Association of radiation-induced normal tissue toxicity with a high genetic risk for rheumatoid arthritis

Year: 2025

Type: article

Abstract: BACKGROUND: Overlapping genes are involved with rheumatoid arthritis (RA) and DNA repair pathways. Therefore, we hypothesized that patients with a high polygenic risk score for RA will have an increased risk of radiotherapy toxicity given the involvement of DNA repair. METHODS: Primary analysis was performed on 1494 prostate cancer, 483 lung cancer, and 1820 breast cancer patients assessed for development of radiotherapy toxicity in the REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) study. Validation cohorts were available from the Radiogenomics Consortium. All patients had undergone curative-intent radiotherapy and were assessed prospectively for toxicity. Germline genomic data was available for all patients, allowing a polygenic risk score to be calculated using 101 RA risk variants. Polygenic risk score was analyzed as a continuous variable and with a more than 90th percentile cutoff. Associations with acute and late standardized total average toxicity (STAT) scores and individual toxicity endpoints were analyzed in multivariable models with preselected adjustment variables. RESULTS: Increasing polygenic risk score for RA did not increase the risk of STAT-acute or STAT-late in any cohort. There was an increased risk of late esophagitis in the lung cancer cohort (coefficient = 0.018, P = .01), however this was not validated (P = .79). No individual acute or late toxicity endpoints were statistically significantly associated with polygenic risk score for the prostate or breast cohorts. No statistically significant results were found in the validation cohorts in multivariable models. CONCLUSIONS: Patients with a high genetic risk for RA do not show increased levels of toxicity after radiotherapy suggesting treatment planning does not need to be modified for such patients.

Source: JNCI Journal of the National Cancer Institute

DOI: 10.1093/jnci/djae349

Institutions: University of Manchester, The Christie NHS Foundation Trust, Icahn School of Medicine at Mount Sinai, Medical College of Wisconsin, Cambridge University Hospitals NHS Foundation Trust, Centre for Biomedical Network Research on Rare Diseases, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago, Fondazione IRCCS Istituto Nazionale dei Tumori, Inserm, Institut de Recherche en Cancérologie de Montpellier, Institut Regional du Cancer de Montpellier, Universität Hamburg, German Cancer Research Center, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Universidade de Santiago de Compostela, University of Cambridge, Centre Hospitalier Universitaire de Nîmes, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology, Complejo Hospitalario Universitario de Santiago, Servicio Gallego de Salud, KU Leuven, University of Leicester, Maastro Clinic, Heidelberg University, University Medical Centre Mannheim, Medizinische Fakultät Mannheim, Ghent University Hospital, Ghent University

Language: English

Topic: Effects of Radiation Exposure

Subfield: Radiology, Nuclear Medicine and Imaging

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,436

Funders: National Institute on Handicapped Research, Fundación Cellex, Centres de Recerca de Catalunya, Cancer Research UK, National Institute for Health and Care Research, European Commission, Generalitat de Catalunya, National Institutes of Health, Manchester Biomedical Research Centre, Agencia Estatal de Investigación, NIHR Leicester Biomedical Research Centre

OpenAlex ID: W4406098043