ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy.
OBJECTIVE
To examine the hypothesis that women who are carriers of genetic alterations in the ATM gene are more likely to develop subcutaneous fibrosis after radiotherapy for treatment of breast cancer compared with patients who do not possess DNA sequence variations in this gene.


METHODS
DNA samples isolated from fibroblast cell lines established from 41 women treated with postmastectomy radiotherapy for breast cancer were screened for genetic variants in ATM using denaturing high-performance liquid chromatography (DHPLC). A minimum follow-up of 2 years enabled analysis of late effects to generate dose-response curves and to estimate the dose that resulted in a 50% incidence of Grade 3 fibrosis (ED50).


RESULTS
A total of 26 genetic alterations in the expressed portions of the ATM gene, or within 10 bases of each exon in regions encompassing putative splice sites, were detected in 22 patients. The ED50 (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED50 of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED50 of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G-->A polymorphism at nucleotide 5557, which results in substitution of asparagine for aspartic acid at position 1853 of the ATM protein, was substantially lower than the ED50 of 60.8 (57.0-64.8) Gy for patients not carriers of this sequence alteration. This resulted in an enhancement ratio (ratio of the ED50 values) of 1.13 (1.05-1.22), which was significantly greater than unity.


CONCLUSIONS
The results of this study suggest an association between the ATM codon 1853 Asn/Asp and Asn/Asn genotypes with the development of Grade 3 fibrosis in breast cancer patients treated with radiotherapy.
Andreassen
Christian N
CN
Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
Overgaard
Jens
J
Alsner
Jan
J
Overgaard
Marie
M
Herskind
Carsten
C
Cesaretti
Jamie A
JA
Atencio
David P
DP
Green
Sheryl
S
Formenti
Silvia C
SC
Stock
Richard G
RG
Rosenstein
Barry S
BS
D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000532:radiotherapy* / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005355:Fibrosis; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011832:Radiation Injuries / Q000150:complications*; D040521:Subcutaneous Tissue / Q000473:pathology* / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases