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Tawk, B.* ; Rein, K.* ; Schwager, C.* ; Knoll, M.* ; Wirkner, U.* ; Hörner-Rieber, J.* ; Liermann, J.* ; Kurth, I.* ; Balermpas, P.* ; Rödel, C.* ; Linge, A.* ; Löck, S.* ; Lohaus, F.* ; Tinhofer, I.* ; Krause, M.* ; Stuschke, M.* ; Grosu, A.L.* ; Zips, D.* ; Combs, S.E.* ; Belka, C. ; Stenzinger, A.* ; Herold-Mende, C.* ; Baumann, M.* ; Schirmacher, P.* ; Debus, J.* ; Abdollahi, A.*

DNA-methylome–based tumor hypoxia classifier identifies HPV-negative head and neck cancer patients at risk for locoregional recurrence after primary radiochemotherapy.

Clin. Cancer Res. 29, 3051-3064 (2023)
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Purpose: 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. Experimental Design: 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). Results: Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P ¼ 0.001) and overall survival (HR, 2.34; P ¼ 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 ¼ 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. Conclusions: 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene-expression Classifier; Good Prognosis Subgroups; Squamous-cell Carcinoma; Postoperative Radiochemotherapy; Marker Expression; Radiotherapy; Multicenter; Stanniocalcin-2; Interference; Metastasis
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1078-0432
e-ISSN 1557-3265
Journal Clinical Cancer Research
Quellenangaben Volume: 29, Issue: 16, Pages: 3051-3064 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Reviewing status Peer reviewed
Institute(s) Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Radiation Sciences
PSP Element(s) G-501000-001
Grants Zentrum fur Personalisierte Medizin
Dieter Morszeck Foundation
National Center for Tumor Diseases (NCT) Heidelberg Radiation Oncology Program
Helmholtz Cross-Program Initiative Personalized Medicine (iMed)
German Cancer Consortium (DKTK)
DOI 10.1158/1078-0432.CCR-22-3790
WOS ID 001054740200001
Scopus ID 85168221541
PubMed ID 37058257
Erfassungsdatum 2023-12-05
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