High-Penetrance Rare Variants Underlying Familial Lung Cancer Risk: Insights From Genetic Epidemiology of Lung Cancer Consortium+I7

Yanhong Liu, Baylor College of Medicine, Houston, TX
Yafang Li, The University of New Mexico, Albuquerque, NM
Jinyoung Byun, The University of New Mexico, Albuquerque, NM
Vikram R. Shaw, Baylor College of Medicine, Houston, TX
Claudio Pikielny, Dartmouth College, Lebanon, NH
Bo Peng, Baylor College of Medicine, Houston, TX
Chao Cheng, Baylor College of Medicine, Houston, TX
Spiridon Tsavachidis, Baylor College of Medicine, Houston, TX
Xiangjun Xiao, The University of New Mexico, Albuquerque, NM
Dakai Zhu, The University of New Mexico, Albuquerque, NM
Younghun Han, Baylor College of Medicine, Houston, TX
Ivan P. Gorlov, Baylor College of Medicine, Houston, TX
Olga Y. Gorlova, Baylor College of Medicine, Houston, TX
Michael Cole, Dartmouth College, Lebanon, NH
Colette R. Gaba, The University of Toledo, Toledo, OH
Erin L. Crawford, The University of Toledo, Toledo, OH
Kristen Purrington, Wayne State University School of Medicine, Detroit, MI
Ellen L. Goode, Mayo Clinic, Rochester, MN
Ping Yang, Mayo Clinic, Scottsdale, AZ
James McKay, International Agency for Research on Cancer, Lyon, France
John K. Field, The University of Liverpool, Liverpool, United Kingdom
Geoffrey Liu, Princess Margaret Cancer Center, Toronto, Canada
Rayjean J. Hung, Sinai Health System, Toronto, Canada
Jun Xia, Texas A&M University, Houston, TX
Jiyeon Choi, National Cancer Institute, Bethesda, MA
Matthew B. Schabath, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Jaclyn LoPiccolo, Harvard Medical School, Boston, MA
David C. Christiani, Harvard University T. H. Chan School of Public Health, Boston, MA
Diptasri Mandal, LSU Health Sciences Center - New OrleansFollow
et al.

Document Type

Article

Publication Date

12-11-2025

Publication Title

Journal of Thoracic Oncology

Abstract

INTRODUCTION: Rare, deleterious germline variants are key contributors to inherited lung cancer (LC) risk. The Genetic Epidemiology of LC Consortium (GELCC) has curated valuable high-risk LC families and is uniquely positioned to uncover rare, high-penetrance variants underlying familial LC (FLC). METHODS: We performed whole-genome and exome sequencing on germline DNA from 120 high-risk LC families (177 FLC cases, 309 unaffected relatives). We prioritized rare (allele frequency < 1% in the genome aggregation database), potentially deleterious variants present in two or more FLC cases. These variants were then validated in 10,085 sporadic LC (SLC) cases and 612,970 controls. RESULTS: We identified 118 candidate variants, 28 of which were validated in SLC with strong statistical support. We discovered a novel pathogenic axis of three truncating variants in GALNT6, MUC4, and ERBB3 genes, which are critical regulators of mucin-type O-glycosylation. Nine top hits were mapped to the known 6q23-25 linkage region (ROS1, LAMA2, PRKN, SYNE1). Other candidates were clustered in DNA repair (ATM, BRCA2, MLH1), oncogenic signaling (ERBB3, JAK1, PIM1), and extracellular matrix genes (COL6A3, FLG). Carriers of two or more variant alleles had a strong dose-dependent risk. Furthermore, gene-based burden tests revealed strong associations between RARB, MGMT, and EBF1 with FLC susceptibility. CONCLUSION: Our findings underscore the important role of rare, high-penetrance genetic variants in FLC susceptibility, particularly in mucin glycosylation and DNA repair genes. These findings offer promising targets for early detection and personalized therapies.

First Page

103534

PubMed ID

41390056

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Rights

© 2025 International Association for the Study of Lung Cancer.

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