Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity

Journal Article · Thu Nov 15 04:00:00 EST 2012 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/J.IJROBP.2012.02.018· OSTI ID:22149648

Tanteles, George A. ^[1]; Murray, Robert J.S. ^[1]; Mills, Jamie ^[2]; Barwell, Julian ^[1]; Chakraborti, Prabir ^[3]; Chan, Steve ^[4]; Cheung, Kwok-Leung ^[5]; Ennis, Dawn ^[3]; Khurshid, Nazish ^[1]; Lambert, Kelly ^[6]; Machhar, Rohan; Meisuria, Mitul ^[1]; Osman, Ahmed; Peat, Irene ^[2]; Sahota, Harjinder ^[1]; Woodings, Pamela ^[3]; others, and

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1. Department of Genetics, University of Leicester, Leicester (United Kingdom)
2. Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom)
3. Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)
4. Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom)
5. Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom)
6. Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom)

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.

• OSTI ID: 22149648
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 4 Vol. 84; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

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