PuSH - Publikationsserver des Helmholtz Zentrums München: Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy.

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Tawk, B.* ; Wirkner, U.* ; Schwager, C.* ; Rein, K.* ; Zaoui, K.* ; Federspil, P.A.* ; Adeberg, S.* ; Linge, A.* ; Ganswindt, U.* ; Hess J. ; Unger, K. ; Tinhofer, I.* ; Budach, V.* ; Lohaus, F.* ; Krause, M.* ; Guberina, M.* ; Stuschke, M.* ; Balermpas, P.* ; Rödel, C.* ; Grosu, A.L.* ; Schäfer, H.* ; Zips, D.* ; Combs, S.E.* ; Pigorsch, S.* ; Zitzelsberger, H. ; Baumeister, P. ; Kirchner, T.* ; Bewerunge-Hudler, M.* ; Weichert, W.* ; Hess, J.* ; Herpel, E.* ; Belka, C. ; Baumann, M.* ; Debus, J.* ; Abdollahi, A.*

Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy.

Int. J. Cancer, DOI: 10.1002/ijc.33842 (2021)

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Biomarkers with relevance for loco-regional therapy are needed in Human Papillomavirus negative aka HPV(-) Head and Neck Squamous Cell Carcinoma (HNSCC). Based on the premise that DNA methylation pattern is highly conserved, we sought to develop a reliable and robust methylome-based classifier identifying HPV(-) HNSCC patients at risk for loco-regional recurrence (LR) and all-event progression after postoperative radiochemotherapy (PORT-C). The training cohort consisted of HPVDNA negative HNSCC patients (n=128) homogeneously treated with PORT-C in frame of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA Methylation analysis was performed using Illumina 450K and 850K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in training set, namely hypoxia-, 5-microRNA (5-miR)-, stem-cell gene-expression signatures and immunohistochemistry (IHC)-based immunological characterization of tumors (CD3/CD8/PD-L1/PD1). Validation occurred in an independent cohort of HPV(-) HNSCC patients, pooled from two German centers (n=125). We identified a 38-methylation probe-based HPV(-) Independent Classifier of disease Recurrence (HICR) with high prognostic value for LR, distant metastases and overall survival (p<10^-9 ). HICR remained significant after multivariate analysis adjusting for anatomical site, lymph node extracapsular extension (ECE) and size (T-stage). HICR high-risk tumors were enriched for younger patients with hypoxic tumors (15-gene signature) and elevated 5-miR score. After adjustment for hypoxia and 5-miR covariates, HICR maintained predicting all endpoints. HICR provides a novel mean for assessing the risk of LR in HPV(-) HNSCC patients treated with PORT-C and opens a new opportunity for biomarker-assisted stratification and therapy adaptation in these patients. This article is protected by copyright. All rights reserved.

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