126P - Genomic and transcriptomic profiles define smokers and non-smokers lung squamous cell carcinoma patients

Background

Lung Squamous Cell Carcinoma (SCC) is a non-small cell lung cancer (NSCLC) subtype with a strong clinical association with smoking habits, and a very low incidence in never smokers. Deep mutational and transcriptomic profiling could characterize SCC in never smokers, unveiling tumor vulnerabilities and new treatment strategies.

Methods

We considered a patients cohort of 17 former or current smoker (48.5%) and 16 never smoker SCC patients (51.5%). TruSight Oncology® 500 (Illumina), investigating hotspots in 523 cancer-related genes, Tumor Mutation Burden (TMB) and microsatellite instability (MSI) was performed on tumor DNA, while RNA-Sequencing was performed on tumor RNA. Genomic and transcriptomic profiles were compared between smokers and never smokers patients.

Results

The most frequently altered genes were TP53 (67%), CDKN2A (20%) and PIK3CA (17%), with no substantial differences between groups, apart for TP53 which was more frequently mutated in smoker patients (86.7% vs 46.7%, p=0.05), who showed a higher TMB with respect to non-smokers (median 11 mut/Mb vs 5.5 mut/Mb, p=0.028), while all patients were stable for MSI score (median 1.87 vs 1.82, p=0.87). Activating mutations in EGFR and MET were found in one and two never smokers, respectively. Three smoker patients had simultaneous amplifications in FGF3, FGF19 and FGF4. Enrichment analyses showed that cyclin-dependent protein Ser/Thr kinase activity and PI3K signaling pathways were affected in both groups, while cellular damage response was exclusively altered in never smokers. Unsupervised hierarchical clustering on transcriptome effectively identified different specific transcriptional subtypes between smokers and never smokers. Gene set enrichment analysis highlighted that tumors from never smokers are characterized by dysregulation in cell membrane potential and ion homeostasis across cell membranes pathways.

Conclusions

Genomic and transcriptomic profiles deeply differentiate SCC occurring in never smokers with respect to SCC in smoker patients. Moreover, SCC could carry classical NSCLC activating mutations. Our data suggest that deep molecular analyses resolve tumor heterogeneity and may help for new treatment algorithms strategies for SCC.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.