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Variation in telangiectasia predisposing genes is associated with overall radiation toxicity.

AbstractPURPOSE:
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.
AuthorsGeorge A Tanteles, Robert J S Murray, Jamie Mills, Julian Barwell, Prabir Chakraborti, Steve Chan, Kwok-Leung Cheung, Dawn Ennis, Nazish Khurshid, Kelly Lambert, Rohan Machhar, Mitul Meisuria, Ahmed Osman, Irene Peat, Harjinder Sahota, Pamela Woodings, Christopher J Talbot, R Paul Symonds
JournalInternational journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 84 Issue 4 Pg. 1031-6 (Nov 15 2012) ISSN: 1879-355X [Electronic] United States
PMID22677372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • Antigens, CD
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type II
Topics
  • Activin Receptors, Type II (genetics)
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD (genetics)
  • Ataxia Telangiectasia Mutated Proteins
  • Breast (radiation effects)
  • Breast Neoplasms (radiotherapy, surgery)
  • Cell Cycle Proteins (genetics)
  • DNA-Binding Proteins (genetics)
  • Endoglin
  • Female
  • Genetic Predisposition to Disease (genetics)
  • Genetic Variation
  • Humans
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide (genetics)
  • Protein Serine-Threonine Kinases (genetics)
  • Radiation Injuries (genetics)
  • Receptors, Cell Surface (genetics)
  • Regression Analysis
  • Skin Diseases, Vascular (genetics)
  • Telangiectasia, Hereditary Hemorrhagic (genetics)
  • Telangiectasis (genetics)
  • Tumor Suppressor Proteins (genetics)

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