Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the tumour suppressor gene product p53 is common in oesophageal adenocarcinoma. This may be due to gene mutation, but overexpression can also result from complexing between viral proteins and p53; a number of viruses are causally linked with malignancy. This study therefore investigated the prevalence in oesophageal adenocarcinoma of viruses whose gene products are capable of interacting with p53. Seventeen tumours and 17 normal oesophagi were screened for specific DNA sequences from human papilloma virus (HPV), Adenovirus type 12, Epstein-Barr Virus (EBV), and cytomegalovirus (CMV). Frozen sections were analysed by polymerase chain reaction, and results were confirmed by Southern blot hybridization. Overexpression of p53 was studied immunohistochemically. Overexpression of p53 was identified in 11 of 17 tumours. No viral sequences were detected for HPV, CMV, or Adenovirus in any tumour. EBV sequences were found in eight of 17 tumours, and eight of 17 negative controls. There is therefore no evidence of HPV 16, 18 and 33, Adenovirus 12 or CMV infection in oesophageal adenocarcinoma. EBV infection in the oesophagus is of doubtful significance, in view of the high incidence in the control population. Overexpression of p53 cannot be explained by complexing with common viral proteins, and must be related to other intracellular mechanisms.
 ...
PMID:Investigation of oesophageal adenocarcinoma for viral genomic sequences. 906 43

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.
 ...
PMID:Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). 1055 88

The incidence of gastric cancer has been declining globally in the last decades. Despite the improvements in the diagnostic procedures, most cases are still detected at advanced stages due to lack of specific symptoms associated with early phases of tumour development. Consequently, gastric cancer poses a major health burden worldwide due to high mortality rates. Continuing advances in high-throughput technologies are revealing an intricate network of genetic and epigenetic changes associated with carcinogenesis. In addition, several risk factors, both environmental and genetic, have been recognized, which promote accumulation of diverse alterations affecting the expression of oncogenes, tumour suppressor genes, DNA repair genes, and other genes, implicated in normal gastric cell functions. A plethora of aberrant molecular events found in patients with this disease and intragenic heterogeneity of tumours from individuals are delaying the development of targeted biological therapies. Frequent occurrence of characteristic CpG island methylator phenotypes (CIMP phenotypes) in gastric cancers, particularly in association with Helicobacter pylori or EBV infection, could lead to introduction of epigenetic modulators into standard treatment regimens used against early and advanced forms of adenocarcinomas. This review highlights aberrant DNA methylation events in the development of gastric tumours and addresses the different aspects associated with the application of therapeutic epigenetic modulation in the management of the disease.
 ...
PMID:Outlook on Epigenetic Therapeutic Approaches for Treatment of Gastric Cancer. 2817 56

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK-cell lymphoma that is characteristically associated with Epstein-Barr virus (EBV) infection and cytotoxic tissue-destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T-cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV-negative ENKTL, where the absence of EBV in the true NK-lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next-generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV-positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone-modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV-negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK- and T-cell neoplasms and broadens the therapeutic options for potential targets.
 ...
PMID:Epstein-Barr virus-negative extranodal "true" natural killer-cell lymphoma harbouring a KDM6A mutation. 2869 59

Epstein-Barr virus (EBV) infection is associated with tumours such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer. We previously showed that EBV(+) gastric cancer presents an extremely high-methylation epigenotype and this aberrant DNA methylation causes silencing of multiple tumour suppressor genes. However, the mechanisms that drive EBV infection-mediated tumorigenesis, including other epigenomic alteration, remain unclear. We analysed epigenetic alterations induced by EBV infection especially at enhancer regions, to elucidate their contribution to tumorigenesis. We performed ChIP sequencing on H3K4me3, H3K4me1, H3K27ac, H3K27me3, and H3K9me3 in gastric epithelial cells infected or not with EBV. We showed that repressive marks were redistributed after EBV infection, resulting in aberrant enhancer activation and repression. Enhancer dysfunction led to the activation of pathways related to cancer hallmarks (e.g., resisting cell death, disrupting cellular energetics, inducing invasion, evading growth suppressors, sustaining proliferative signalling, angiogenesis, and tumour-promoting inflammation) and inactivation of tumour suppressive pathways. Deregulation of cancer-related genes in EBV-infected gastric epithelial cells was also observed in clinical EBV(+) gastric cancer specimens. Our analysis showed that epigenetic alteration associated with EBV-infection may contribute to tumorigenesis through enhancer activation and repression.
 ...
PMID:Regulation of tumour related genes by dynamic epigenetic alteration at enhancer regions in gastric epithelial cells infected by Epstein-Barr virus. 2880 83