title: TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases.
abstract: The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1A protein, and CDKN1A mRNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and mRNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and mRNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases.
authors: Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84112-0565, USA.
authors: Vasiliki
authors: V
authors: Leventaki
authors: Vladimir
authors: V
authors: Rodic
authors: Sheryl R
authors: SR
authors: Tripp
authors: Michael G
authors: MG
authors: Bayerl
authors: Sherrie L
authors: SL
authors: Perkins
authors: Phillip
authors: P
authors: Barnette
authors: Joshua D
authors: JD
authors: Schiffman
authors: Rodney R
authors: RR
authors: Miles
mesh_terms: D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; C482775:MDM4 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2