Liverpool Head & Neck Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, University of Liverpool, United Kingdom; The Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, United Kingdom.
Technology Directorate, Computational Biology Facility, University of Liverpool, United Kingdom; Institute of Systems, Molecular and Integrative Biology, Biochemistry and Systems Biology, University of Liverpool, United Kingdom; Center for Molecular Medicine Cologne, Faculty of Medicine and Cologne University Hospital, University of Cologne, Germany.
Radiother Oncol. 2021 Dec;165:87-93. doi: 10.1016/j.radonc.2021.10.020. Epub 2021 Oct 30.
BACKGROUND/AIM: Utilising radiotherapy in the management of head and neck cancer (HNC) often results in long term toxicities. Mandibular osteoradionecrosis (ORN) represents a late toxicity associated with significant morbidity. We aim to identify a panel of common genetic variants which can predict ORN to aid development of personalised radiotherapy protocols.
Single nucleotide polymorphism (SNP) arrays were applied to DNA samples from patients who had prior HNC radiotherapy and minimum two years follow-up. A case cohort of mandibular ORN was compared to a control group of participants recruited to CRUK HOPON clinical trial. Relevant clinical parameters influencing ORN risk (e.g. smoking/alcohol) were collected. Significant associations from array data were internally validated using polymerase chain reaction (PCR) and pyrosequencing.
Following inclusion of 141 patients in the analysis (52 cases, 89 controls), a model predictive for ORN was developed; after controlling for alcohol consumption, smoking, and age, 4053 SNPs were identified as significant. This was reduced to a representative model of 18 SNPs achieving 92% accuracy. Following internal technical validation, a six SNP model (rs34798038, rs6011731, rs2348569, rs530752, rs7477958, rs1415848) was retained within multivariate regression analysis (ROC AUC 0.859). Of these, four SNPs (rs34798038 (A/G) (p 0.006), rs6011731 (C/T) (p 0.018), rs530752 (A/G) (p 0.046) and rs2348569 (G/G) (p 0.005)) were significantly associated with the absence of ORN.
This is the first genome wide association study in HNC using ORN as the endpoint and offers new insight into ORN pathogenesis. Subject to validation, these variants may guide patient selection for personalised radiotherapy strategies.
背景/目的：在头颈部癌症（HNC）的治疗中使用放射疗法通常会导致长期毒性。下颌骨放射性骨坏死（ORN）是与显著发病率相关的一种晚期毒性。我们旨在确定一组常见的遗传变异体，这些变异体可以预测 ORN，以帮助制定个性化的放射治疗方案。
对接受过头颈部放射治疗且至少随访两年的患者的 DNA 样本应用单核苷酸多态性（SNP）阵列。将下颌骨 ORN 的病例队列与英国癌症研究中心 HOPON 临床试验招募的对照组进行比较。收集影响 ORN 风险的相关临床参数（例如吸烟/饮酒）。使用聚合酶链反应（PCR）和焦磷酸测序对内数组数据进行了显著关联的内部验证。
在对 141 例患者进行分析（52 例病例，89 例对照）后，建立了一个预测 ORN 的模型；在控制饮酒、吸烟和年龄后，鉴定出 4053 个 SNP 具有显著性。这被简化为一个具有 92%准确性的代表性 18SNP 模型。经过内部技术验证，保留了一个由 6 个 SNP 组成的模型（rs34798038、rs6011731、rs2348569、rs530752、rs7477958、rs1415848）用于多元回归分析（ROC AUC 0.859）。在这些 SNP 中，有 4 个 SNP（rs34798038（A/G）（p 0.006）、rs6011731（C/T）（p 0.018）、rs530752（A/G）（p 0.046）和 rs2348569（G/G）（p 0.005））与 ORN 不存在显著相关。
这是首次对头颈部癌症（HNC）使用 ORN 作为终点的全基因组关联研究，为 ORN 发病机制提供了新的见解。在经过验证后，这些变体可能会指导患者选择个性化的放射治疗策略。
