RESUMO
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.
Assuntos
Neoplasias da Mama/radioterapia , Predisposição Genética para Doença/genética , Variação Genética , Polimorfismo de Nucleotídeo Único/genética , Lesões por Radiação/genética , Dermatopatias Vasculares/genética , Telangiectasia/genética , Receptores de Activinas Tipo II/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Proteínas Mutadas de Ataxia Telangiectasia , Mama/efeitos da radiação , Neoplasias da Mama/cirurgia , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Endoglina , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Receptores de Superfície Celular/genética , Análise de Regressão , Telangiectasia Hemorrágica Hereditária/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Many genes have been associated with radiotherapy toxicity, but most have only been found in a single study. Using our cohort of 480 breast cancer patients, we provide replicated evidence that a polymorphism near the LIG3 gene is associated with acute skin toxicity following radiotherapy.