Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients.
OBJECTIVE
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
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.
Mangoni
Monica
M
Clinical Physiopathology Department, Radiotherapy Unit, University of Florence, Italy.
Bisanzi
Simonetta
S
Carozzi
Francesca
F
Sani
Cristina
C
Biti
Giampaolo
G
Livi
Lorenzo
L
Barletta
Emanuela
E
Costantini
Adele Seniori
AS
Gorini
Giuseppe
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy* / Q000601:surgery; D015254:DNA Modification Methylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011836:Radiation Tolerance / Q000235:genetics*; D011855:Radiodermatitis / Q000235:genetics*; D011879:Radiotherapy Dosage; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005982:Glutathione Transferase; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein; C501486:MLH1 protein, human; C078444:MSH3 protein, human; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; C515491:MGMT protein, human; C413545:glutathione S-transferase T1; C497172:MSH2 protein, human; C497292:ERCC2 protein, human