Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes.
OBJECTIVE
Single nucleotide polymorphisms (SNPs) in genes related to the biological response to radiation injury may affect clinical normal tissue radiosensitivity. This study investigates whether seven selected SNPs in five candidate genes influence risk of subcutaneous fibrosis and telangiectasia after radiotherapy.


METHODS
The 41 patients included in this study were given post-mastectomy radiotherapy in 1978-1982 and subsequently evaluated in detail with regard to several different normal tissue reactions. SNPs in TGFB1 (codons 10, 25 and position -509), SOD2 (codon 16), XRCC3 (codon 241), XRCC1 (codon 399) and APEX (codon 148) were analyzed by PCR and single nucleotide primer extension. Dose-response curves were established for subcutaneous fibrosis and telangiectasia in patients with different genotypes. Differences in radiosensitivity were quantified in terms of ED(50) values and enhancement ratios.


RESULTS
For TGFB1, the Pro/Pro genotype in codon 10 and the T/T genotype in position -509 correlated positively with risk of subcutaneous fibrosis. The SOD 2 codon 16 Val/Ala genotype was associated with increased risk of subcutaneous fibrosis when compared to the Val/Val genotype. The Thr/Thr genotype in XRCC3 codon 241 correlated with increased risk of subcutaneous fibrosis as well as telangiectasia. The Arg/Arg genotype in XRCC1 codon 399 was associated with increased risk of radiation-induced subcutaneous fibrosis. For these polymorphisms, enhancement ratios between 1.09 and 1.25 were found. Combined analysis of multiple SNPs demonstrated that the risk of subcutaneous fibrosis correlated with the number of risk alleles in such a manner that patients with few risk alleles exhibited a remarkable degree of radioresistance.


CONCLUSIONS
The present study established significant correlations between five SNPs and risk of radiation-induced normal tissue reactions. These findings support the assumption that clinical normal tissue radiosensitivity should be regarded as a phenomenon dependent on the combined effect of variation in several genes and indicate that models based on multiple genetic markers may have the potential to predict normal tissue responses after radiotherapy.
Andreassen
Christian Nicolaj
CN
Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 44, Aarhus C DK 8000, Denmark.
Alsner
Jan
J
Overgaard
Marie
M
Overgaard
Jens
J
D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy* / Q000601:surgery; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005355:Fibrosis / Q000209:etiology; D005838:Genotype; D006801:Humans; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects; D040521:Subcutaneous Tissue / Q000473:pathology