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Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.

ABSTRACT: Human DNA glycosylases NEIL1 and NEIL2 participate in oxidized base excision repair and protect cells from DNA damage. NEIL1 (MIM:608844) and NEIL2 (MIM:608933) variants may affect their protein functions, leading to altered cell death and carcinogenesis. To date, only one reported study has investigated the association between NEIL1 and NEIL2 polymorphisms and cancer risk.Genotype and haplotypes of the NEIL1 NT_010194.16:g.46434077G>T (rs7182283) and g.46438282C>G (rs4462560) and NEIL2 NT_077531.3:g.4102971C>G (rs804270) polymorphisms were determined for 872 patients with newly diagnosed squamous cell carcinomas of the oral cavity and oropharynx (SCCOOP) and 1,044 cancer-free non-Hispanic white control subjects frequency-matched by age and sex. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression, and false-positive report probabilities were also calculated.We found no overall differences in the frequencies of alleles, genotypes, and haplotypes of NEIL1 g.46434077G>T and NEIL1 g.46438282C>G polymorphisms between cases and controls. However, the NEIL2 g.4102971CC genotype was associated with a significantly increased risk of SCCOOP (adjusted OR, 1.30; 95% CI, 1.02-1.65); this increase in risk was the highest among current alcohol drinkers (adjusted OR, 1.87; 95% CI, 1.28-2.72), particularly in patients with oropharyngeal cancer (adjusted OR, 1.35; 95% CI, 1.04-1.76). The NEIL2 g.4102971CC genotype was also significantly associated with SCCOOP of advanced stages.Polymorphisms of the NEIL2 gene may be markers for risk and progression of SCCOOP, particularly in patients with oropharyngeal cancer. Larger studies are needed to confirm our findings.

SUBMITTER: Zhai X

PROVIDER: S-EPMC3025759 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.

Zhai Xiadong X Zhao Hui H Liu Zhensheng Z Wang Li-E LE El-Naggar Adel K AK Sturgis Erich M EM Wei Qingyi Q

Clinical cancer research : an official journal of the American Association for Cancer Research 20080701 13

<h4>Purpose</h4>Human DNA glycosylases NEIL1 and NEIL2 participate in oxidized base excision repair and protect cells from DNA damage. NEIL1 (MIM:608844) and NEIL2 (MIM:608933) variants may affect their protein functions, leading to altered cell death and carcinogenesis. To date, only one reported study has investigated the association between NEIL1 and NEIL2 polymorphisms and cancer risk.<h4>Experimental design</h4>Genotype and haplotypes of the NEIL1 NT_010194.16:g.46434077G>T (rs7182283) and ...[more]

PMID: 18594018

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Project description:BackgroundSquamous cell carcinoma of the oral cavity (SCCOC) is the dominant origin of cancer associated mortality. Previous findings by our study reported that acquisition of anoikis resistance has a significant role in tumor progression of oral cavity. Several genes were over-expressed in anoikis-resistant cells under detached conditions which we confirmed earlier by microarray. Normal oral squamous epithelia grow adherent to a basement membrane, and when detached from the extracellular matrix, undergoes programmed cell death. The acquisition of anoikis-resistance is crucial phenomena in oral tumor advancement. In the current study, we have identified S100A7 expression as contributing factor for anoikis resistance and tumorigenicity in human oral cancer cells. Further, we have explored that elevated S100A7 expression in anoikis-sensitive oral keratinocytes and cancer cells reshape them more resistant to anoikis and apoptosis inducers via activation of cellular intrinsic and extrinsic avenue.MethodsA subset of human cancer cell lines TU167, JMAR, JMARC39, JMARC42 and MDA-MB-468 were utilized for the generation of resistant stable cell lines. Further, immunohistochemistry, western blot and immunoprecipitation, assays of apoptosis, soft agar assay, orthotopic animal model and signaling elucidation were performed to establish our hypothesis.ResultsS100A7 gene is found to be responsible for anoikis resistance and tumorigenicity in human oral cancer cells. We have observed up-regulation of S100A7 in anoikis resistant cell lines, orthotropic model and patients samples with head and neck cancer. It is also noticed that secretion of S100A7 protein in conditioned medium by anoikis resistant head & neck cancer cell and in saliva of head and neck cancer patients. Up-regulation of S100A7 expression has triggered enhanced tumorigenicity and anchorage-independent growth of cancer cells through Akt phosphorylation leading to development of aniokis resistance in head and neck cancer cells.ConclusionsThese data have led us to conclude that S100A7 is the major contributing factor in mediating anoikis-resistance of oral cancer cells and local tumor progression, and S100A7 might be useful as diagnostic marker for early detection of primary and recurrent squamous cell cancer.

Dataset Information

Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.

Publications

Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.

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