Genetic variants associated with mandibular osteoradionecrosis following radiotherapy for head and neck malignancy. (December 2021)

• Record Type: Journal Article
• Authors: Brooker, Rachel C.; Antczak, Philipp; Liloglou, Triantafillos; Risk, Janet M.; Sacco, Joseph J.; Schache, Andrew G.; Shaw, Richard J.
• Is Part Of: Radiotherapy and oncology. Volume 165(2021)
• Page Start: 87
• Page End: 93
• Publication Date: 2021-12
• Subjects: Head and neck cancer -- Radiotherapy -- Osteoradionecrosis -- Mandible -- Single nucleotide polymorphism -- Genome wide association studies; HNC head and neck cancer -- ORN osteoradionecrosis -- SNP single nucleotide polymorphism -- PCR polymerase chain reaction -- ROC receiver operator characteristic -- AUC area under curve -- CRUK Cancer research UK -- HOPON hyperbaric oxygen for the prevention of osteoradionecrosis -- GWAS genome wide association study -- STAT standardised average toxicity score -- GALGO genetic algorithm based predictive modelling -- RF random forests -- UVA univariate analysis -- MVA multivariate analysis -- PCA principle component analysis; Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2021.10.020
• Languages: English
• ISSNs: 0167-8140

Abstract

Highlights: Osteoradionecrosis is a highly morbid complication of head and neck radiotherapy. Osteoradionecrosis was used as toxicity outcome for genome wide analysis. A panel of SNPs were associated with the absence of osteoradionecrosis. Functional enrichment analysis highlighted neural development/organisation pathways. Abstract: 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. Method: 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. Results: 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. Conclusion: 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.