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

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). 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. 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. 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.