P53 deregulation in Epstein-Barr virus-associated gastric cancer

Authors and affiliations:
Joana Ribeiro^a,b,1, Mariana Malta^b,c,1, Ana Galaghar^d, Fernanda Silva^d, Luís Pedro Afonso^d, Rui Medeiros^b,c,e,f, Hugo Sousa^b,e

¹Joint first authors

^a Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal

^b Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portugal

^c Abel Salazar Institute for the Biomedical Sciences, University of Porto, Rua de Jorge Viterbo Ferreira, 4050-313 Porto, Portugal

^d Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

^e Virology Service, Portuguese Oncology Institute of Porto FG EPE, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal

^f Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal

Abstract:
TP53 is a tumour suppressor gene frequently mutated in human cancers; nevertheless, in EBV-associated malignancies mutations are uncommon despite frequent deregulation of the p53 pathway. In this study, we aimed to investigate p53 expression, TP53 mRNA levels and TP53 mutations in EBV-associated gastric carcinoma (EBVaGC). A case-control study was performed using 46 patients: 15 EBVaGC and 31 EBV-negative GC (EBVnGC) cases. p53 expression was detected by immunohistochemistry (IHC), the evaluation of p53 mRNA levels was performed by RT-qPCR and TP53 mutations were investigated only in EBVaGC cases using the DNA sanger sequencing method. p53 expression was found in 97.8% (45/46) of all gastric cancer cases (including EBVaGC and EBVnGC groups). Despite the high frequency of p53 expression in both groups, the percentages of cells are significantly higher among EBVaGC cases (p = 0.027). Regarding the mRNA levels, we found a significantly increased expression of p53 mRNA in EBVnGC (2-ΔΔCt = 13.4 ± 2.4; p = 0.0029) when compared with EBVaGC. Furthermore, the sequencing analysis of TP53 gene revealed that only one of the 15 EBVaGC cases presented a missense mutation. Our results demonstrated that EBV-associated gastric carcinomas are characterized by a significant decrease of TP53 mRNA levels with a strong p53 expression and rare TP53 mutations when compared with EBV-negative cancers. Considering these results, EBV seems to induce a stabilization of p53 in the EBVaGC independently of the presence of mutations, which remains to be explained.

Journal: Cancer Letters

Link: http://www.cancerletters.info/article/S0304-3835(17)30436-6/fulltext