2294P - Whole genome sequencing to define the germline-somatic interaction in young-onset lung cancer

Background

Although the average age of lung cancer diagnosis is 70, thousands of cases are diagnosed annually in patients under 45. Previous work has shown that lung cancers in younger patients frequently harbor targetable somatic alterations, suggesting young age may be an emerging clinical biomarker of lung cancer biology. Given young age at diagnosis and absence of known environmental insults, we hypothesized that underlying germline variation predisposes to developing lung cancer at a young age.

Methods

We assembled a cohort of 350 patients diagnosed with NSCLC/SCLC at age 45 or younger and performed germline multi-gene panel testing and whole-genome sequencing (WGS) from peripheral blood, along with tumor panel-based NGS. Germline results were compared to WGS from ancestry-matched, uniformly processed non-cancer controls as part of the 1000 Genomes Project as well as exomes from lung cancer patients diagnosed over 45 as part of The Cancer Genome Atlas (TCGA).

Results

Preliminary WGS from 243 patients shows at least 30% of patients carry clinically actionable pathogenic germline variants (PGVs) in cancer-associated genes, at rates exceeding those seen in other cancers – with gene set enrichment analyses (GSEA) showing key age-specific differences compared to lung cancer patients in TCGA. GSEA show high carrier rates of rare PGVs in several cancer-related pathways, including genes mediating DNA damage repair and receptor tyrosine kinase signaling. Common variant polygenic risk scores were negatively associated with rare PGVs, suggesting an independent contribution to risk. Clinicopathologic analysis of this cohort shows enrichment for never-smoking status (74%), female sex (59%), and adenocarcinoma (LUAD, 89%). Of LUAD, 88% harbor targetable somatic alterations: 38.9% EGFR-mutant (75% exon 19 deleted), 24.1% ALK-rearranged, and 33% fusion-positive.

Conclusions

Rare PGVs mediate lung cancer risk in young lung cancer patients, with age-specific differences compared to patients diagnosed at older ages. These results prompt consideration of a group based on germline risk that may benefit from CT screening as part of future changes to clinical care. Further work will delineate additional risk mediated by non-coding and structural variants.

Clinical trial identification

NCT05265429: Biology of Young Lung Cancer (The YOUNG LUNG Study)

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

DFCI Wong Family Award in Translational Oncology, Friends of Dana-Farber, and NIH Training Grant (T32CA009172).

Disclosure

J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines; Financial Interests, Personal, Other, Consulting: Nuvalent; Financial Interests, Personal, Other, Consulting: Elevation Oncology; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Personal, Advisory Board, Consulting: Genentech; Financial Interests, Personal, Other, Consulting: C4 Therapeutics; Financial Interests, Personal, Other, Consulting: Bayer; Financial Interests, Personal, Other, Consulting: Novartis; Financial Interests, Personal, Other, Consulting: Mirati Therapeutics; Financial Interests, Personal, Other, Consulting: Regeneron; Financial Interests, Personal, Other, Consulting: CLaiM Therapeutics; Financial Interests, Institutional, Local PI: Turning Point Therapeutics; Financial Interests, Institutional, Local PI: Neon Therapeutics; Financial Interests, Institutional, Local PI: Relay Therapeutics; Financial Interests, Institutional, Local PI: Bayer; Financial Interests, Institutional, Local PI: Elevation Oncology; Financial InterJ.E. Garber: Financial Interests, Personal, Advisory Board: Helix, Konica-Minolta, American Association for Cancer Research, The James P. Wilmot Foundation, Inc., Earli Inc.; Financial Interests, Personal, Full or part-time Employment: Breast Cancer Research Foundation. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, Puma, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. All other authors have declared no conflicts of interest.