PI3K/mTORC2-RICTOR axis in early squamous non-small-cell lung cancer: genomics, molecular expression, and clinical relevance

Background: Although considerable discoveries have been made in the genomic landscape of lung adenocarcinoma, to date, little is known regarding potential prognostic factors and altered pathways in resected squamous non-small-cell lung cancer (squamous-NSCLC).Objective: We aimed to analyze the genomic background of prognostic outlier patients, selected based on a previously validated model, to assess differential genomics, and to investigate its relationship with prognosis.Design: We conducted a retrospective study on three squamous-NSCLC cohorts, integrating next-generation sequencing (NGS)-based genomic profiling and NanoString expression analysis to identify molecular alterations associated with patient prognosis.Methods: NGS analysis of somatic mutations (SM) and copy number variations (CNV) was performed by applying a 409-gene Comprehensive Cancer panel in the training set (Cohort #1) and a 56-gene customized panel in the validation set (Cohort #2). Genomic expression (NanoString) was further evaluated on an additional cohort (Cohort #3).Results: Sixty and thirty-seven (n = 97) Caucasian patients with available tissue out of the original 176 and 46 (n = 222) samples were evaluated as training and validation cohorts, respectively. CNVs were the most frequent genomic events. Molecular alterations were distributed regardless of prognosis, except for DDR2 mutations in the good prognosis (GP) and SMAD4 loss in the poor prognosis (PP) group. The PI3KCA/mTOR axis represented the most frequently altered pathway (42%), with PI3KCA mutations and RICTOR high gain reported only in the PP group. A genomic expression analysis performed in Cohort #3 (n = 35) showed that a downregulation in the PI3K/AKT/mTOR pathway was mainly evident in the GP group of patients.Conclusion: This integrated multi-step analysis identified potentially altered pathways with a biological impact on squamous-NSCLC oncogenesis, suggesting that the PI3KCA/mTOR pathway could affect the prognosis of resected SCC patients through both genomic aberrations and impaired expression.