Whole exome sequencing of lung cancer in Indian patients reveals driver genes and novel mutations with therapeutic potential.

[UNLABELLED] Lung cancer remains a leading cause of cancer mortality in India, yet its genomic landscape remains understudied. To address this gap, we performed whole-exome sequencing (WES) on tumor and matched blood samples from 47 lung cancer patients [adenocarcinoma (ADC): 30; squamous cell carcinoma (SqCC): 10; and small cell lung cancer (SCLC): 7] to comprehensively analyze somatic mutations across all protein-coding genes. Our analysis revealed novel and recurrent alterations, with being the most recurrently mutated gene, and emerging as the most frequently mutated across subtypes. Shared mutations included and , the latter not previously associated with lung cancer. ADC exhibited the highest mutational diversity, particularly in RTK/MAPK pathway genes (). Notably, mutations were identified in 26.7% of ADC cases, including exon 19 deletions (5 cases), exon 21 missense mutations (2 cases), and exon 20 insertions (3 cases) and a novel exon 20 duplication (p.Ser768_Asp770dup). SqCC showed frequent mutations in and , suggesting a role for epigenetic dysregulation. One SqCC case harbored a rare p.Glu866Gly mutation. SCLC was enriched for (43%) and (14%) mutations, along with alterations in and Importantly, therapeutically actionable mutations were identified in 91.5% patients, including those with NCCN-recommended (25.5%) and FDA-approved off-label drug targets (68.1%). These findings underscore the value of WES in uncovering clinically relevant mutations and support the integration of genomic profiling into precision oncology strategies for Indian lung cancer patients.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s13193-025-02359-9.