TY - JOUR
T1 - Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy
AU - for the DKTK-ROG
AU - Tawk, Bouchra
AU - Wirkner, Ute
AU - Schwager, Christian
AU - Rein, Katrin
AU - Zaoui, Karim
AU - Federspil, Philippe A.
AU - Adeberg, Sebastian
AU - Linge, Annett
AU - Ganswindt, Ute
AU - Hess, Julia
AU - Unger, Kristian
AU - Tinhofer, Ingeborg
AU - Budach, Volker
AU - Lohaus, Fabian
AU - Krause, Mechthild
AU - Guberina, Maja
AU - Stuschke, Martin
AU - Balermpas, Panagiotis
AU - Rödel, Claus
AU - Grosu, Anca L.
AU - Schäfer, Henning
AU - Zips, Daniel
AU - Combs, Stephanie E.
AU - Pigorsch, Steffi
AU - Zitzelsberger, Horst
AU - Baumeister, Philipp
AU - Kirchner, Thomas
AU - Bewerunge-Hudler, Melanie
AU - Weichert, Wilko
AU - Hess, Jochen
AU - Herpel, Esther
AU - Belka, Claus
AU - Baumann, Michael
AU - Debus, Jürgen
AU - Abdollahi, Amir
N1 - Publisher Copyright:
© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2022/2/15
Y1 - 2022/2/15
N2 - 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.
AB - 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.
KW - DNA methylation
KW - disease recurrence
KW - head and neck cancers
KW - radiotherapy
KW - stratification
UR - http://www.scopus.com/inward/record.url?scp=85118946409&partnerID=8YFLogxK
U2 - 10.1002/ijc.33842
DO - 10.1002/ijc.33842
M3 - Article
C2 - 34648658
AN - SCOPUS:85118946409
SN - 0020-7136
VL - 150
SP - 603
EP - 616
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 4
ER -