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

Tawk, Bouchra; Wirkner, Ute; Schwager, Christian; Rein, Katrin; Zaoui, Karim; Federspil, Philippe A.; Adeberg, Sebastian; Linge, Annett; Ganswindt, Ute; Hess, Julia; Unger, Kristian; Tinhofer, Ingeborg; Budach, Volker; Lohaus, Fabian; Krause, Mechthild; Guberina, Maja; Stuschke, Martin; Balermpas, Panagiotis; Rodel, Claus; Grosu, Anca L.; Schaefer, Henning; Zips, Daniel; Combs, Stephanie E.; Pigorsch, Steffi; Zitzelsberger, Horst; Baumeister, Philipp; Kirchner, Thomas; Bewerunge-Hudler, Melanie; Weichert, Wilko; Hess, Jochen; Herpel, Esther; Belka, Claus; Baumann, Michael; Debus, Jürgen und Abdollahi, Amir (2021): Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy. In: International Journal of Cancer, Bd. 150, Nr. 4: S. 603-616

Abstract

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 HPV-DNA 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 450 K and 850 K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in the 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 metastasis 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0020-7136
• Sprache: Englisch