Biochemistry- DNA/RNA Metabolism

Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer.

Gu, J et al., 2005. Clin. Cancer Res. 11(4):1408-1415.

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

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MGMT gene silencing and benefit from temozolomide in glioblastoma.

Hegi, M.E. et al., 2005. N. Engl. J. Med. 352(10):997-1003

Abstract

Background Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. Methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. Results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit

Journal Link | PMID

Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer

Gu, J et al., 2005. Clin. Cancer Res. 11(4):1408-1415.

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.

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Nucleotide excision repair, oxidative damage, DNA sequence polymorphisms, and cancer treatment

Hutsell, SQ & Sancar, A, 2005. Clin. Cancer. Res. 11(4):1355-1357.

Commentary Intro.

Can a single polymorphic site help tailor a cancer patient's chemotherapy regimen? The study by Zhao et al. presented in this issue of Clinical Cancer Research suggests that in fact polymorphic sites in noncoding gene regions may determine how a patient will react to a given chemotherapy and the likelihood of cancer recurrence after treatment. The group focused their investigation on a common polymorphism termed xeroderma pigmentosum group A (-4) [XPA (-4)], whereby the fourth nucleotide before the ATG start codon is A in about half the population and G in about the other half. The polymorphism is in the Kozak sequence and thus the A form of the allele may affect the translation efficiency of XPA resulting in reduced XPA level and reduced excision repair capacity. Indeed, this group previously reported that the A allele (XPA A variant in the authors' terminology) is associated with reduced excision repair capacity. In the current study, the authors report that the XPA G variant in which both alleles contain G at the fourth position before the initiation codon is associated with a higher rate of recurrence of superficial bladder cancer after Bacillus Calmette-Guerin (BCG) treatment. The authors report that during the follow-up period of 27.6 months from diagnosis, tumor recurred in 44% of patients with the AA genotype, 62% in those with the AG genotype, and 74% in those with the GG genotype. To explain these findings, the authors suggest that the XPA G variant exhibits increased DNA repair capacity by nucleotide excision repair. This allows cancer cells to bypass the apoptotic response induced by BCG treatment.

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Comment

this severs as a short review of and introduction to the article above by Gu et al.

Predicting lung cancer by detecting aberrant promoter methylation in sputum.

Palmisano, WA et al., 2000.  Cancer Res. 60(21):5954-5958.

Abstract

Despite the promise of using DNA markers for the early detection of cancer, none has proven universally applicable to the most common and lethal forms of human malignancy. Lung carcinoma, the leading cause of tumor-related death, is a key example of a cancer for which mortality could be greatly reduced through the development of sensitive molecular markers detectable at the earliest stages of disease. By increasing the sensitivity of a PCR approach to detect methylated DNA sequences, we now demonstrate that aberrant methylation of the p16 and/or O6-methylguanine-DNA methyltransferase promoters can be detected in DNA from sputum in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis. Moreover, the prevalence of these markers in sputum from cancer-free, high-risk subjects approximates lifetime risk for lung cancer. The use of aberrant gene methylation as a molecular marker system seems to offer a potentially powerful approach to population-based screening for the detection of lung cancer, and possibly the other common forms of human cancer.

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HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance.

Ren, J & Stammers, DK. 2005. Trends Pharmacol. Sci. 26(1):4-7.

Abstract

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. The selection of drug-resistant HIV is a key problem in the continued treatment of the infection and thus new drugs are required. A significant body of information consisting of HIV-1 RT crystal structures with bound inhibitors has become available during the past several years, and, increasingly, such data will be of use in developing novel inhibitors. Two examples of crystal structures of HIV-1 RT with bound inhibitors have been published recently, one with the non-nucleoside CP94707 and the second with the nucleotide analogue drug tenofovir. Such structures will help the design of new drugs and improve our understanding of the mechanisms of resistance.

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