Gene Expression Profiling and Prediction of Survival in Oropharyngeal Tumors. Gene Expression Profiling and Prediction of Survival in Oropharyngeal Tumors

Background: Oropharynx squamous cell carcinoma (OPSCC) is a subtype of HNSCC, arising from the base of tongue, lingual tonsil, tonsil, oropharynx, pharynx. The majority of OPSCC positive for HPV infection is associated with better prognosis, but a fraction of them, similarly to HPV-negative ones, is resistant to therapy and has poor prognosis. A deep molecular study of OPSCC is mandatory to identify either prognostic markers or targets for therapy, in particular in patients with worse prognosis. Methods: 14 HPV-positive and 15 HPV-negative Italian OPSCC (n=29) with complete clinical information and follow-up of more than 5 years were molecularly characterized by gene expression profiling and compared to three cohorts of OPSCC extracted from public HNSCC datasets. AKR1C3 emerged as robust marker overexpressed in HPV-negative OPSCC and in HPV-positive lesions with worse prognosis. Fadu and Cal-27 OPSCC cell lines were treated with AKR1C3 inhibitors, alone or in combination with Cisplatin. Results: Gene set enrichment analysis revealed that up-regulated genes in HPV-positive samples are involved in immune system, muscle related processes, response to stimuli, actin organization, tissue development and adhesion, while down-regulated genes participated in glutathione derivative biosynthetic and xenobiotic metabolic processes, hypoxia and oxidative stress. AKR1C3, coding for an enzyme involved in chemio-radioresistance, is in the top10 genes with higher upregulation in HPV-negative samples. Pre-treatment with a selective AKR1C3 inhibitor potentiated the effect of Cisplatin in cells with higher basal level of the enzyme. Conclusions: We identified a druggable target, AKR1C3, associated with survival in subgroups of OPSCC patients either positive or negative for HPV infection and to resistance to chemo-radiotherapy in HNSCC. Pretreatment of OPSCC cell lines expressing this enzyme with a selective AKR1C3 inhibitor is able to enhance Cisplatin efficacy. Overall design: Gene expression of 29 cases of squamous cell carcinomas of the oropharynx (OPSCC) were profiled with Agilent microarrays. Each sample was analyzed with a dye-swap technical replicate.