Christian Nicolaj Andreassen1, Barry S Rosenstein2, Sarah L Kerns3, Harry Ostrer4, Dirk De Ruysscher5, Jamie A Cesaretti6, Gillian C Barnett7, Alison M Dunning7, Leila Dorling8, Catharine M L West9, Neil G Burnet10, Rebecca Elliott10, Charlotte Coles10, Emma Hall11, Laura Fachal12, Ana Vega12, Antonio Gómez-Caamaño13, Christopher J Talbot14, R Paul Symonds15, Kim De Ruyck16, Hubert Thierens16, Piet Ost17, Jenny Chang-Claude18, Petra Seibold19, Odilia Popanda20, Marie Overgaard21, David Dearnaley22, Matthew R Sydes23, David Azria24, Christine Anne Koch25, Matthew Parliament26, Michael Blackshaw26, Michael Sia27, Maria J Fuentes-Raspall28, Teresa Ramon Y Cajal29, Agustin Barnadas29, Danny Vesprini30, Sara Gutiérrez-Enríquez31, Meritxell Mollà32, Orland Díez33, John R Yarnold22, Jens Overgaard21, Søren M Bentzen34, Jan Alsner21. 1. Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. Electronic address: nicolaj@oncology.au.dk. 2. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, USA. 3. Department of Radiation Oncology, University of Rochester Medical Center, USA; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, USA. 4. Departments of Pathology and Pediatrics, Albert Einstein College of Medicine, New York, USA. 5. Department of Radiotherapy (Maastro Clinic), Maastricht University Medical Center, The Netherlands. 6. Southpoint Cancer Center, Jacksonville, USA. 7. Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK; Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, UK. 8. Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, UK. 9. Institute of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust, UK. 10. Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK. 11. Clinical Trials & Statistics Unit (ICR-CTSU), The Institute of Cancer Research, London, UK. 12. Fundacion Publica Galega de Medicina Xenomica-SERGAS, Grupo de Medicina Xenomica-USC, IDIS, CIBERER, Santiago de Compostela, Spain. 13. Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain. 14. Department of Genetics, University of Leicester, UK. 15. Department of Cancer Studies, University of Leicester, UK. 16. Department of Basic Medical Sciences, Ghent University, Belgium. 17. Department of Radiotherapy, Ghent University Hospital, Belgium. 18. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg, University (UCCH), University Medical Center Hamburg-Eppendorf, Germany. 19. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 20. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. 21. Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. 22. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK. 23. MRC Clinical Trials Unit at UCL, London, UK. 24. Department of Radiation Oncology and Medical Physics, Institut regional du Cancer Montpellier, France. 25. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. 26. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada. 27. Department of Radiation Oncology, British Columbia Cancer Agency Abbotsford Clinic, Canada. 28. Department of Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 29. Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 30. Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada. 31. Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Spain. 32. Department of Radiation Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 33. Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Area of Clinical and Molecular Genetics, Vall d'Hebron University Hospital, Barcelona, Spain. 34. Greenebaum Cancer Center and Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, USA.
Abstract
PURPOSE: Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. MATERIALS AND METHODS: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. RESULTS: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. CONCLUSION: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.
PURPOSE: Several small studies have indicated that the ATMrs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. MATERIALS AND METHODS: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. RESULTS: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. CONCLUSION: This study convincingly showed a significant association between the ATMrs1801516Asn allele and increased risk of radiation-induced normal tissue toxicity.
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