Germline Variants in Indian Non-Small Cell Lung Cancer Patients With Familial Aggregation: A Prospective Cohort Study

While smoking is a principal risk factor for lung cancer, the steadily increasing incidence in never smokers is underscoring the impact of additional factors, such as genetic predisposition. The presence of pathogenic or likely pathogenic germline variants in cancer predisposition genes has been recognized as a contributing factor to lung cancer, suggesting that familial aggregation is a pertinent criterion for genetic testing. This study attempts to identify the prevalence of Pathogenic germline variants (PGVs) in Indian lung cancer patients with familial aggregation.

Patients with non-small cell lung cancer (NSCLC) were screened for significant family history and they underwent genetic testing. Germline DNA from blood samples was analyzed using a next-generation sequencing panel of 143 cancer predisposition genes. The clinical, pathological, demographic, and survival data of patients with positive family history and PGVs were analyzed.

A total of 750 patients were screened, with 137 (18.26%) identified as having a significant family history, and a median age of 60 years (range: 21-79 years). Of these, 103 patients underwent next-generation sequencing (NGS), revealing pathogenic or likely pathogenic alterations in 17 individuals. These 17 patients exhibited mutations across 12 genes, 10 of which were associated with DNA damage repair pathways. Most commonly mutated genes were ATM and BRCA2. One unaffected first-degree relative (FDR) from 12 of these 17 patient's family were tested, and 8 such FDRs were found to carry the same mutation as that of the index patient.

In this study we report the frequency of pathogenic/likely pathogenic (P/LP) germline variants in Indian patients with NSCLC with significant family history of cancer to be 16.5%. It suggests the potential utility of genetic testing to guide targeted screening strategies in this high-risk population.