Telomere attrition and telomerase activity are associated with GSTM1 polymorphism in oral cancer.

Telomere attrition is an important event during tumorigenesis regulated by factors including oxidative stress, mitochondrial function, DNA adducts etc. Critically short telomeres act as signal for telomerase activity in the cancer cells. To determine whether null genotype of GSTM1 gene has any association with telomere length shortening and telomerase activity, we analyzed telomere length, telomerase activity and GSTM1 polymorphism in oral tissues. We observed that malignant tissues exhibited shorter telomere length. Telomerase activity was observed in about 75% malignant tissues. 40% of the oral cancer patients exhibited GSTM1 polymorphism. Further, shorter telomere lengths were observed in patients having GSTM1 polymorphism. Also, the GSTM1 genotype showed negative correlation with telomerase activity and telomere length. Our study proposes role of GSTM1 polymorphism in telomere attrition and subsequent telomerase activity in the cancer cells. The results are suggestive of possible link between absence of GSTM1 gene and telomere length alterations.

Clinical significance of telomere length and associated proteins in oral cancer.

PURPOSE: Telomere shortening is an important event during carcinogenesis. Although studies suggest role of multiple proteins in telomere length regulation, there is dearth of reports in oral cancer which is a leading malignancy in Asian countries especially in India. Thus the present study was carried out to study these mechanisms and explore the pathways involved in telomere-telomerase regulation and identify possible prognostic markers to understand the biology of oral tumors for better treatment approaches. METHODS: Telomere length was determined by Southern Hybridisation method, telomeric repeat binding factor (TRF) 1 and 2 expression was detected by Western blot method and telomerase activation by telomeric repeat amplification protocol. Statistical analysis was done using SPSS (Version 10) software. RESULTS: Significant shortening of telomeres was seen in the tumor tissues as compared to normal tissues. Poor prognosis was observed in the patients with higher telomere length in malignant tissue, higher tumor to normal telomere length ratio (T/N TRF LR). Expression of TRF-2 but not TRF-1 protein was significantly higher in the malignant tissues. We also observed telomerase activation in 75 malignant tissues. CONCLUSIONS: Our results reveal significant clinical usefulness of telomere length, T/N TRF LR and telomerase activation in the prognosis of oral cancer patients. TRF-2 overexpression in malignant tissues appears to play an important role in telomere length shortening in oral cancer.

Clinical usefulness of telomerase activation and telomere length in head and neck cancer.

BACKGROUND: Telomere shortening at every replication cycle is postulated to limit the life span of human somatic cells. In contrast, activation of telomerase is proposed to be an essential step for cancer cell immortalization. Head and neck cancer is the most common malignancy in the Indian population compared with Western countries. However, there are very few reports on telomerase activity and telomere length in head and neck cancer. METHODS: Telomerase activation and telomere length alterations were studied in tumor and adjacent normal tissues in 110 patients with head and neck cancer and 40 patients with precancerous/benign conditions. Telomerase activity and telomere lengths were determined by Telomeric Repeat Amplification Protocol (TRAP assay) and Southern blot analysis, respectively. RESULTS: Telomerase activation was observed in 78.2% of the malignant tissues, 85% of the precancerous tissues, and 53.1% of the adjacent normal tissues. Peak terminal restriction fragment length (TRF) was observed to be significantly lower in malignant tissues compared with the adjacent normal tissues. No significant correlation could be observed between telomerase activation and clinicopathologic characteristics of the patients. Two-year disease-free survival analysis showed that patients showing telomerase activation in the adjacent normal tissues and patients showing higher telomere length in malignant tissues had poor disease-free survival. CONCLUSIONS: Our results demonstrate the significant clinical usefulness of telomerase activation and telomere length for head and neck cancer patients. These markers may be helpful in predicting the clinical course of the disease and thus in identifying the patients in need of a close follow-up and vigorous adjuvant treatment.

Vitamin B(12) and Folate Status in Head and Neck Cancer.

Deficiency of vitamin B(12) and folate is associated with causation of certain precancerous conditions and cancer. The present study was carried out on 56 controls, 167 patients with oral precancerous conditions (OPC) and 214 head and neck cancer patients, to evaluate the plasma vitamin B(12) and folate levels to determine their association with tobacco habits and vegetarianism and several sociodemographic factors. The subjects were interviewed using a health habit and diet questionnaire at the time of blood collection. Simultaneous estimations of plasma vitamin B(12) and folate were done by Dual Count Radioassay. It was found that the habit of tobacco consumption, lower education and low income were among the risk factors. A decrease in the plasma vitamin B(12) and folate levels with respect to tobacco habits, disease progression, and vegetarian diet was also observed. The individuals in the ower quartile for vitamin B(12) and folate were at a higher risk of developing OPC, as compared to those in higher quartiles. Similarly, the patients with OPC in lower quartiles were found to be at a higher risk of developing cancer than their counterparts. There was a significant positive correlation between vitamin B(12) and folate levels in the subjects consuming tobacco, and more so in patients with OPC (r=0.4330, p=0.000). Folate levels were significantly lower in patients with advanced as compared with early disease (ANOVA p=0.006 and Spearman's Rho = -0.211 and p=0.01). The results suggest, potential significance of plasma vitamin B(12) and folate levels in head and neck malignancies which needs to be confirmed by further studies on a large population.

A Study of Various Sociodemographic Factors and Plasma Vitamin Levels in Oral and Pharyngeal Cancer in Gujarat, India.

Present study examined various socio-demographic factors, dietary patterns, habit of tobacco consumption and plasma vitamin levels in 56 healthy individuals, 146 patients with oral precancerous conditions (OPC) and 132 untreated oral and pharyngeal cancer patients. The subjects were interviewed with a detailed health, habit and diet questionnaire. Plasma b-carotene, vitamin-A and vitamin-E levels were determined spectrophotometrically. An increased incidence of OPC was observed in the age group of <30 years which was associated with tobacco chewing. Whereas, incidence of cancer was in the age group of 30-60 years where habit of tobacco smoking was more prevalent. Majorities of the subjects were from rural area, poor, unaware about association of diet with cancer. The body mass index was lower (p=0.045) in patients with OPC and cancer patients as compared to the controls. Plasma b-carotene and vitamin-E levels were lower in patients with OPC (p=0.000 and 0.031, respectively) and untreated cancer patients (p=0.000 and 0.071, respectively) than the controls. ROC curve revealed that plasma vitamin levels have ability to discriminate between controls and cancer patients. Lower plasma b-carotene and vitamin-E levels were observed in tobacco consumers as compared to non-consumers. Odds ratio revealed that controls and patients with OPC having tobacco habit and lower plasma levels of b-carotene were at a higher risk (p<0.05) of developing cancer. Regression study and Analysis of Variance revealed that plasma b-carotene levels were inversely associated (r(2)=0.14, p=0.001 and F=0.000, respectively) with increase in the stage of cancer. The data provide interesting clues of potential role of diet, tobacco habits, socio-demographic status and plasma vitamin levels in etiology of oral and pharyngeal cancer in Gujarat, where no such findings are reported.