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Kerns SL, Fachal L, Dorling L, et al. Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy. J Natl Cancer Inst. 2020;112(2):179-190doi: 10.1093/jnci/djz075.
Kerns, S. L., Fachal, L., Dorling, L., Barnett, G. C., Baran, A., Peterson, D. R., Hollenberg, M., Hao, K., Narzo, A. D., Ahsen, M. E., Pandey, G., Bentzen, S. M., Janelsins, M., Elliott, R. M., Pharoah, P. D. P., Burnet, N. G., Dearnaley, D. P., Gulliford, S. L., Hall, E., Sydes, M. R., Aguado-Barrera, M. E., Gómez-Caamaño, A., Carballo, A. M., Peleteiro, P., Lobato-Busto, R., Stock, R., Stone, N. N., Ostrer, H., Usmani, N., Singhal, S., Tsuji, H., Imai, T., Saito, S., Eeles, R., DeRuyck, K., Parliament, M., Dunning, A. M., Vega, A., Rosenstein, B. S., & West, C. M. L. (2020). Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy. Journal of the National Cancer Institute, 112(2), 179-190. https://doi.org/10.1093/jnci/djz075
Kerns, Sarah L, et al. "Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy." Journal of the National Cancer Institute vol. 112,2 (2020): 179-190. doi: https://doi.org/10.1093/jnci/djz075
Kerns SL, Fachal L, Dorling L, Barnett GC, Baran A, Peterson DR, Hollenberg M, Hao K, Narzo AD, Ahsen ME, Pandey G, Bentzen SM, Janelsins M, Elliott RM, Pharoah PDP, Burnet NG, Dearnaley DP, Gulliford SL, Hall E, Sydes MR, Aguado-Barrera ME, Gómez-Caamaño A, Carballo AM, Peleteiro P, Lobato-Busto R, Stock R, Stone NN, Ostrer H, Usmani N, Singhal S, Tsuji H, Imai T, Saito S, Eeles R, DeRuyck K, Parliament M, Dunning AM, Vega A, Rosenstein BS, West CML. Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy. J Natl Cancer Inst. 2020 Feb 01;112(2):179-190. doi: 10.1093/jnci/djz075. PMID: 31095341; PMCID: PMC7019089.
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J Natl Cancer Inst. 2020 Feb 01;112(2):179-190. doi: 10.1093/jnci/djz075.

Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.

Journal of the National Cancer Institute

Sarah L Kerns, Laura Fachal, Leila Dorling, Gillian C Barnett, Andrea Baran, Derick R Peterson, Michelle Hollenberg, Ke Hao, Antonio Di Narzo, Mehmet Eren Ahsen, Gaurav Pandey, Søren M Bentzen, Michelle Janelsins, Rebecca M Elliott, Paul D P Pharoah, Neil G Burnet, David P Dearnaley, Sarah L Gulliford, Emma Hall, Matthew R Sydes, Miguel E Aguado-Barrera, Antonio Gómez-Caamaño, Ana M Carballo, Paula Peleteiro, Ramón Lobato-Busto, Richard Stock, Nelson N Stone, Harry Ostrer, Nawaid Usmani, Sandeep Singhal, Hiroshi Tsuji, Takashi Imai, Shiro Saito, Rosalind Eeles, Kim DeRuyck, Matthew Parliament, Alison M Dunning, Ana Vega, Barry S Rosenstein, Catharine M L West

Affiliations

  1. Departments of Radiation Oncology and Surgery, University of Rochester Medical Center, Rochester, NY.
  2. Department of Oncology.
  3. Department of Public Health and Primary Care.
  4. Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  5. Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY.
  6. Department of Computational Biology, University of Rochester, Rochester, NY.
  7. Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY.
  8. Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore.
  9. Division of Cancer Sciences, the University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, UK.
  10. Academic Urooncology Unit, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
  11. Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
  12. MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
  13. Fundación Pública Galega de Medicina Xenómica-Servizo Galego de Saude (SERGAS & Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
  14. Department of Radiation Oncology.
  15. Department of Medical Physics.
  16. Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain; Department of Radiation Oncology.
  17. Department of Urology.
  18. Icahn School of Medicine at Mount Sinai, New York, NY; Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, NY.
  19. Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.
  20. National Institute of Radiological Science, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  21. Department of Pathology and Cell Biology, Columbia University, New York, NY.
  22. Department of Urology, National Tokyo Medical Center, Tokyo, Japan.
  23. Division of Genetics and Epidemiology, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
  24. Departments of Basic Medical Sciences and Radiotherapy, Ghent University Hospital, Ghent, Belgium.
  25. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
  26. Departments of Radiation Oncology & Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.

PMID: 31095341 PMCID: PMC7019089 DOI: 10.1093/jnci/djz075

Abstract

BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies.

METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.

RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.

CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

© The Author(s) 2019. Published by Oxford University Press.

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