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Title: Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity

Abstract

Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage. Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia. Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of amore » ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs. Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [2];  [4];  [5];  [6];  [4];  [1];  [7]; ;  [1]; ;  [3];  [1];  [4];  [1];
  1. Department of Genetics, University of Leicester, Leicester (United Kingdom)
  2. (United Kingdom)
  3. Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom)
  4. Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)
  5. Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom)
  6. Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom)
  7. Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom)
Publication Date:
OSTI Identifier:
22149648
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 84; Journal Issue: 4; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CARDIOVASCULAR DISEASES; FIBROSIS; GENE MUTATIONS; GENES; HEALTH HAZARDS; HEART; MAMMARY GLANDS; NEOPLASMS; NUCLEOTIDES; PATIENTS; PHENOTYPE; RADIATION INJURIES; RADIOTHERAPY; RECEPTORS; SURGERY; TOXICITY

Citation Formats

Tanteles, George A., Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, Murray, Robert J.S., Mills, Jamie, Barwell, Julian, Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, Chakraborti, Prabir, Chan, Steve, Cheung, Kwok-Leung, Ennis, Dawn, Khurshid, Nazish, Lambert, Kelly, Machhar, Rohan, Meisuria, Mitul, Osman, Ahmed, Peat, Irene, Sahota, Harjinder, Woodings, Pamela, Talbot, Christopher J., E-mail: cjt14@le.ac.uk, and and others. Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity. United States: N. p., 2012. Web. doi:10.1016/J.IJROBP.2012.02.018.
Tanteles, George A., Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, Murray, Robert J.S., Mills, Jamie, Barwell, Julian, Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, Chakraborti, Prabir, Chan, Steve, Cheung, Kwok-Leung, Ennis, Dawn, Khurshid, Nazish, Lambert, Kelly, Machhar, Rohan, Meisuria, Mitul, Osman, Ahmed, Peat, Irene, Sahota, Harjinder, Woodings, Pamela, Talbot, Christopher J., E-mail: cjt14@le.ac.uk, & and others. Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity. United States. doi:10.1016/J.IJROBP.2012.02.018.
Tanteles, George A., Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, Murray, Robert J.S., Mills, Jamie, Barwell, Julian, Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, Chakraborti, Prabir, Chan, Steve, Cheung, Kwok-Leung, Ennis, Dawn, Khurshid, Nazish, Lambert, Kelly, Machhar, Rohan, Meisuria, Mitul, Osman, Ahmed, Peat, Irene, Sahota, Harjinder, Woodings, Pamela, Talbot, Christopher J., E-mail: cjt14@le.ac.uk, and and others. Thu . "Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity". United States. doi:10.1016/J.IJROBP.2012.02.018.
@article{osti_22149648,
title = {Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity},
author = {Tanteles, George A. and Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester and Murray, Robert J.S. and Mills, Jamie and Barwell, Julian and Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester and Chakraborti, Prabir and Chan, Steve and Cheung, Kwok-Leung and Ennis, Dawn and Khurshid, Nazish and Lambert, Kelly and Machhar, Rohan and Meisuria, Mitul and Osman, Ahmed and Peat, Irene and Sahota, Harjinder and Woodings, Pamela and Talbot, Christopher J., E-mail: cjt14@le.ac.uk and and others},
abstractNote = {Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage. Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia. Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs. Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.},
doi = {10.1016/J.IJROBP.2012.02.018},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 4,
volume = 84,
place = {United States},
year = {2012},
month = {11}
}