Nucleotide Excision Repair Gene Polymorphisms and Recurrence after Treatment for Superficial Bladder Cancer

Abstract

Purpose: Interindividual differences in DNA repair capacity not only modify individual susceptibility to carcinogenesis, but also affect individual response to cancer treatment. Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells involved in the removal of a wide variety of DNA lesions. Polymorphisms in NER genes may influence DNA repair capacity and affect clinical outcome of bladder cancer treatment. Experimental Design: To test the influence of NER gene polymorphisms on superficial bladder cancer outcome (recurrence and progression), we conducted a follow-up study of 288 patients with superficial bladder cancer. Median follow-up among patients who were recurrence-free at the end of observation was 21.7 months from diagnosis. The specific polymorphic loci examined include XPA [A/G at 5′ untranslated region (UTR)], XPC (poly AT, Ala499Val, Lys939Gln), XPD (Asp312Asn, Lys751Gln), XPG (His1104Asp), ERCC 1 (G/T at 3′ UTR), and ERCC6 (Met1097Val, Arg1230Pro). Results: The ERCC6 (Met1097Val) polymorphism had a significant impact on recurrence: carriers of at least one variant allele (Val) had a significantly higher recurrence risk than carriers of the wild-type allele (Met/Met; hazard ratio, 1.54; 95% confidence interval, 1.02-2.33). There were no overall statistically significant differences in the distributions of the other polymorphisms between patients with and without recurrence. However, when we combined these variant genotypes, there was a significant trend for an increased recurrence risk with an increasing number of putative high-risk alleles. Using individuals with five or fewer putative high-risk alleles as the reference group, individuals with six to seven risk alleles and individuals with eight or more risk alleles had higher recurrence risks, with hazard ratios of 0.92 (0.54-1.57) and 2.53 (1.48-4.30), respectively (P for trend < 0.001). There was also a significant trend for shorter recurrence-free survival time with increasing number of variant alleles (log rank test, P = 0.0007). When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively). There were no significant individual or joint associations between these polymorphisms and progression. Conclusions: These data suggest that interindividual differences in DNA repair capacity may have an important impact on superficial bladder cancer recurrence. A pathway-based approach is preferred to study the effects of individual polymorphism on clinical outcomes.

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

“…Concerning bladder cancer, Gu et al (2005) showed that the NER gene Sak et al (2005) indicated that high expression levels of APE1 and XRCC1 are associated with improved cancer-specific survival following radical radiotherapy in muscle-invasive bladder cancer. However, reports on the associations between DNA repair gene polymorphisms and clinical response or prognosis in muscle-invasive bladder cancer patients treated with chemotherapy or radiotherapy are lacking.…”

“…Sak et al (2005) stated that one possible explanation is that the reduced expression of XRCC1 and APE1 merely reflects the poorly differentiated nature of tumour cells in more aggressive tumours, and that cells from aggressive tumours with extensive genomic instability could contain chromosomal aberrations that result in the failure of transcription of genes, including DNA repair genes, thus resulting in lower protein expression of the gene products. Gu et al (2005) analysed the association between the total number of variant alleles in eight NER genes and the recurrence of superficial bladder cancer. They emphasised that because the prognosis of cancer patients likely involves multistep, multigenic pathways, it is unlikely that any one single genetic polymorphism would have a dramatic effect on clinical outcome, and that it is important to take a pathway-based analysis of multiple polymorphic genes (Gu et al, 2005).…”

“…Gu et al (2005) analysed the association between the total number of variant alleles in eight NER genes and the recurrence of superficial bladder cancer. They emphasised that because the prognosis of cancer patients likely involves multistep, multigenic pathways, it is unlikely that any one single genetic polymorphism would have a dramatic effect on clinical outcome, and that it is important to take a pathway-based analysis of multiple polymorphic genes (Gu et al, 2005). Thus, we also analysed the numbers of total variant alleles both in all DNA repair genes studied and in NER genes.…”

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

“…Genotyping for the Lys939Gln and Ala499Val polymorphisms were performed as described previously using the TaqMan assay [23]. PCR-RFLP was conducted to genotype the PAT polymorphism according to a previous protocol with minor modifications [24].…”

A variant of the Cockayne syndrome B geneERCC6 confers risk of lung cancer

“…Hundreds of polymorphisms in DNA repair genes have been identified and some of them have been consistently associated with cancer susceptibility [Hung et al, 2005;Spitz et al, 2003;Ribas et al, 2006]. For example, the OGG1 p.S326C and the XRCC1 p.R194W have been shown to be associated with an increased risk of various types of human cancer; while the BRCA2 p.N372H was reported to be more specifically associated with an increased risk of breast cancer [Goode et al, 2002;Gu et al, 2005]. A number of SNPs were also identified in the ERCC6 gene and a recent study reported that the ERCC6 p.M1097V had a significant impact on bladder cancer recurrence [Gu et al, 2005].…”