Association Between Genetic Polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT Genes and Radiosensitivity in Breast Cancer Patients
- Clinical Physiopathology Department, Radiotherapy Unit, University of Florence (Italy)
- Analytical and Biomolecular Cytology Unit, Cancer Prevention and Research Institute (ISPO), Florence (Italy)
- Department of Experimental Pathology and Oncology, University of Florence, Florence (Italy)
- Occupational and Environmental Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), Florence (Italy)
Purpose: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Methods and Materials: Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR = 53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR = 38.26; 95% CI, 1.19-1232.52). Conclusions: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.
- OSTI ID:
- 21587705
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 81, Issue 1; Other Information: DOI: 10.1016/j.ijrobp.2010.04.023; PII: S0360-3016(10)00599-7; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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DNA REPAIR
GENES
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NEOPLASMS
NUCLEOTIDES
POLYMERASE CHAIN REACTION
RADIATION INJURIES
RADIOSENSITIVITY
RADIOTHERAPY
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X-RAY DIFFRACTION
X-RAY PHOTOELECTRON SPECTROSCOPY
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
BODY
COHERENT SCATTERING
DIFFRACTION
DISEASES
ELECTRON SPECTROSCOPY
GENE AMPLIFICATION
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MEDICINE
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANS
PHOTOELECTRON SPECTROSCOPY
RADIATION EFFECTS
RADIOLOGY
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