Phenotypic alterations in Rb pathway have more prognostic influence than p53 pathway proteins in oral carcinoma

Abstract

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...

Risk Stratification of Early Stage Oral Tongue Cancers Based on HPV Status and p16 Immunoexpression

“…Scale 1-faint or low cytoplasmic and nuclear staining (LS) in less than 20% of tumour cells, Scale 2-High cytoplasmic and low nuclear staining (HC) in less than 50% of tumour cells and Scale -3-High nuclear and high cytoplasmic staining in greater than 50% of tumour cells. We considered Scale 3 tumors showing intense nuclear and cytoplasmic staining as positive for p16 expression (Jayasurya et al, 2005).…”

H-Ras mutation modulates the expression of major cell cycle regulatory proteins and disease prognosis in oral carcinoma

“…21 Availability of tumour biopsy for DNA isolation was the criteria for selecting the present cohort from the original one. The clinical findings, treatment and follow-up have been recorded prospectively.…”

“…21 Standard avidinbiotin complex (ABC) method was employed for immunohistochemical studies. 21 Briefly, 5 mm thick tissue sections were cut from buffered formalinfixed, paraffin-embedded tissues.…”

“…21 Standard avidinbiotin complex (ABC) method was employed for immunohistochemical studies. 21 Briefly, 5 mm thick tissue sections were cut from buffered formalinfixed, paraffin-embedded tissues. After blocking the nonspecific sites, the sections were incubated overnight at 41C with optimally diluted respective primary antibodies: Rb (clone IF8), cyclin D1 (clone DCS6), CDK4 (clone DCS35), p16 (clone ZJ14), p53 (clones DO7 and PAb240), p21 (clone DCS60.2) and PCNA (clone PC10).…”

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

“…Como já antes mencionado, a ciclina D1 é um potencial biomarcador do câncer humano, como o câncer de boca (153)(154)(155) , e alguns estudos mostram que seu envolvimento na formação de tumores pode independer do complexo formado entre ciclina e CDKs (156,157) .…”