title: Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. Electronic address: nicolaj@oncology.au.dk.
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authors.affiliation: Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, USA.
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authors.affiliation: Department of Radiation Oncology, University of Rochester Medical Center, USA; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, USA.
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authors.initials: SL
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authors.affiliation: Departments of Pathology and Pediatrics, Albert Einstein College of Medicine, New York, USA.
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authors.affiliation: Department of Radiotherapy (Maastro Clinic), Maastricht University Medical Center, The Netherlands.
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authors.affiliation: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK; Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, UK.
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authors.affiliation: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK; Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, UK.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, UK.
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authors.affiliation: Institute of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust, UK.
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authors.affiliation: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK.
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authors.affiliation: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK.
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authors.affiliation: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, UK.
authors.forename: Charlotte
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authors.affiliation: Clinical Trials & Statistics Unit (ICR-CTSU), The Institute of Cancer Research, London, UK.
authors.forename: Emma
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authors.affiliation: Fundacion Publica Galega de Medicina Xenomica-SERGAS, Grupo de Medicina Xenomica-USC, IDIS, CIBERER, Santiago de Compostela, Spain.
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authors.affiliation: Fundacion Publica Galega de Medicina Xenomica-SERGAS, Grupo de Medicina Xenomica-USC, IDIS, CIBERER, Santiago de Compostela, Spain.
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authors.affiliation: Department of Basic Medical Sciences, Ghent University, Belgium.
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authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
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authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.
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authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada.
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authors.affiliation: Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Spain.
authors.forename: Sara
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authors.lastname: Gutiérrez-Enríquez
authors.affiliation: Department of Radiation Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
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authors.affiliation: The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Yarnold
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
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authors.affiliation: Greenebaum Cancer Center and Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, USA.
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authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
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mesh_terms: D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000209:etiology / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics; D011878:Radiotherapy / Q000009:adverse effects; D012307:Risk Factors
chemical_list: C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Ataxia telangiectasia mutated; Normal tissue toxicity; Radiosensitivity; c.5557G>A; p.Asp1853Asn