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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dna Methylation ; Disease Recurrence ; Head And Neck Cancers ; Radiotherapy ; Stratification; Good Prognosis Subgroups; Cell Marker Expression; Locally Advanced Head; Cancer; Multicenter; Methylation; Chemoradiotherapy; Carcinomas; Signatures; Biomarker
ISSN (print) / ISBN 0020-7136
e-ISSN 1097-0215
Zeitschrift International Journal of Cancer
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Radiation Cytogenetics (ZYTO)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)
Förderungen Helmholtz Cross-Program Initiative Personalized Medicine (iMed) project on "Multi-Scale Integrative Biology of HNSCC"
Joint Funding Grant within the German Cancer Consortium (DKTK), the National German Health Centers by the Federal German Ministry of Education
Intramural Funds of the National Center for Tumor Diseases (NCT) Heidelberg Radiation Oncology Program