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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)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Gene-expression Classifier; Good Prognosis Subgroups; Squamous-cell Carcinoma; Postoperative Radiochemotherapy; Marker Expression; Radiotherapy; Multicenter; Stanniocalcin-2; Interference; Metastasis
ISSN (print) / ISBN 1078-0432
e-ISSN 1557-3265
Zeitschrift Clinical Cancer Research
Quellenangaben Band: 29, Heft: 16, Seiten: 3051-3064 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Translational Metabolic Oncology (TMO)
Förderungen 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)