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Single Nucleotide Polymorphisms, Apoptosis, and the Development of Severe Late Adverse Effects After Radiotherapy

Authors' Affiliations: ¹ Inserm, U896, Institut de Recherche en Cancérologie de Montpellier, ² Department of Radiation Oncology, and ³ Biostatistics Unit, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France; ⁴ Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Departments of ⁵ Radiation Oncology, ⁶ Dermatology, and ⁷ Community and Preventive Medicine, Mount Sinai School of Medicine and, ⁸ Department of Radiation Oncology, NYU School of Medicine, New York, New York; ⁹ Laboratory of Noninvasive Imaging and Radiation Biology, Van Andel Research Institute, Grand Rapids, Michigan; and ¹⁰ Department of Radiation Oncology, Centre Hospitalier Universitaire Lyon Sud, Pierre Benite, France

Requests for reprints: Barry S. Rosenstein, Box 1236, Department of Radiation Oncology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029. Phone: 212-241-9408; Fax: 212-996-8927; E-mail: barry.rosenstein{at}mssm.edu.

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, 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 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 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 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.