Synonymous Variants of Potential Significance Identified by a 52‐Gene Clinical Sequencing Panel in Non‐Small Cell Lung Cancer

INTRODUCTION: Next-generation sequencing (NGS) is routinely used for lung cancer genomic profiling to identify known, actionable, non-synonymous driver mutations. Recent findings suggest that synonymous variants may also be cancer drivers. MATERIALS AND METHODS: We analyzed genomic data and clinical outcomes for patients (n = 353) with non-small cell lung cancer (NSCLC) sequenced with the Oncomine Focus 52-gene NGS panel (ThermoFisher Scientific, Waltham, MA, USA) at the Saint John Regional Hospital in New Brunswick, Canada, from January 2019 to January 2023. RESULTS: KRAS was the most commonly mutated gene in this cohort from Saint John, New Brunswick, with a higher prevalence than reported in other populations. Several novel synonymous variants were identified, including in ALK, EGFR, FGFR2, FGFR3, MYC, NF1, NRAS, and PIK3CA, with potential effects on MAPK/ERK and PI3K/AKT signaling. CONCLUSION: This cohort demonstrates both expected and distinct genomic features, including novel synonymous variants in oncogenic pathways. These findings suggest regional variation in NSCLC genomics and support further study of synonymous variants in disease progression.