A tumor DNA-Methylome derived signature of Hypoxia Identifies HPV-negative head and neck cancer patients at risk for distant metastasis after postoperative radiochemotherapy (PORT-C)

IF 5.8 1区医学 Q1 ONCOLOGY

Radiotherapy and Oncology Pub Date : 2026-04-01 Epub Date: 2026-02-09 DOI:10.1016/j.radonc.2026.111433

Bouchra Tawk , Gordana Halec , Katrin Rein , Christian Schwager , Maximillian Knoll , Ute Wirkner , Thomas Held , Fabian Weykamp , Jakob Liermann , Juliane Hoerner-Rieber , Ina Kurth , Panagiotis Balermpas , Claus Rödel , Maximilian Fleischmann , Annett Linge , Steffen Löck , Fabian Lohaus , Ingeborg Tinhofer , Mechthild Krause , Martin Stuschke , Amir Abdollahi

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引用次数: 0

Abstract

Background and purpose

Tumor hypoxia is a predictive biomarker of treatment resistance in patients with head and neck squamous cell carcinoma (HNSCC). We previously reported the discovery of a tumor DNA methylation signature of hypoxia (Hypoxia-M), identifying HNSCC patients at risk for local recurrence (LR), all event progression, and death after primary radiochemotherapy (RCHT). We further validate Hypoxia-M in an independent cohort of HNSCC patients who underwent surgical resection followed by postoperative radiochemotherapy (PORT-C)

Methods

Hypoxia-M was validated in HPV-negative HNSCC patients (n = 134) homogeneously treated with PORT-C in the frame of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA methylation was profiled using Illumina450K technology. The performance of Hypoxia-M was integrated with previously reported biomarkers, including gene expression signatures (GES) of hypoxia, a methylome-based HPV-Independent Classifier of disease Recurrence (HICR), and immune cell score using immunohistochemistry (CD3/CD8/PD-L1/PD1).

Results

Hypoxia-M was independently prognostic for overall survival (OS, HR = 2.34, p = 0.03) and distant metastasis (DM, HR = 4.3, p = 0.001), but not for LR after PORT-C. Hypoxia-M remained significant after adjusting for patientś age, gender, smoking status, tumor stage, and high-risk features (ECE&/R1 resection). Hypoxia-M status was inversely associated with CD8 T-cell infiltration. Patient stratification improved by integrating previously reported biomarkers, with Hypoxia-M demonstrating independent prognostic performance.

Conclusions

The prognostic utility of Hypoxia-M was validated in an independent cohort. Our results highlighted a difference in recurrence patterns of hypoxic tumors treated in the primary setting (local recurrence) versus postoperatively (distant metastasis) and the utility of Hypoxia-M for identifying the main pattern of recurrence.

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肿瘤dna甲基化组衍生的缺氧特征识别hpv阴性头颈癌患者术后放化疗后有远处转移风险（PORT-C）。

背景与目的：肿瘤缺氧是头颈部鳞状细胞癌（HNSCC）患者治疗耐药的预测性生物标志物。我们之前报道了肿瘤DNA甲基化特征缺氧（hypoxia - m）的发现，确定了HNSCC患者在初次放化疗（RCHT）后存在局部复发（LR）、所有事件进展和死亡风险。我们进一步验证了Hypoxia-M在接受手术切除后术后放化疗（PORT-C）的HNSCC患者的独立队列中的有效性。方法：在德国癌症协会放射肿瘤学组（DKTK-ROG）多中心生物标志物试验的框架中，Hypoxia-M在接受PORT-C均质治疗的hpv阴性HNSCC患者（n = 134）中得到验证。使用Illumina450K技术分析DNA甲基化。hypoxia - m的表现与先前报道的生物标志物相结合，包括缺氧的基因表达特征（GES），基于甲基组的hpv独立疾病复发分类器（HICR），以及使用免疫组织化学（CD3/CD8/PD-L1/PD1）的免疫细胞评分。结果：缺氧- m对总生存（OS, HR = 2.34,p = 0.03）和远处转移（DM, HR = 4.3,p = 0.001）有独立的预后影响，但对PORT-C术后LR无影响。在调整患者年龄、性别、吸烟状况、肿瘤分期和高危特征（ece和/R1切除）后，低氧- m仍然显著。低氧m状态与CD8 t细胞浸润呈负相关。通过整合先前报道的生物标志物，患者分层得到改善，其中Hypoxia-M显示了独立的预后表现。结论：在一个独立队列中，Hypoxia-M的预后效用得到了验证。我们的研究结果强调了原发性缺氧肿瘤（局部复发）与术后（远处转移）复发模式的差异，以及缺氧- m在确定主要复发模式方面的应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Radiotherapy and Oncology 医学-核医学

CiteScore

10.30

自引率

10.50%

发文量

2445

审稿时长

45 days

期刊介绍： Radiotherapy and Oncology publishes papers describing original research as well as review articles. It covers areas of interest relating to radiation oncology. This includes: clinical radiotherapy, combined modality treatment, translational studies, epidemiological outcomes, imaging, dosimetry, and radiation therapy planning, experimental work in radiobiology, chemobiology, hyperthermia and tumour biology, as well as data science in radiation oncology and physics aspects relevant to oncology.Papers on more general aspects of interest to the radiation oncologist including chemotherapy, surgery and immunology are also published.