Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy

Abstract

DNA repair enzymes repair DNA damaged by platinum agents and ionising radiation. Single nucleotide polymorphisms (SNPs) in DNA repair genes modulate the repair capacity and might affect response and prognosis following platinum-based chemoradiotherapy (CRT). We investigated associations between the functional SNPs in DNA repair genes and response and survival in muscle-invasive bladder cancer patients treated with CRT to determine the predictive value of the SNPs in patient selection for bladder conservation therapy. The study group comprised 78 patients who underwent CRT for transitional cell carcinoma of the bladder. Single nucleotide polymorphisms in xeroderma pigmentosum complementation groups C (Lys939Gln, A/ C), D (XPD; Lys751Gln, A/C), and G (Asp1104His, G/C), and X-ray repair cross-complementing groups 1 (XRCC1; Arg399Gln, G/ A) and 3 (Thr241Met, T/C) genes were genotyped. Combined genotypes with at least one variant allele in XPD or XRCC1 were significantly associated with improved cancer-specific survival compared with remaining groups (P ¼ 0.009). In multivariate analysis, only the combined XPD and XRCC1 genotypes were independently associated with cancer-specific survival (P ¼ 0.04). The association was stronger in stage T3/T4 patients (P ¼ 0.0008). These results suggest that combined XPD and XRCC1 genotypes might be prognostic factors in muscle-invasive bladder cancer patients treated with CRT.

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

“…36,37 In contrast, ERCC1 gene, included in the nucleotide excision repair pathway, is mostly involved in the repair of bulky DNA adducts associated with the action of platinum derivatives. [38][39][40] Nonetheless, recent data highlighted that genetic polymorphisms of ERCC1 and of nucleotide excision repair pathway in general have an effect also on the therapeutic efficacy of RT. 41 The CART analysis pointed out an increased response chance to RT associated with the XRCC1-28152G4A polymorphism.…”

“…Higher radio-sensitivity and favorable prognosis in individuals with the XRCC1-28152G4A variant had already been reported by other investigators. 40,42 An inefficient removal of the DNA adducts after irradiation associated with the defective XRCC1-28152AA genotype, appears to cause an enhancement of radiation sensitivity. The XRCC3-4541A4G, a non-coding polymorphism in the 5 0 UTR of the gene, has a not clarified effect on protein expression.…”

Evaluation of DNA Repair Gene XRCC1 Polymorphism in Prediction and Prognosis of Hepatocellular Carcinoma Risk

“…There are limited reports (Sakano et al, 2006;Ang et al, 2010;Long et al, 2010) on the role of XRCC1-Arg399Cln polymorphism on the survival of cancer patients. We found decreased median survival in variant allele carriers (Arg/Gln+Gln/Gln), which is obvious because Arg/Gln and Gln/Gln genotypes carriers have reduced XRCC1 enzyme activity and thus may have decrease DNA repair captivities.…”

ERCC1 and XRCC1 expression predicts survival in bladder cancer patients receiving combined trimodality therapy

“…The patients received combined platinum-based systemic CRT. In the majority of patients, one cycle of the regimen (based on Shipley's method with slight modification) (17) included administration of cisplatin (70 mg̸m 2 ) on day 1, followed by radiation at 1.8 Gy per fraction on days 2-5 in the first week and every 5 days consecutively in the second week (18)(19)(20). Radiotherapy involved 10-MV photons with a 4-field technique, treating the bladder and pelvic lymph nodes to 32.4 Gy during 2 cycles, followed by a CT-planned whole-bladder boost of 16.2 Gy for an additional cycle.…”