Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients


Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients

Hess, J.; Unger, K.; Maihoefer, C.; Schüttrumpf, L.; Weber, P.; Marschner, S.; Wintergerst, L.; Pflugradt, U.; Baumeister, P.; Walch, A.; Woischke, C.; Kirchner, T.; Werner, M.; Sörensen, K.; Baumann, M.; Tinhofer, I.; Combs, S. E.; Debus, J.; Schäfer, H.; Krause, M.; Linge, A.; von der Grün, J.; Stuschke, M.; Zips, D.; Canis, M.; Lauber, K.; Ganswindt, U.; Henke, M.; Zitzelsberger, H.; Belka, C.

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.

Keywords: head and neck cancer; HNSCC; HPV; miRNA; signature; prediction; prognosis; mRNA; interaction; signaling pathways

Permalink: https://www.hzdr.de/publications/Publ-35115
Publ.-Id: 35115