Mutations in genes connected with the TCF7L2 transcription factor are associated with a poor prognosis in non-small cell lung cancer

Objectives: Precision medicine with molecular profiling has revolutionized the management of lung cancer leading to improved outcomes. Patients with actionable mutations receive targeted therapy. As next-generation sequencing (NGS) becomes standard in lung cancer clinics, we sought to use molecular information to identify novel pathways to target in order to improve survival for non-small cell lung cancer (NSCLC) patients. Materials and methods: This retrospective analysis included 183 lung cancer patients who received commercial NGS sequencing as part of their clinical care, as well as the lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) dataset from the Cancer Genome Atlas (TCGA). We grouped mutations using a transcription factor enrichment analysis (TFEA), and the resulting TFEA groups were used to sort patients for survival analyses. Results: Mutations connected to transcription factor 7 like 2/ Transcription Factor 4 (TCF7L2/TCF4) were associated with poor survival in NSCLC patients. Furthermore, Mutations in CCND1, IDH1, SMARC4, and TP53 are the primary contributors to a poor prognosis in these patients. This four gene panel was also found to be associated with a poor prognosis in the LUAD data of TCGA dataset. Conclusions: We determined that the TCF7L2 pathway is associated with a poor prognosis in patients with lung adenocarcinoma. Therefore, targeting the TCF7L2 pathway may improve outcomes for this group of patients.