Andy J Pangilinan1,2,3, Richard M Erwin9, Barbara J Gitlitz10, Silvia Novello11, Geoffrey R Oxnard1,2,3, Ugonma N Chukwueke1,2,12, Priscilla K Brastianos2,13, Ayal A Aizer1,2,14, Mizuki Nishino Hatabu1,2,15, Narjust Florez1,2,3, Kevin M Haigis1,2, Eliezer M Van Allen1,2,4, Jorge J Nieva9, Judy E Garber1,2,6, David C Christiani2,5,16, Pasi A Jänne1,2,3, Alexander Gusev1,2,4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2Harvard Medical School, Boston, MA, USA.
3The Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
6Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
7Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA.
8Labcorp (formerly Invitae Corp), San Francisco, CA, USA.
9Addario Lung Cancer Medical Institute (ALCMI), San Carlos, CA, USA.
10University of Southern California/Norris Cancer Center, Los Angeles, CA, USA.
11University of Turin, Department of Oncology, AOU San Luigi, Orbassano (Turin), Italy.
12Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
13Mass General Brigham Center for Tumors of the Nervous System, Boston, MA, USA.
14Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, USA.
15Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.
16Division of Pulmonary Care and Critical Medicine, Massachusetts General Hospital, Boston, MA, USA.
Abstract
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…
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