Genetic variants associated with mandibular osteoradionecrosis following radiotherapy for head and neck malignancy

  • Author Footnotes
    1 Joint first author.
    Rachel C. Brooker
    Correspondence
    Corresponding author at: The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral CH63 4JY, United Kingdom.
    Footnotes
    1 Joint first author.
    Affiliations
    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
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  • Author Footnotes
    1 Joint first author.
    Philipp Antczak
    Footnotes
    1 Joint first author.
    Affiliations
    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
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  • Triantafillos Liloglou
    Affiliations
    Liverpool Head & Neck Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, University of Liverpool, United Kingdom

    Institute of Systems, Molecular and Integrative Biology, Dept of Molecular & Clinical Cancer Medicine, University of Liverpool, United Kingdom
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  • Janet M. Risk
    Affiliations
    Liverpool Head & Neck Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, University of Liverpool, United Kingdom
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  • Joseph J. Sacco
    Affiliations
    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
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  • Andrew G. Schache
    Affiliations
    Liverpool Head & Neck Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, University of Liverpool, United Kingdom

    Head and Neck Unit, Liverpool University Hospital NHS Foundation Trust, Aintree University Hospital, United Kingdom
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  • Richard J. Shaw
    Affiliations
    Liverpool Head & Neck Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, University of Liverpool, United Kingdom

    Head and Neck Unit, Liverpool University Hospital NHS Foundation Trust, Aintree University Hospital, United Kingdom
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  • Author Footnotes
    1 Joint first author.
Published:October 29, 2021DOI:https://doi.org/10.1016/j.radonc.2021.10.020

      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.

      Keywords

      Abbreviations:

      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)
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