Rate of Pathogenic Germline Variants in Patients With Lung Cancer

Abstract

Purpose: Germline genetic testing (GGT) is now recommended for all patients diagnosed with ovarian or pancreatic cancer and for a large proportion of patients based solely on a diagnosis of colorectal or breast cancer. However, GGT is not yet recommended for all patients diagnosed with lung cancer (LC), primarily because of a lack of evidence that supports a significant frequency of identifying pathogenic germline variants (PGVs) in these patients. This study characterizes GGT results in a cohort of patients with LC.

Methods: We reviewed deidentified data for 7,788 patients with GGT (2015-2022). PGV frequencies were compared to a control cohort of unaffected individuals. GGT results were stratified by genomic ancestry, history of cancer, and PGV clinical actionability per current guidelines.

Results: Of all patients with LC, 14.9% (1,161/7,788) had PGVs. The rate was similar when restricted to patients with no cancer family history (FH) or personal history (PH) of other cancers (14.3%). PGVs were significantly enriched in BRCA2, ATM, CHEK2, BRCA1, and mismatch repair genes compared with controls. Patients of European (EUR) genomic ancestry had the highest PGV rate (18%) and variants of uncertain significance were significantly higher in patients of non-EUR genomic ancestry. Of the PGVs identified, 61.3% were in DNA damage repair (DDR) genes and 95% were clinically actionable.

Conclusion: This retrospective study shows a LC diagnosis identifies patients with a significant likelihood of having a cancer-predisposing PGV across genomic ancestries. Enrichment of PGVs in DDR genes suggests that these PGVs may contribute to LC cancer predisposition. The frequency of PGVs among patients with LC did not differ significantly according to FH or PH of other cancers.

FIG 1.

Genetic test results among all individuals in the study cohort. (A) Overall genetic test results. See the Data Supplement (Methods) (Genetic testing) for definitions of positive, carrier, uncertain, and negative. (B) Proportion of individuals with a positive result in genes. Proportion is based on the total number of individuals who had the gene ordered by their clinician. Positive rates for all genes can be found in the Data Supplement (Table S2).

FIG 2.

Genetic test results by (A) genomic ancestry and (B) personal history of other cancers. Proportion is based on the number of patients in each category, with the total number of patients in each category reported on the x-axis. Of note, 20 patients (0.02% of cohort) did not demonstrate a clearly predominant genomic ancestry and are not included in the analysis in panel (A). AFR, African; AMR, Ad Mixed American; EAS, East Asian; EUR, European; SAS, South Asian.

FIG 3.

Genetic test results among patients with only a personal history of lung cancer, per clinician report. (A) Overall genetic test results. See the Data Supplement (Methods) (Genetic testing) for definitions of positive, carrier, uncertain, and negative. (B) Proportion of patients with a positive result in genes. Proportion is based on the total number of patients who had the gene ordered by their clinician. Positive rates for all genes can be found in the Data Supplement (Table S3).