Possession of ATM sequence variants as predictor for late normal tissue responses in breast cancer patients treated with radiotherapy.
OBJECTIVE
The ATM gene product is a central component of cell cycle regulation and genomic surveillance. We hypothesized that DNA sequence alterations in ATM predict for adverse effects after external beam radiotherapy for early breast cancer.


METHODS
A total of 131 patients with a minimum of 2 years follow-up who had undergone breast-conserving surgery and adjuvant radiotherapy were screened for sequence alterations in ATM using DNA from blood lymphocytes. Genetic variants were identified using denaturing high performance liquid chromatography. The Radiation Therapy Oncology Group late morbidity scoring schemes for skin and subcutaneous tissues were applied to quantify the radiation-induced effects.


RESULTS
Of the 131 patients, 51 possessed ATM sequence alterations located within exons or in short intron regions flanking each exon that encompass putative splice site regions. Of these 51 patients, 21 (41%) exhibited a minimum of a Grade 2 late radiation response. In contrast, of the 80 patients without an ATM sequence variation, only 18 (23%) had radiation-induced adverse responses, for an odds ratio of 2.4 (95% confidence interval, 1.1-5.2). Fifteen patients were heterozygous for the G-->A polymorphism at nucleotide 5557, which causes substitution of asparagine for aspartic acid at position 1853 of the ATM protein. Of these 15 patients, 8 (53%) exhibited a Grade 2-4 late response compared with 31 (27%) of the 116 patients without this alteration, for an odds ratio of 3.1 (95% confidence interval, 1.1-9.4).


CONCLUSIONS
Sequence variants located in the ATM gene, in particular the 5557 G-->A polymorphism, may predict for late adverse radiation responses in breast cancer patients.
Ho
Alice Y
AY
Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Fan
Grace
G
Atencio
David P
DP
Green
Sheryl
S
Formenti
Silvia C
SC
Haffty
Bruce G
BG
Iyengar
Preetha
P
Bernstein
Jonine L
JL
Stock
Richard G
RG
Cesaretti
Jamie A
JA
Rosenstein
Barry S
BS
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics*; D016001:Confidence Intervals; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D015412:Mastectomy, Segmental; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011832:Radiation Injuries / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D018714:Radiotherapy, Adjuvant; D012867:Skin / 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