Polymorphisms in methylenetetrahydrofolate reductase, glutathione transferase, tumor necrosis factor alpha and its receptors in oral epithelial tumors.

Abstract

Background: Keratocystic Odontogenic Tumour (KCOT) and Oral Squamous Cell Carcinoma (OSCC) are classified as oral epithelial tumours. Although, the first one has benign and the second one malignant characteristics, they both have aggressive growth, sophisticated pathology and high tendency for recurrence following surgical treatment. Genetic factors including the polymorphism of the genes are thought to play an important role in their ethology. Aims: Polymorphisms in several gene classes, involved in DNA methylation and synthesis (MTHFR-677C>T), detoxification (GSTM1/T1) and immunomodulation (TNF-α -308G>A; TNF-α R1 -36A>G; TNF-α R2 -676T>G) were studied with the aim of identifying potential risk factors for oral epithelial tumour development. Materials and Methods: Genotyping was performed on DNA obtained from 71 biopsy specimens of KCOTs, 78 of OSCCs and from 182 buccal swabs of healthy individuals, using PCR and restriction fragment length polymorphism analysis. Chi square test and Fisher exact test were used to determine possible differences in the genotype and allele frequencies. The association of gene variants with risk of disease was examined by use of unconditional logistic regression analysis to calculate odds ratios (OR) and their 95% confidence intervals (CI). P values of lt 0.05 were considered statistically significant. Results: Among the KCOT group, there was a highly significant difference in genotype and allele frequencies between the patients and controls for the TNF-alpha and TNF-alpha receptor one polymorphism (p=0.00). Carriers of the allele A had a remarkably increased risk of developing KCOT (OR 4.41, CI 2.66-7.27, p=0.00). The other analysed polymorphisms did not show statistically significant association with KCOT. Among the OSCC group, there was a highly significant difference in genotype and allele frequencies between the patients and controls for the GSTT1 polymorphism (p=0.00). The subjects with the deletion of gene had a remarkably increased risk of developing OSCC (OR 3.56, CI 1.94-6.50, p=0.00). The other analysed polymorphisms did not show statistically significant association with OSCC...

Uvod: Odontogeni keratocistični tumor (OKT) i oralni planocelularni karcinom (OPK) pripadaju grupi oralnih epitelnih tumora. Iako je prvi benignog, a drugi malignog karaktera, odlikuje ih agresivan rast, složena patogeneza i relativno visok stepen recidiva nakon hirurške intervencije. Nasledne (germinativne) promene koje su deo genetičke konstitucije svakog pojedinca, a koje uključuju i polimorfizme gena, imaju značajnu ulogu u etiologiji ovih tumora. Cilj: Utvrditi da li polimorfizmi gena odgovornog za sintezu i metilaciju DNK (MTHFR -677C>T), gena odgovornog za detoksifikaciju (GSTM1/T1) i gena odgovornog za imunomodulaciju (TNF-α -308G>A; TNF-α R1 -36A>G; TNF-α R2 -676T>G) predstavljaju faktore rizika za nastanak epitelnih tumora usne duplje. Materijal i metode: Ispitivanja su rađena na uzorku od 71 pacijenta lečenog zbog OKT i 78 pacijenata lečenih zbog OPK. Kontrolnu grupu sačinjavalo je 182 zdravih osoba kod kojih je DNK dobijena brisom bukalne sluzokože. Genotipizacija je vršena pomoću lančane reakcije polimeraze (PCR) i analize restrikcionih fragmenata (RFLP). Chi kvadrat i Fišerov test su korišćeni kako bi se utvrdile eventualne razlike u genotipovima i alelnim učestalostima. Povezanost različitih genetskih oblika sa rizikom za nastanak ova dva epitelna tumora vršena je upotrebom logističke regresione analize izračunavanjem odnos šansi (odds ratios) i 95% intervala pouzdanosti (confidence intervals). P vrednosti manje od 0.05 smatrane su za statistički značajne. Rezultati: U okviru grupe ispitanika obolelih od OKT, postojala je visoka statistička značajnost između genotipova i alelnih učestalosti (kod obolelih i zdravih ispitanika), za analizirani TNF alfa (p=0.00) i TNF alfa receptor 1 polimorfizam (p=0.00). Nosioci alela A za TNF alfa, imali su izrazito visok rizik za nastanak OKT (OR 4.41, CI 2.66-7.27, p=0.00). Ostali ispitivani polimorfizmi nisu pokazali statistički značajnu razliku između ispitivanih grupa. U okviru grupe ispitanika obolelih od OPK, postojala je visoka statistička značajnost između genotipova i alelnih učestalosti (kod obolelih i zdravih ispitanika), za analizirani GST1 polimorfizam (p=0.00). Ispitanici kod kojih je bila ispoljena delecija gena, imali su izrazito visok rizik za nastanak OKT (OR 3.56, CI 1.94-6.50, p=0.00). Ostali ispitivani polimorfizmi nisu pokazali statistički značajnu razliku između ispitivanih grupa...