Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences.
Authors
Kaymaz, YasinOduor, Cliff I.
Yu, Hongbo
Otieno, Juliana A.
Ong'echa, John Michael
Moormann, Ann M.
Bailey, Jeffrey A.
UMass Chan Affiliations
Division of Transfusion Medicine, Department of MedicineDepartment of Pathology
Program in Molecular Medicine
Program in Bioinformatics and Integrative Biology
Document Type
Journal ArticlePublication Date
2017-05-01Keywords
UMCCTS fundingBioinformatics
Computational Biology
Hemic and Lymphatic Diseases
Immune System Diseases
Molecular Biology
Neoplasms
Virus Diseases
Metadata
Show full item recordAbstract
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome. IMPLICATIONS: Genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions.Source
Mol Cancer Res. 2017 May;15(5):563-576. doi: 10.1158/1541-7786.MCR-16-0305.
DOI
10.1158/1541-7786.MCR-16-0305.Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29129PubMed ID
28465297ae974a485f413a2113503eed53cd6c53
10.1158/1541-7786.MCR-16-0305.