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 S2. (Top) Hypoxia-M V2 is prognostic in the DKTK-ROG cohort. Patients predicted to have higher tumor hypoxia by Hypoxia-M V2 had higher rates of death (p=0.0097), local recurrence (p=0.0037), distant metastasis (p=0.027) and disease progression (p=0.00096). (Bottom) Hypoxia-M V2 remains an independent prognosticator of OS, LR and disease progression after adjusting for age, smoking status, GTV and anatomical site. Additionally, there is a trend towards higher rates of distant metastasis (HR=2.33, p=0.13)
Funding
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)
History
ARTICLE ABSTRACT
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
