The two well-defined pathways that are shown to be prominently altered in a variety of cancers are the cell cycle regulatory pathways led by either p53 or Rb genes. The present study is undertaken to find the pathway that is more altered in oral carcinoma at protein level, with special emphasis on its prognostic significance. The expression pattern of key molecules of the Rb and p53 pathways, such as Rb, cyclin D1, CDK4, p16, p53, p21 and Bcl-2 and the proliferative marker PCNA were analysed in 348 oral carcinoma specimens by immunohistochemical technique. The expression index of these molecules and various clinicopathological factors were statistically correlated with treatment end points to assess its prognostic efficacy after following up these patients up to a maximum of 48 months with a median of 23 months. Rb pathway proteins, Rb (P ¼ 0.016), cyclin D1 (P ¼ 0.0001) and p16 (P ¼ 0.012) showed significant association with disease-free survival, and p16 (P ¼ 0.041) and cyclin D1 (P ¼ o0.0001) with the overall survival. Among p53 pathway proteins studied, only p53 expression index showed association with both disease-free survival and overall survival. Multivariate analyses confirmed that the biological variables, cyclin D1 and p16 and the clinical variable, 'stage of disease' were independent predictors of disease-free survival and overall survival. Subgrouping of the patients on the basis of p16 and cyclin D1 expression revealed that the subgroup having downregulation of p16 and overexpression of cyclin D1 exhibited the worst disease-free survival and overall survival compared to the other subgroups. The present data showed that disabling of the Rb and p53 pathways were frequent events in oral carcinoma. The study also demonstrated that the Rb pathway proteins are comparatively more important than p53 pathway proteins for the prognostication of oral carcinoma patients. The combined evaluation of p16 and cyclin D1 in oral carcinoma could identify a group of patients with the worst survival who might therefore need alternate or more intense treatment strategies. Oral cancer is one of the 10 most common cancers in the world and is commonest in India and other south-east Asian countries.1 In India, oral cancer is highly prevalent, comprising a large fraction of all malignancies, due to the habit of tobacco chewing alone or with betel quid, which is commonly observed in the population.2 Although recent advances have reduced the morbidity of oral cancer, the 5-year survival rate for these patients has remained almost unchanged at B50% for the last 30 years.3 Oral cancers are highly heterogeneous in nature regarding site, biology and treatment response. In clinical practice, the treatment planning and prognosis of oral cancer is mainly based on the TNM classification; however, there is increasing evidence that in its current form, it is probably insufficient to predict the clinical outcome of patients with oral carcinoma. Therefore, it is important to look for new biological prognostic markers that might add inform...

Background: Oral cancer patients are found to have poor clinical outcome and high disease recurrence rate, in spite of an aggressive treatment regimen. The inactivation of INK4A/ARF loci is reported to be second to p53 inactivation in human cancers. The purpose of this study was to assess the prognostic significance of the molecular aberrations in the INK4A locus for effective identification of aggressive oral carcinoma cases needing alternate therapy. Materials and Methods: The study composed of 116 patients freshly diagnosed with oral carcinoma. The genetic and epigenetic status of the p16 INK4A and p14ARF genes was evaluated. The relation between these genic alterations and different treatment end points, such as residual disease (initial response), disease recurrence, and overall survival, along with the standard clinical markers, were analyzed. Results: 62% of the study cases had p16INK4A gene abnormalities, with deletion accounting for 33% and methylation for 29%. Alterations in p14 ARF gene either by deletion (12%) and/or methylation (18%) were

MicroRNAs are endogenous small noncoding RNAs that negatively regulate gene expression at posttranscriptional level. The discovery of microRNAs has identified a new layer of gene regulation mechanisms, which play a pivotal role in development as well as in various cellular processes, such as proliferation, differentiation, cell growth, and cell death. Deregulated microRNA expression favors acquisition of cancer hallmark traits as well as transforms the tumor microenvironment, leading to tumor development and progression. Many recent studies have revealed altered expression of microRNAs in oral carcinoma with several microRNAs shown to have key biological role in tumorigenesis functioning either as tumor suppressors or as tumor promoters. MicroRNA expression levels correlate with clinicopathological variables and have a diagnostic and prognostic value in oral carcinoma. For these reasons, microRNA has been a hot topic in oral cancer research for the last few years. In this review, we attempt to summarize the present understanding of microRNA deregulation in oral carcinoma, their role in acquiring cancer hallmarks, and their potential diagnostic and prognostic value for oral cancer management.

Aim-To study p53 expression in relation to proliferative status in normal and nondysplastic, dysplastic and malignant lesions of the oral mucosa. Method-The standard avidin-biotin complex (ABC) immunohistochemical staining method was used to study the expression of p53 and Ki67 on frozen sections of oral leukoplakias and carcinomas.Results-Of the leukoplakia and carcinoma samples, 70% expressed p53 in over 5% ofcells. In normal mucosa less than 5% of cells expressed p53. The proliferation index, as assessed by expression of Ki67, was highest in the malignant lesions (43%) and lowest in normal mucosa (11% Of the pre-malignant lesions, oral leukoplakia has greatest relevance in the study of the biology of carcinogenesis because the oral cavity is easily accessible for clinical examination4 and also because it has a multistage carcinogenesis pathway and of the concept of field cancerisation.' The oral carcinogenesis pathway can be broadly classified histopathologically into normal, non-dysplastic, dysplastic, carcinoma-insitu, and invasive carcinoma.4 Molecular biological studies on oral cancer have identified several genetic aberrations in the cells during various tumour stages.6 7Mutations in the p53 tumour suppresser gene are the most common genetic changes in humans cancers and are regarded as early events in carcinogenesis.8"-In pre-malignant and malignant oral lesions, alterations in p53 expression have been reported both at protein and DNA levels.12-18 As cancer is characterised by uncontrolled cell proliferation, markers of proliferation, such as Ki67 and proliferating cell nuclear antigen, have been studied extensively in neoplastic lesions.'9 Ki67 is a nuclear antigen which is present in the perichromosomal region during mitosis and seems to be a non-histone protein, representing a new class of cell cycle maintaining proteins.20 Studies on proliferation markers in lesions of the oral mucosa have shown that expression of Ki67 is correlated with the severity of the lesion. [21][22][23][24] Studies on the relation between p53 and the proliferation index in various malignancies, including lesions of the oral mucosa, have been reported previously.25"-Our aim was to elucidate the relation, if any, between expression of p53 and Ki67 in normal, non-dysplastic, dysplastic, and neoplastic lesions of the oral mucosa and to determine whether these markers have potential as early indicators of malignancy. MethodsFifty tissue samples, five of normal oral mucosa, 30 of leukoplakia and 15 of invasive carcinoma, were studied. Demographic details were recorded for all patients and included age, sex and whether they used tobacco products. Only those patients with oral leukoplakia and carcinoma at non-keratinising sites of the oral cavity were included. A 4 mm punch biopsy specimen was collected from each patient, immediately snap frozen and stored in liquid nitrogen. Cryostat sections, 5 ,um thick, were cut from each biopsy specimen and fixed in cold acetone. One section from each biopsy