Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer

Objective: To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treated with three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer. Experimental Design: One hundred twenty-four patients with prostate cancer underwent 3-DCRT at our institution between September 1996 and December 2000. Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade ≥2 late bladder or rectal toxicity (scoring system of Radiation Therapy Oncology Group) on at least one follow-up visit. We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2, TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2 , and CYP17A1 genes using the Pyrosequencing technique. Results: Significant univariate associations with late rectal or bladder toxicity (grade ≥2) were found for XRCC3 (A>G 5′ untranslated region NT 4541), LIG4 (T>C Asp 568 Asp), MLH1 (C>T, Val 219 Ile), CYP2D6*4 (G>A splicing defect), mean rectal and bladder dose, dose to 30% of rectum or bladder, and age C, Asp 568 Asp), ERCC2 (G>A, Asp 711 Asp), CYP2D6*4 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy. Conclusions: In this study, we identified SNPs in LIG4, ERCC2 , and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.