Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity.
OBJECTIVE
To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity.


METHODS
Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR-RFLP and MALDI-TOF, respectively.


RESULTS
Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs)=2.09, 95% confidence interval (CI): 1.32-3.55, p=0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity.


CONCLUSIONS
It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.
Zschenker
Oliver
O
Hubertus Wald Tumorzentrum, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Raabe
Annette
A
Boeckelmann
Inga Kathleen
IK
Borstelmann
Sonko
S
Szymczak
Silke
S
Wellek
Stefan
S
Rades
Dirk
D
Hoeller
Ulrike
U
Ziegler
Andreas
A
Dikomey
Ekkehard
E
Borgmann
Kerstin
K
D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000235:genetics; D003062:Codon; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects*; D011879:Radiotherapy Dosage; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D000099156:Superoxide Dismutase 2
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D003062:Codon; D004268:DNA-Binding Proteins; D051549:Glutathione S-Transferase pi; D017346:Protein Serine-Threonine Kinases; D013482:Superoxide Dismutase; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein; D000099156:Superoxide Dismutase 2; C508960:TGFB1 protein, human; C000619371:XRCC1 protein, human; C496556:GSTP1 protein, human; C576324:ATM protein, human; C497292:ERCC2 protein, human