Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy

Abstract

Purpose: 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.

Experimental design: 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.

Fig. 1

Distribution of the number of Single Nucleotide Polymorphisms (SNPs) in the study population. The candidate genes were selected from previous studies as ATM, SOD2, TGFb, XRCC3, XRCC1, RAD21. Thirteen and 21 patients presented less than three and four or more SNPs, respectively.

Fig. 2

Distribution of the number of Single Nucleotide Polymorphisms (SNPs) according to radiation-induced late effects (grade ≥3 vs grade <3). Ninety-four percent (15/16) patients presented ≥4 SNPs in the grade ≥3 toxicity group compared to 33% (6/18) in the “control” group without any severe clinical radiation-induced toxicity (p <0.001).

Fig. 3

The probability of grade 3 or more toxicity as a function of the cumulative number of Single Nucleotide Polymorphisms (SNPs). Four and more SNPs are strongly correlated with the risk of grade ≥3 toxicity; OR, odds ratio = 9.3, 95%CI: 1.4–62, p = 0.003).

Fig. 3

The probability of grade 3 or more toxicity as a function of the cumulative number of Single Nucleotide Polymorphisms (SNPs). Four and more SNPs are strongly correlated with the risk of grade ≥3 toxicity; OR, odds ratio = 9.3, 95%CI: 1.4–62, p = 0.003).