Prevalence and characteristics of lung cancer in families harboring Pathogenic Germline Variants in cancer predisposing genes: A 20-year retrospective analysis.

INTRODUCTION

Genetic predisposition for lung cancer has historically been underexplored. However, increasing evidence indicates the presence of pathogenic germline variants (PGV) in cancer predisposition genes among patients with lung cancer, highlighting a need for further investigation. Here, we report the prevalence and characteristics of lung cancer in families harboring PGVs studied in our genetic counseling unit (GCU).

METHODS

We conducted a retrospective analysis of clinical, molecular, and germline genetic data from patients with lung cancer within families harboring PGVs from the GCU at Hospital Clinic of Barcelona (Spain) over a 20-year period (2001-2021).

RESULTS

Of 2521 families with germline testing information, 702 families were identified as PGV carriers. Among these, 107 families (15 %) had ≥ 1 relative with lung cancer (n = 130 patients), particularly in those with PGVs in DNA-repair genes. Males predominated, yet limited pathological and molecular data was available. Despite familial PGV identification, only 13 % of the patients with lung cancer underwent germline testing, with a positive result in 88 % of cases (e.g., BRCA1/2, PALB2, CDKN2A). A significant proportion of them (67 %) had a history of multiple neoplasms, primarily colorectal, melanoma and lung cancer. Tumor panel sequencing in 3 PGV carriers revealed actionable driver mutations (e.g., KRAS, EGFR).

CONCLUSIONS

Lung cancer is prevalent among relatives of PGV carriers. However, germline testing is rarely performed in practice. PGV carriers with lung cancer may exhibit distinct clinical and molecular profiles. Establishing specific genetic testing criteria for lung cancer is imperative to identify high-risk individuals who may benefit from genetic assessment.