Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy

被引：2

作者：

Tawk, Bouchra ^{[1
,2
,3
,4
,5
,6
]}

Wirkner, Ute ^{[1
,2
,3
,4
,5
,6
]}

Schwager, Christian ^{[1
,2
,3
,4
,5
,6
]}

Rein, Katrin ^{[1
,2
,3
,4
,5
,6
]}

Zaoui, Karim ^{[7
]}

Federspil, Philippe A. ^{[7
]}

Adeberg, Sebastian ^{[1
,2
,8
,9
]}

Linge, Annett ^{[3
,10
,11
,12
,13
,14
,15
,16
]}

Ganswindt, Ute ^{[17
,18
]}

Hess, Julia ^{[19
,20
,21
]}

Unger, Kristian ^{[19
,20
,21
]}

Tinhofer, Ingeborg ^{[22
,23
]}

Budach, Volker ^{[22
,23
]}

Lohaus, Fabian ^{[3
,10
,11
,12
,13
,14
,15
,16
]}

Krause, Mechthild ^{[3
,10
,11
,12
,13
,14
,15
,16
]}

Guberina, Maja ^{[24
,25
]}

Stuschke, Martin ^{[11
,12
,25
]}

Balermpas, Panagiotis ^{[26
,27
]}

Rodel, Claus ^{[26
,28
]}

Grosu, Anca L. ^{[29
,30
,31
]}

Schaefer, Henning ^{[29
,30
]}

Zips, Daniel ^{[32
,33
,34
]}

Combs, Stephanie E. ^{[17
,35
]}

Pigorsch, Steffi ^{[17
,35
]}

Zitzelsberger, Horst ^{[19
,20
,21
]}

Baumeister, Philipp ^{[20
,36
]}

Kirchner, Thomas ^{[17
,37
]}

Bewerunge-Hudler, Melanie ^{[38
]}

Weichert, Wilko ^{[17
,39
]}

Hess, Jochen ^{[7
,40
]}

Herpel, Esther ^{[1
,2
,41
,42
]}

Belka, Claus ^{[17
,19
,20
]}

Baumann, Michael ^{[1
,2
,10
,11
,12
,13
]}

Debus, Juergen ^{[1
,2
,3
,4
,5
,6
]}

Abdollahi, Amir ^{[1
,2
,3
,4
,5
,6
]}

机构：

[1] German Canc Res Ctr, Heidelberg, Germany

[2] German Canc Consortium DKTK, Core Ctr Heidelberg, Heidelberg, Germany

[3] Heidelberg Univ Hosp UKHD, Clin Cooperat Unit Translat Radiat Oncol, Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[4] Heidelberg Fac Med MFHD, Dept Radiat Oncol, Div Mol & Translat Radiat Oncol, Heidelberg, Germany

[5] Heidelberg Univ Hosp UKHD, Heidelberg Ion Beam Therapy Ctr HIT, Heidelberg, Germany

[6] Heidelberg Univ, Natl Ctr Radiat Oncol NCRO, Heidelberg Inst Radiat Oncol HIRO, Heidelberg, Germany

[7] Heidelberg Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Heidelberg, Germany

[8] Univ Hosp Heidelberg, Dept Radiat Oncol, Heidelberg, Germany

[9] Heidelberg Inst Radiat Oncol HIRO, Heidelberg, Germany

[10] German Canc Consortium DKTK, Partner Site Dresden, Dresden, Germany

[11] Tech Univ Dresden, Fac Med, Dept Radiotherapy & Radiat Oncol, Dresden, Germany

[12] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dresden, Germany

[13] Tech Univ Dresden, Fac Med, OncoRay Natl Ctr Radiat Res Oncol, Dresden, Germany

[14] Natl Ctr Tumor Dis NCT, Partner Site Dresden, Dresden, Germany

[15] Tech Univ Dresden, Fac Med, Dresden, Germany

[16] Helmholtz Zentrum Dresden Rossendorf HZDR, Helmholtz Assoc, Dresden, Germany

[17] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany

[18] Med Univ Innsbruck, Dept Radiat Oncol, Innsbruck, Austria

[19] Univ Hosp Ludwig Maximilians Univ Munich, Dept Radiat Oncol, Munich, Germany

[20] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Res Unit Radiat Cytogenet, Neuherberg, Germany

[21] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Clin Cooperat Grp Personalized Radiotherapy Head, Neuherberg, Germany

[22] German Canc Consortium DKTK, Partner Site Berlin, Berlin, Germany

[23] Charite, Dept Radiooncol & Radiotherapy, Berlin, Germany

[24] German Canc Consortium DKTK, Partner Site Essen, Essen, Germany

[25] Univ Duisburg Essen, Med Fac, Dept Radiotherapy, Essen, Germany

[26] German Canc Consortium DKTK, Partner Site Frankfurt, Frankfurt, Germany

[27] Univ Hosp Zurich, Dept Radiat Oncol, Zurich, Switzerland

[28] Goethe Univ Frankfurt, Dept Radiotherapy & Oncol, Frankfurt, Germany

[29] German Canc Consortium DKTK, Partner Site Freiburg, Freiburg, Germany

[30] Univ Freiburg, Clin Study Sect, Dept Radiat Oncol, Freiburg, Germany

[31] Univ Freiburg, Dept Radiat Oncol, Freiburg, Germany

[32] German Canc Consortium DKTK, Partner Site Tuebingen, Tubingen, Germany

[33] Eberhard Karls Univ Tubingen, Dept Radiat Oncol, Fac Med, Tubingen, Germany

[34] Eberhard Karls Univ Tubingen, Univ Hosp Tubingen, Tubingen, Germany

[35] Tech Univ Munich, Dept Radiat Oncol, Munich, Germany

[36] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Munich, Germany

[37] Ludwig Maximilians Univ Munchen, Fac Med, Inst Pathol, Munich, Germany

[38] German Canc Res Ctr, Genom & Prote Core Facil, Heidelberg, Germany

[39] Tech Univ Munich, Inst Pathol, Munich, Germany

[40] German Canc Res Ctr, Dept Mol Mech Head & Neck Tumors, Heidelberg, Germany

[41] Natl Ctr Tumor Dis NCT, Tissue Bank, Heidelberg, Germany

[42] Heidelberg Univ Hosp, Inst Pathol, Dept Appl Tumor Biol, Heidelberg, Germany

来源：

INTERNATIONAL JOURNAL OF CANCER | 2022年 / 150卷 / 04期

关键词：

disease recurrence; DNA methylation; head and neck cancers; radiotherapy; stratification; GOOD PROGNOSIS SUBGROUPS; CELL MARKER EXPRESSION; LOCALLY ADVANCED HEAD; CANCER; MULTICENTER; METHYLATION; CHEMORADIOTHERAPY; CARCINOMAS; SIGNATURES; BIOMARKER;

D O I：

10.1002/ijc.33842

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：603 / 616

页数：14

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