American Association for Cancer Research
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Supplementary Figures S1 from DNA-Methylome–Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy

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journal contribution
posted on 2023-08-15, 08:21 authored by Bouchra Tawk, Katrin Rein, Christian Schwager, Maximilian Knoll, Ute Wirkner, Juliane Hörner-Rieber, Jakob Liermann, Ina Kurth, Panagiotis Balermpas, Claus Rödel, Annett Linge, Steffen Löck, Fabian Lohaus, Ingeborg Tinhofer, Mechtild Krause, Martin Stuschke, Anca Ligia Grosu, Daniel Zips, Stephanie E. Combs, Claus Belka, Albrecht Stenzinger, Christel Herold-Mende, Michael Baumann, Peter Schirmacher, Jürgen Debus, Amir Abdollahi

Supplementary Figure 1. (Top) Venn Diagram showing the intersect between Hypoxia-M V2 significant DMPs (n=3397) and Hypoxia-M V1 significant DMPs (n=5129) 2551 (66%) of significant DMPs identified based on the 85th percentile of standard deviation are also included in the selection criteria of Hypoxia-M V1. (middle) Hypoxia-M V2 is prognostic in the TCGA HNSCC cohort (p=0.041) and the prognostic effect remained independent on multivariate analysis. (bottom) Multivariate Analysis revealed that patients predicted to have high Hypoxia by Hypoxia-M V2 had worsened OS outcomes (HR=1.59, p<0.026). Additionally, increasing age and pN2 nodal status were negatively prognostic of OS (p<0.05)


Zentrum für Personalisierte-Medizin (ZPM-Network BW)

Helmholtz Cross-Program Initiative Personalized Medicine (iMed)

Nationales Centrum für Tumorerkrankungen Heidelberg (NCT Heidelberg)

Dieter Morszeck Stiftung (DMF)

Deutsches Krebsforschungszentrum (DKFZ)

Deutschen Konsortium für Translationale Krebsforschung (DKTK)



Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia. A DNA-methylome–based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression–based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)–negative patients with HNSCC treated with primary radiochemotherapy (RCHT). Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. Our findings highlight an unexplored avenue for DNA methylation–based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors.See related commentary by Heft Neal and Brenner, p. 2954

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