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Cyclooxygenase-2 gene polymorphisms reduce the risk of oral premalignant lesions.

ABSTRACT: Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. Overexpression of the cyclooxygenase-2 gene (COX-2) is observed frequently in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single-nucleotide polymorphisms of COX-2 have been associated with the risk of multiple cancers; however, to date, their effects on OPL susceptibility have not been evaluated sufficiently.The authors conducted a case-control study that included 147 patients with OPL and a group of 147 healthy, matched controls. The effects of 3 potentially functional COX-2 polymorphisms on the risk of OPL were evaluated: the -765 G-->C polymorphism (rs20417), the exon 10 +837 T-->C polymorphism (rs5275), and the exon 10 -90 C-->T polymorphism (rs689470).The variant-containing genotypes of COX-2 exon 10 +837T-->C variant were associated with a significantly reduced risk of OPL (odds ratio [OR], 0.48; 95% confidence interval [95% CI], 0.28-0.80). This protective effect also was significant in men, younger individuals, ever smokers, and ever drinkers. Consistently, a common halotype WMW (in the following order: -765G-->C, exon 10 +837T-->C, and exon 10 -90C-->T; w, widetype; M, variable allele) and a common diplotype (WWW/WMW) that contained the variant allele of exon 10 +837T-->C, both were associated with a reduced risk of OPL (WMW: OR, 0.55; 95% CI, 0.33-0.93; WWW/WMW: OR, 0.44; 95% CI, 0.22-0.89). In addition, using never smokers with the variant-containing genotypes as the reference group, interaction effects were observed between specific COX-2 variants and tobacco smoking in the modulation of OPL risk.Overall, the current results provided the first epidemiologic evidence indicating that potentially functional polymorphisms of the COX-2 gene may have an impact on individual susceptibility to OPLs.

SUBMITTER: Pu X

PROVIDER: S-EPMC2666299 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Cyclooxygenase-2 gene polymorphisms reduce the risk of oral premalignant lesions.

Pu Xia X Lippman Scott M SM Yang Hushan H Lee J Jack JJ Wu Xifeng X

Cancer 20090401 7

<h4>Background</h4>Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. Overexpression of the cyclooxygenase-2 gene (COX-2) is observed frequently in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single-nucleotide polymorphisms of COX-2 have been associated with the risk of multiple cancers; however, to date, their effects on OPL susceptibility have not been evaluated sufficiently.<h4>Method ...[more]

PMID: 19197984

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Project description:Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this field is the identification of OPLs at higher risk for oral squamous cell cancer (OSCC) development, by discovering molecular pathways deregulated in the early steps of malignant transformation. Analysis of deregulated levels of single genes and pathways has been successfully applied to head and neck squamous cell cancers (HNSCC) and OSCC with prognostic/predictive implications. Exploiting the availability of gene expression profile and clinical follow-up information of a well-characterized cohort of OPL patients, we aim to dissect tissue OPL gene expression to identify molecular clusters/signatures associated with oral cancer free survival (OCFS). The gene expression data of 86 OPL patients were challenged with: an HNSCC specific 6 molecular subtypes model (Immune related: HPV related, Defense Response and Immunoreactive; Mesenchymal, Hypoxia and Classical); one OSCC-specific signature (13 genes); two metabolism-related signatures (3 genes and signatures raised from 6 metabolic pathways associated with prognosis in HNSCC and OSCC, respectively); a hypoxia gene signature. The molecular stratification and high versus low expression of the signatures were correlated with OCFS by Kaplan-Meier analyses. The association of gene expression profiles among the tested biological models and clinical covariates was tested through variance partition analysis. Patients with Mesenchymal, Hypoxia and Classical clusters showed an higher risk of malignant transformation in comparison with immune-related ones (log-rank test, p = 0.0052) and they expressed four enriched hallmarks: "TGF beta signaling" "angiogenesis", "unfolded protein response", "apical junction". Overall, 54 cases entered in the immune related clusters, while the remaining 32 cases belonged to the other clusters. No other signatures showed association with OCFS. Our variance partition analysis proved that clinical and molecular features are able to explain only 21% of gene expression data variability, while the remaining 79% refers to residuals independent of known parameters. Applying the existing signatures derived from HNSCC to OPL, we identified only a protective effect for immune-related signatures. Other gene expression profiles derived from overt cancers were not able to identify the risk of malignant transformation, possibly because they are linked to later stages of cancer progression. The availability of a new well-characterized set of OPL patients and further research is needed to improve the identification of adequate prognosticators in OPLs.

Project description:Oral cancers are attributed to a number of causal agents including tobacco, alcohol, human papillomavirus (HPV), and areca (betel) nut. Although betel nut chewing has been established as an independent cause of oral cancer, the mechanisms of carcinogenesis are poorly understood. An investigation was undertaken to evaluate the influence of betel nut chewing on the oral microbiome and oral premalignant lesions. Study participants were recruited from a dental clinic in Guam. Structured interviews and oral examinations were performed. Oral swabbing and saliva samples were evaluated by 454 pyrosequencing of the V3- V5 region of the 16S rRNA bacterial gene and genotyped for HPV. One hundred twenty-two adults were enrolled including 64 current betel nut chewers, 37 former chewers, and 21 with no history of betel nut use. Oral premalignant lesions, including leukoplakia and submucous fibrosis, were observed in 10 chewers. Within-sample bacterial diversity was significantly lower in long-term (≥10 years) chewers vs. never chewers and in current chewers with oral lesions vs. individuals without lesions. Between-sample bacterial diversity based on Unifrac distances significantly differed by chewing status and oral lesion status. Current chewers had significantly elevated levels of Streptococcus infantis and higher and lower levels of distinct taxa of the Actinomyces and Streptococcus genera. Long-term chewers had reduced levels of Parascardovia and Streptococcus. Chewers with oral lesions had significantly elevated levels of Oribacterium, Actinomyces, and Streptococcus, including Streptococcus anginosus. In multivariate analyses, controlling for smoking, oral HPV, S.anginosus, and S. infantis levels, current betel nut chewing remained the only predictor of oral premalignant lesions. Our study provides evidence that betel nut chewing alters the oral bacterial microbiome including that of chewers who develop oral premalignant lesions. Nonetheless, whether microbial changes are involved in betel nut-induced oral carcinogenesis is only speculative. Further research is needed to discern the clinical significance of an altered oral microbiome and the mechanisms of oral cancer development in betel nut chewers.

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Cyclooxygenase-2 gene polymorphisms reduce the risk of oral premalignant lesions.

Publications

Cyclooxygenase-2 gene polymorphisms reduce the risk of oral premalignant lesions.

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