Abstract

There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity1. However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype2, which could emerge years after the completion of treatment3. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of 633 cases from the UK4 and 368 cases from North America5. One locus comprising TANC1 (lowest unadjusted P value for overall late toxicity = 6.85 × 10−9, odds ratio (OR) = 6.61, 95% confidence interval (CI) = 2.23–19.63) was replicated in the second stage (lowest unadjusted P value for overall late toxicity = 2.08 × 10−4, OR = 6.17, 95% CI = 2.25–16.95; Pcombined = 4.16 × 10−10). The inclusion of the third cohort gave unadjusted Pcombined = 4.64 × 10−11. These results, together with the role of TANC1 in regenerating damaged muscle, suggest that the TANC1 locus influences the development of late radiation-induced damage.

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Acknowledgements

We are grateful to all participating patients for their cooperation. We thank I. Quintela from CEGEN (Spanish National Genotyping Center) for her support as Affymetrix genotyping platform manager. We also thank the Galician Supercomputation Centre for providing computing infrastructures and the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai for providing computational resources and staff expertise. This work was funded by grants from the Instituto de Salud Carlos III (FIS PI10/00164 and PI13/02030) and the Fondo Europeo de Desarrollo Regional (FEDER 2007–2013). L.F. is supported by the Isabel Barreto program from Xunta de Galicia and Fondo Social Europeo and was granted by an ESTRO Technology Transfer Grant (2012). The RAPPER group is supported by Cancer Research UK and Experimental Cancer Medicine Centre funding. Investigators from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust acknowledge support from the National Institute for Health Research (NIHR) Royal Marsden NHS Foundation Trust and The Institute of Cancer Research Biomedical Research Centre. Sample and data collection within the CHHiP trial (CRUK/06/16) were supported by Cancer Research UK (SP2312/021 and C8262/A7253) and the UK Department of Health, with patient recruitment at participating sites supported by the NIHR Cancer Research Network. B.S.R. and S.L.K. are funded by grants RSGT-05-200-01-CCE from the American Cancer Society, PC074201 from the US Department of Defense and 1R01CA134444 from the US National Institutes of Health. Á.C. acknowledges support from the Instituto de Salud Carlos III and the Fondo Europeo de Desarrollo Regional (PI13/01136, FEDER 2007–2013), a King Abdulaziz University grant (1-117-1434-HiCi), Innopharma and the Botin Foundation. The research collaboration leading to this paper was developed under the framework of the Radiogenomics Consortium.

Author information

Affiliations

  1. Fundación Pública Galega de Medicina Xenómica, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Spain.

    • Laura Fachal
    • , Ángel Carracedo
    •  & Ana Vega
  2. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.

    • Laura Fachal
    • , Ángel Carracedo
    •  & Ana Vega
  3. Department of Radiation Oncology, USC University Hospital Complex, SERGAS, Santiago de Compostela, Spain.

    • Antonio Gómez-Caamaño
    • , Paula Peleteiro
    • , Ana M Carballo
    •  & Patricia Calvo-Crespo
  4. Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Gillian C Barnett
    • , Leila Dorling
    •  & Alison M Dunning
  5. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Sarah L Kerns
    •  & Barry S Rosenstein
  6. Department of Medical Physics, USC University Hospital Complex, SERGAS, Santiago de Compostela, Spain.

    • Manuel Sánchez-García
    •  & Ramón Lobato-Busto
  7. Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK.

    • Rebecca M Elliott
    •  & Catharine M L West
  8. Institute of Cancer Research and Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, UK.

    • David P Dearnaley
  9. Cancer and Other Non-Infectious Diseases, Medical Research Council (MRC) Clinical Trials Unit, London, UK.

    • Matthew R Sydes
  10. Clinical Trials and Statistics Unit, Institute of Cancer Research, London, UK.

    • Emma Hall
  11. Department of Oncology, University of Cambridge, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Neil G Burnet
  12. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.

    • Ángel Carracedo

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Contributions

A.V. conceived and coordinated the study and obtained financial support. A.V. and L.F. designed the GWAS. L.F. performed laboratory work, data analysis, quality control analysis and imputation of the RADIOGEN study. L.F. and A.V. drafted the manuscript with contributions from C.M.L.W., G.C.B., A.M.D., S.L.K., B.S.R. and L.D. L.F., A.G.-C. and A.V. collated and managed the RADIOGEN database. A.G.-C., P.P., A.M.C. and P.C.-C. were involved in the collection of cases, and clinical and toxicity data for the RADIOGEN study. G.C.B., N.G.B., C.M.L.W. and A.M.D. were involved in the conception and design of the RAPPER study. G.C.B. and L.D. were involved in quality control analysis and imputation for the RAPPER study. G.C.B., R.M.E., D.P.D., M.R.S. and E.H. were involved in RAPPER data acquisition. S.L.K. was involved in laboratory work, quality control analysis and imputation for the Gene-PARE study. M.S.-G. and R.L.-B. were involved in the collection of dosimetric data for the RADIOGEN study. D.P.D. designed, initiated and was chief investigator for the RAPPER RT01 and CHHiP trials. Á.C. contributed to the RADIOGEN study. B.S.R. was involved in the conception and design of the Gene-PARE study. All authors were involved in the writing or critical review of the draft report, and all approved the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ana Vega.

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https://doi.org/10.1038/ng.3020

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