Search

Simple Summary: Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC), regarded as a distinct clinical entity, are characterized by a considerably favourable prognosis after radio(chemo)therapy and a not yet fully understood distinct molecular pathogenesis. We aimed to develop a miRNA-signature that identifies HPV-associated HNSCC according to their specific molecular pathogenesis, and to characterise the transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of n = 229 HPV characterized HNSCC specimens of patients treated by adjuvant radio(chemo) therapy. Using lasso-regression, a 24-miRNA signature predicting HPV-status was built in a multicentre cohort and validated in a single-centre cohort. Its combination with p16/HPV DNA status improved clinically relevant risk stratification, allowed the identification of an HPV-associated patient subgroup with impaired overall survival, and might be considered for future clinical decision-making. miRNA-transcriptome integration identified HPV-specific signaling pathways. Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours (n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK, Estrogen, EGFR, TGFbeta, WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD−L1 expression/PD−1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC. [ABSTRACT FROM AUTHOR]

Previously, we have shown that copy number gain of the chromosomal band 16q24.3 is associated with impaired clinical outcome of radiotherapy‐treated head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify a prognostic mRNA signature from genes located on 16q24.3 in radio(chemo)therapy‐treated HNSCC patients of the TCGA (The Cancer Genome Atlas, n = 99) cohort. We applied stepwise forward selection using expression data of 41 16q24.3 genes. The resulting optimal Cox‐proportional hazards regression model included the genes APRT, CENPBD1, CHMP1A, and GALNS. Afterward, the prognostic value of the classifier was confirmed in an independent cohort of HNSCC patients treated by adjuvant radio(chemo)therapy (LMU‐KKG cohort). The signature significantly differentiated high‐ and low‐risk patients with regard to overall survival (HR = 2.01, 95% CI 1.10–3.70; P = 0.02125), recurrence‐free survival (HR = 1.84, 95% CI 1.01–3.34; P = 0.04206), and locoregional recurrence‐free survival (HR = 1.87, 95% CI 1.03–3.40; P = 0.03641). The functional impact of the four signature genes was investigated after reconstruction of a gene association network from transcriptome data of the TCGA HNSCC cohort using a partial correlation approach. Subsequent pathway enrichment analysis of the network neighborhood (first and second) of the signature genes suggests involvement of HNSCC‐associated signaling pathways such as apoptosis, cell cycle, cell adhesion, EGFR, JAK‐STAT, and mTOR. Furthermore, a detailed analysis of the first neighborhood revealed a cluster of co‐expressed genes located on chromosome 16q, substantiating the impact of 16q24.3 alterations in poor clinical outcome of HNSCC. The reported gene expression signature represents a prognostic marker in HNSCC patients following postoperative radio(chemo)therapy. A classifier consisting of four genes located on 16q24.3 allows the stratification of head and neck squamous cell carcinoma (HNSCC) patients undergoing adjuvant radio(chemo)therapy for favorable and poor prognosis. The classifier is independent of other clinical parameters, which may serve as target for molecular therapy since it seems to be part of a functional gene expression cluster involved in HNSCC‐associated pathways. [ABSTRACT FROM AUTHOR]