Aberrant ERG expression associates with downregulation of miR-4638-5p and selected genomic alterations in a subset of diffuse large B-cell lymphoma.

Abstract

ERG (avian v-ets erythroblastosis virus E26 oncogene homolog), an oncoprotein in prostate carcinoma and Ewing's sarcoma is associated with poor prognosis in patients with acute myeloid leukemia and T lymphoblastic leukemia. However little is known about ERG in lymphoma. Here we studied ERG in diffuse large B-cell lymphoma (DLBCL) by immunohistochemistry, fluorescence in situ hybridization (FISH), genome-wide microRNA (miRNA) expression profiling, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and whole exome sequencing (WES). Approximately 30% of de novo DLBCLs (37 of 118) expressed ERG (ERG+). ERG expression showed no significant correlation with DLBCL cell-of-origin classification, patient's age, sex, nodal, or extranodal disease status, tumor expression of p53 or p63. There was no ERG rearrangement in 10 randomly selected ERG+ DLBCLs by FISH. Forty-three miRNAs showed significant differential expression between ERG+ and ERG- DLBCLs. Downregulation of miR-4638-5p was confirmed by real-time RT-PCR. WES not only confirmed known gene mutations in DLBCLs but also revealed multiple novel gene mutations in POLA1, E2F1, PSMD8, AXIN1, GAB2, and GNB2L1, which occur more frequently in ERG+ DLBCLs. In conclusion, our studies demonstrated aberrant ERG expression in a subset of DLBCL, which is associated with downregulation of miR-4638-5p. In comparison with ERG-negative DLBCL, ERG+ DLBCL more likely harbors mutations in genes important in cell cycle control, B-cell receptor-mediated signaling and degradation of β-catenin. Further clinicopathological correlation and functional studies of ERG-related miRNAs and pathways may provide new insight into the pathogenesis of DLBCL and reveal novel targets for better management of patients with DLBCL.

• Authors: Shanxiang Zhang, Lin Wang, Liang Cheng
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 58 Issue 10 Pg. 1846-1854 (10 2019) ISSN: 1098-2744 [Electronic] United States
• PMID: 31237044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• ERG protein, human
• MIRN4638 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• Transcriptional Regulator ERG

Topics

• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Genomics
• Humans
• In Situ Hybridization, Fluorescence
• Lymphoma, Large B-Cell, Diffuse (genetics, pathology)
• Male
• MicroRNAs (genetics)
• Middle Aged
• Neoplasm Proteins (genetics)
• Prognosis
• Signal Transduction (genetics)
• Transcriptional Regulator ERG (genetics)
• Exome Sequencing