Expression of P63 and Δnp63 as Potential Biomarkers of Tumor Progression and Prognosis in Oral Epidermoid Carcinoma
Name: ISABELLA BITTENCOURT DO VALLE
Publication date: 23/04/2018
Advisor:
Name |
Role |
|---|---|
| SANDRA LÚCIA VENTORIN VON ZEIDLER | Advisor * |
Examining board:
| Name |
Role |
|---|---|
| BRENO VALENTIM NOGUEIRA | Internal Examiner * |
| SANDRA LÚCIA VENTORIN VON ZEIDLER | Advisor * |
Summary: The prognosis of patients with Oral Epidermoid Carcinoma (CEO) is mostly unfavorable, mainly due to the high rate of relapse and mortality. To date, there are no clinically available biological markers that indicate events of tumor transformation or prognosis in CEO. Therefore, interest has been shown into the the cell cycle regulatory genes, such as the participation of P63 gene expression in oncogenesis through its activity in the regulation of cell proliferation and differentiation in CEO. This work aimed to analyze the applicability of p63 as a biomarker of prognosis and tumor progression. A multi-centered international study was carried out, in which biological samples, clinical data and clinical follow-up of 109 individuals with CEOs from Brazil and the United Kingdom were obtained. The histological slides obtained were evaluated for tumor grading, tumor lymphocyte infiltrate (TIL), tumor invasion pattern and perineural, vascular and lymphatic invasion. Tissue Microarray (TMA) was constructed considering 3 areas: epithelium adjacent to the tumor, dysplasia and tumor. The TMAs were submitted to immunohistochemistry for analysis of p63 and p40 (ΔNp63) expression and in situ hybridization of RNA to investigate p63 mRNA. To evaluate the expression of p63 and p40, nuclear labeling in keratinocytes was considered by H-Score method. The evaluation of p63 mRNA was given by a scoring guide (score 0-4) according to the number of points in each cell. The level of significance considered for all statistical tests was 95%. Chi-square test was used to establish associations between the clinical-pathological variables studied. The comparison between p63, p40 and p63 mRNA protein expression in the different regions was performed by the Wilcoxon test. Overall survival and disease-free survival curves were obtained using the Kaplan-Meier model and Cox regression. Our results showed an association between the high TIL presence in the tumor with initial stages (p=0.001) and smoking (p=0.044) and tumor patterns of invasion types III and IV (p =0.032). Subjects alcoholic/ ex-alcoholic had more vascular invasion than non-alcoholics (p=0.015). Expression of p63 in tumors was greater than in dysplasias (p=0.001) and was associated with larger tumors (T3 and T4) (p=0.001). Differences were observed in p40 expression between dysplasia and tumor (p<0.001) and high risk dysplasias presented high expression of p40 (p=0.022). The high expression of tumor p40 showed association with poorly differentiated tumors (p=0.010) and invasion of lymphatic vessels (p=0.022). No difference in expression of p63 mRNA was observed between the regions studied. Individuals with early stages (p=0.001) and non-smokers (p=0.035) had greater overall survival. Patients whose tumor invasion patterns were III and IV (p=0.014) and had larger tumors (p=0.004) had worse disease-free survival. We conclude from this study that p63 and 40 expression are useful markers of tumor progression but do not behave as good prognostic markers since they have not been shown to influence overall survival and disease-free survival rates.
