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Association between Polymorphisms in the DNA Repair Genes, XRCC1, APE1, and XPD and Acute Side Effects of Radiotherapy in Breast Cancer Patients

Authors' Affiliations: Divisions of ¹ Clinical Epidemiology and ² Toxicology and Cancer Risk Factors, German Cancer Research Center; ³ Department of Gynecological Radiology, Heidelberg University Hospital, Heidelberg, Germany; ⁴ Clinic for Radiotherapy and Radiooncology, St. Vincentius-Kliniken Karlsruhe; ⁵ Clinic for Radiotherapy, Karlsruhe Hospital GmbH, Karlsruhe, Germany; ⁶ Department of Radiation Oncology, Universitätsklinikum Mannheim, Mannheim, Germany; and ⁷ Department of Epidemiology, Division of Cancer Prevention and Population Science, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Jenny Chang-Claude, German Cancer Research Center, Division of Clinical Epidemiology, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. Phone: 49-6221-422373; Fax: 49-6221-422203; E-mail: j.chang-claude{at}dkfz-heidelberg.de.

Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg¹⁹⁴Trp, Arg²⁸⁰His, and Arg³⁹⁹Gln), APE1 (Asp¹⁴⁸Glu), and XPD (Lys⁷⁵¹Gln and Asp³¹²Asn), with the risk of acute skin reactions following radiotherapy.

Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.

Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 ¹⁴⁸Glu and the XRCC1 ³⁹⁹Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 ¹⁴⁸Glu and XRCC1 ³⁹⁹Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; P_interaction = 0.009).

Conclusion: The XRCC1 ³⁹⁹Gln or APE1 ¹⁴⁸Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.

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