Variation in telangiectasia predisposing genes is associated with overall radiation toxicity.
OBJECTIVE
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
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.
Department of Genetics, University of Leicester, Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom.
George A
GA
Tanteles
Robert J S
RJ
Murray
Jamie
J
Mills
Julian
J
Barwell
Prabir
P
Chakraborti
Steve
S
Chan
Kwok-Leung
KL
Cheung
Dawn
D
Ennis
Nazish
N
Khurshid
Kelly
K
Lambert
Rohan
R
Machhar
Mitul
M
Meisuria
Ahmed
A
Osman
Irene
I
Peat
Harjinder
H
Sahota
Pamela
P
Woodings
Christopher J
CJ
Talbot
R Paul
RP
Symonds
D030301:Activin Receptors, Type II / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001940:Breast / Q000528:radiation effects; D001943:Breast Neoplasms / Q000532:radiotherapy* / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000071063:Endoglin; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011832:Radiation Injuries / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012044:Regression Analysis; D017445:Skin Diseases, Vascular / Q000235:genetics*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics; D013684:Telangiectasis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D015703:Antigens, CD; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II