ATM sequence variants are predictive of adverse radiotherapy response among patients treated for prostate cancer.
OBJECTIVE
To examine whether the presence of sequence variants in the ATM (mutated in ataxia-telangiectasia) gene is predictive for the development of radiation-induced adverse responses resulting from (125)I prostate brachytherapy for early-stage prostate cancer.


METHODS
Thirty-seven patients with a minimum of 1-year follow-up who underwent (125)I prostate brachytherapy of early-stage prostate cancer were screened for DNA sequence variations in all 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. The clinical course and postimplant dosimetry for each genetically characterized patient were obtained from a database of 2,020 patients implanted at Mount Sinai Hospital after 1990.


RESULTS
Twenty-one ATM sequence alterations located within exons, or in short intronic regions flanking each exon, were found in 16 of the 37 patients screened. For this group, 10 of 16 (63%) exhibited at least one form of adverse response. In contrast, of the 21 patients who did not harbor an ATM sequence variation, only 3 of 21 (14%) manifested radiation-induced adverse responses (p = 0.005). Nine of the patients with sequence alterations specifically possessed missense mutations, which encode for amino acid substitutions and are therefore more likely to possess functional importance. For this group, 7 of 9 (78%) exhibited at least one form of adverse response. In contrast, of the 28 patients who did not have a missense alteration, only 6 of 28 (21%) manifested any form of adverse response to the radiotherapy (p = 0.004). Of the patients with missense variants, 5 of 9 (56%) exhibited late rectal bleeding vs. 1 of 28 (4%) without such alterations (p = 0.002). Of those patients who were at risk for developing erectile dysfunction, 5 of 8 (63%) patients with missense mutations developed prospectively evaluated erectile dysfunction as opposed to 2 of 20 (10%) without these sequence alterations (p = 0.009).


CONCLUSIONS
Possession of sequence variants in the ATM gene, particularly those that encode for an amino acid substitution, is predictive for the development of adverse radiotherapy responses among patients treated with (125)I prostate brachytherapy.
Cesaretti
Jamie A
JA
Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY 10029, USA. jamie.cesaretti@msnyuhealth.org
Stock
Richard G
RG
Lehrer
Steven
S
Atencio
David A
DA
Bernstein
Jonine L
JL
Stone
Nelson N
NN
Wallenstein
Sylvan
S
Green
Sheryl
S
Loeb
Karen
K
Kollmeier
Marisa
M
Smith
Michael
M
Rosenstein
Barry S
BS
D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D001918:Brachytherapy / Q000009:adverse effects*; D018797:Cell Cycle Proteins; D002851:Chromatography, High Pressure Liquid; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D006801:Humans; D007457:Iodine Radioisotopes / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D007457:Iodine Radioisotopes; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases