Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, <i>O</i><sup>6</sup>‐alkylguanine–DNA alkyltransferase

McGown, Gail; Thorncroft, Mary; O’Donnell, Paul; Barber, Philip; Lewis, Sarah J.; Harrison, Kathryn; Agius, Raymond; Santibanez‐Koref, Mauro; Margison, Geoffrey P.; Povey, Andrew C.

doi:10.1002/ijc.23059

Cited by 21 publications

(9 citation statements)

References 26 publications

(59 reference statements)

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“…Some of these SNPs have been reported to have an effect on MGMT activity (24). In addition, the c.427A>G and c.533A>G polymorphisms have been associated with increased cancer risk by some authors (25,26) whereas others did not detect this association (27,28). In our series, the c.427A>G and c.533A>G SNPs were found in 5% of the patients, i.e., were present at a lower frequency than expected from the reported allele frequency of 11% to 28% in Caucasians (25).…”

Section: Discussioncontrasting

confidence: 64%

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Felsberg

Rapp

Loeser

et al. 2009

Clinical Cancer Research

186

133

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Purpose: Despite multimodal aggressive treatment glioblastoma patients still face a rather poor prognosis. Recent data indicate that certain molecular markers, in particular MGMT promoter hypermethylation, are associated with response to alkylating chemotherapy and longer survival. The clinical significance of other glioblastoma-associated molecular aberrations and their relationship to MGMT promoter hypermethylation is still poorly understood. Experimental Design: We conducted a translational study involving 67 newly diagnosed glioblastoma patients treated at our institution from 1998 to 2004. All patients were treated by open resection, followed by radiotherapy and adjuvant temozolomide chemotherapy. The tumors were investigated for MGMT promoter methylation, mRNA and protein expression, as well as presence of MGMT sequence polymorphisms. In addition, we screened for genetic aberrations of the EGFR, TP53, CDK4, MDM2, and PDGFRA genes as well as allelic losses on chromosomal arms 1p, 10q, and 19q. Results: Correlation of molecular findings with clinical data revealed significantly longer time to progression after onset of chemotherapy and longer overall survival of patients with MGMT-hypermethylated tumors. In contrast, MGMT protein expression, MGMT polymorphisms, and aberrations in any of the other genes and chromosomes were not significantly linked to patient outcome. Multivariate analysis identified MGMT promoter hypermethylation and near-complete tumor resection as the most important parameters associated with better prognosis. Conclusion: Our study provides novel insights into the significance of molecular and clinical markers in predicting the prognosis of glioblastoma patients, which may improve stratification of patients into distinct prognostic subgroups. (Clin Cancer Res 2009;15(21):6683-93) Glioblastoma is the most common primary brain tumor in adults and belongs to the most malignant types of human cancers, as indicated by a median survival time of <1 year in a population-based study (1). The standard treatment for glioblastoma comprises surgical resection followed by local radiotherapy as well as systemic chemotherapy with the DNA alkylating agent temozolomide. According to the results of the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) prospective clinical trial 26981-22981/CE.3, the combination of surgery followed by radiotherapy with concomittant and adjuvant temozolomide increased the median survival of glioblastoma patients by 2.5 months in comparison with treatment with surgery followed by radiotherapy alone (2). Furthermore, the 2-year survival rate increased from 10.4% in the radiotherapy group to 26.5% in the radiotherapy plus temozolomide group (2). Based on molecular analysis of 206 patients from this trial, O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation was shown to play an important role as a molecular predictor for response to temozolomide and longer survival (3). The MGMT ge...

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Section: Discussioncontrasting

confidence: 64%

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Felsberg

Rapp

Loeser

et al. 2009

Clinical Cancer Research

186

133

View full text Add to dashboard Cite

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“…However, six articles [26,27,28,29,30,31] irrelevant to MGMT Leu84Phe polymorphism and four articles [32,33,34,35] without detailed MGMT Leu84Phe genotypes data were excluded. In addition, three articles [10,36,37] were included by literature reading and manual searching.…”

Section: Resultsmentioning

confidence: 99%

MGMT Leu84Phe Polymorphism Contributes to Cancer Susceptibility: Evidence from 44 Case-Control Studies

et al. 2013

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BackgroundO6-methylguanine-DNA methyltransferase is one of the few proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. A large number of case-control studies have been conducted to explore the association between MGMT Leu84Phe polymorphism and cancer risk. However, the results were not consistent.MethodsWe carried out a meta-analysis of 44 case-control studies to clarify the association between the Leu84Phe polymorphism and cancer risk.ResultsOverall, significant association of the T allele with cancer susceptibility was verified with meta-analysis under a recessive genetic model (P<0.001, OR=1.30, 95%CI 1.24-1.50) and TT versus CC comparison (P=0.001, OR=1.29, 95% CI 1.12-1.50). In subgroup analysis, a significant increased risk was found for lung cancer (TT versus CC, P=0.027, OR=1.67, 95% CI 1.06-2.63; recessive genetic model, P=0.32, OR=1.64, 95% CI 1.04-2.58), whereas risk of colorectal cancer was significantly low under a dominant genetic model (P=0.019, OR=0.84, 95% CI 0.72-0.97). Additionally, a significant association between TT genetic model and total cancer risk was found in the Caucasian population (TT versus CC, P=0.014, OR=1.29, 95% CI 1.05-1.59; recessive genetic model, P=0.009, OR=1.31, 95% CI 1.07-1.61), but not in the Asian population. An increased risk for lung cancer was also verified in the Caucasian population (TT versus CC, P=0.035, OR=1.62, 95% CI 1.04-2.53; recessive genetic model, P=0.048, OR=1.57, 95% CI 1.01-2.45).ConclusionsThese results suggest that MGMT Leu84Phe polymorphism might contribute to the susceptibility of certain cancers.

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“…Numerous studies reported an association between intronic SNPs and disease risk [22-24]. Intronic SNPs could affect intronic splicing enhancer or silencer signals and thereby modulate the expression of different splice variants [25].…”

Section: Discussionmentioning

confidence: 99%

Icb-1 gene polymorphism rs1467465 is associated with susceptibility to ovarian cancer

et al. 2014

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In this study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) of differentiation-associated human gene icb-1 (C1orf38) may be associated with ovarian cancer susceptibility. For this purpose, we compared the genotype and allele frequencies of the SNPs rs1467465 and rs12048235 in a group of 184 ovarian cancer patients with a control group of 184 age- and gender-matched women without any malignancy. Genotype-phenotype association revealed that A allele of SNP rs1467465 was more frequent in ovarian cancer patients than in the control group (0.40 vs. 0.33, OR 1.37, 95% CI 1.013-1.853, p = 0.04). After analysis of allele positivity we observed that A-positive genotypes were more frequent in the ovarian cancer group (0.65 vs. 0.53, OR 1.63, 95% CI 1.072-2.483, p = 0.02). Furthermore, the heterozygous genotype of rs1467465 was found to be more frequent in the patients group (0.50 vs. 0.41, OR 1.63, 95% CI 1.045-2.045, p = 0.03). No significant results were obtained with regard to SNP rs1204823. Our data suggest, that SNP rs1467465 of human gene icb-1 might affect susceptibility to ovarian cancer.

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Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O⁶‐alkylguanine–DNA alkyltransferase

Cited by 21 publications

References 26 publications

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

MGMT Leu84Phe Polymorphism Contributes to Cancer Susceptibility: Evidence from 44 Case-Control Studies

Icb-1 gene polymorphism rs1467465 is associated with susceptibility to ovarian cancer

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Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6‐alkylguanine–DNA alkyltransferase

Cited by 21 publications

References 26 publications

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

MGMT Leu84Phe Polymorphism Contributes to Cancer Susceptibility: Evidence from 44 Case-Control Studies

Icb-1 gene polymorphism rs1467465 is associated with susceptibility to ovarian cancer

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Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O⁶‐alkylguanine–DNA alkyltransferase