TP53–EGFR co-mutation landscape in Indian NSCLC: Decoding the genomic blueprint for targeted therapeutic decisions.

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Background: Lung cancer, especially non-small cell lung cancer (NSCLC), exhibits significant molecular heterogeneity that influences treatment response and clinical outcomes. This study aims to explore genetic variations and actionable alterations in Indian NSCLC patients to enhance precision medicine approaches. Methods: FFPE tumor tissue samples from 227 Indian lung cancer patients were analyzed using the 1Cell.Ai OncoTarget panel, a targeted NGS assay covering 126 genes associated with multi-cancer mutations, driver fusions, and microsatellite instability. Genomic DNA extraction, library preparation, and sequencing were performed on the Illumina NextSeq platform. Variant calling and clinical interpretation were conducted using the AI-driven iCARE software to identify somatic mutations, gene fusions, copy number variations (CNVs), and other genomic alterations. Therapeutic recommendations followed ACMG, AMP, ASCO, and CAP guidelines. Results: Comprehensive molecular profiling revealed frequent alterations in TP53 (116 cases; 51.1%), EGFR (98 cases; 43.2%), PIK3CA (20 cases; 8.8%), KRAS (15 cases; 6.6%), APC (12 cases; 5.3%), and ALK (11 cases; 4.8%). A clinically significant TP53–EGFR dual-mutation signature was observed in lung adenocarcinoma, with a high co-occurrence rate of approximately 59% (65 cases), defining a distinct molecular subtype characterized by differential responses to EGFR tyrosine kinase inhibitors, an increased propensity for accelerated therapeutic resistance, and a higher risk of aggressive disease progression. Additionally, KRAS co-mutation with TP53 was identified in 10 cases (66.67%), a pattern associated with adverse clinical outcomes, poorer prognosis, and reduced responsiveness to immunotherapy. Importantly, the detection of the KRAS G12C subtype highlights eligibility for targeted therapies such as sotorasib and adagrasib. Among evaluable cases for therapeutic recommendations (n = 160), EGFR mutations were present in 41.66% (67/160) and demonstrated favourable responses to EGFR-directed TKIs, although TP53 co-mutations contributed to resistance in a subset, while ALK fusions (15.63%; 25/160) showed marked sensitivity to ALK inhibitor–based targeted therapies. Conclusions: This study demonstrates the diverse genomic landscape of Indian NSCLC patients, highlighting TP53 and EGFR as key drivers. Notably, 160 of 227 patients (70.48%) received therapy recommendations based on genomic alterations, underscoring the translational value of targeted NGS panels in advancing precision medicine beyond conventional chemotherapy.