Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy.
OBJECTIVE
Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, > or =3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation.


METHODS
DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18).


RESULTS
Overall, 13 and 21 patients were found to possess a total of <4 and > or =4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had > or =4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had > or =4 SNPs (P < 0.001).


CONCLUSIONS
The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro.
Azria
David
D
INSERM U896, Institut de Recherche en Cancérologie de Montpellier, Department of Radiation Oncology, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France.
Ozsahin
Mahmut
M
Kramar
Andrew
A
Peters
Sheila
S
Atencio
David P
DP
Crompton
Nigel E A
NE
Mornex
Françoise
F
Pèlegrin
André
A
Dubois
Jean-Bernard
JB
Mirimanoff
René-Olivier
RO
Rosenstein
Barry S
BS
D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D020641:Polymorphism, Single Nucleotide; D011832:Radiation Injuries / Q000175:diagnosis / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects*; D012306:Risk; D013997:Time Factors; D016896:Treatment Outcome