Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients.
OBJECTIVE
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.


METHODS
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; Pinteraction = 0.009).


CONCLUSIONS
The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.
Division of Clinical Epidemiology and Toxicology, German Cancer Research Center, Heidelberg, Germany. j.chang-claude@dkfz-heidelberg.de
Jenny
J
Chang-Claude
Odilia
O
Popanda
Xiang-Lin
XL
Tan
Silke
S
Kropp
Irmgard
I
Helmbold
Dietrich
D
von Fournier
Wulf
W
Haase
Marie Luise
ML
Sautter-Bihl
Frederik
F
Wenz
Peter
P
Schmezer
Christine B
CB
Ambrosone
D000368:Aged; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011878:Radiotherapy / Q000009:adverse effects* / Q000706:statistics & numerical data; D011879:Radiotherapy Dosage; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D051759:Xeroderma Pigmentosum Group D Protein; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C497292:ERCC2 protein, human