title: Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma.
abstract: Endemic Burkitt lymphoma (eBL) is an aggressive B cell lymphoma and is associated with Epstein-Barr virus (EBV) andPlasmodium falciparummalaria co-infections. Central to BL oncogenesis is the over-expression of the MYC proto-oncogene which is caused by a translocation of an Ig enhancer in approximation to the myc gene. While whole genome/transcriptome sequencing methods have been used to define driver mutations and transcriptional dysregulation, microRNA (miRNA) dysregulation and differential expression has yet to be fully characterized. We hypothesized that both human and EBV miRNAs contribute to eBL clinical presentation, disease progression, and poor outcomes. Using sensitive and precise deep sequencing, we identified miRNAs from 17 Kenyan eBL patient tumor samples and delineated the complement of both host and EBV miRNAs. One human miRNA, hsa-miR-10a-5p was found to be differentially expressed (DE), being down-regulated in jaw tumors relative to abdominal and in non-survivors compared to survivors. We also examined EBV miRNAs, which made up 2.7% of the miRNA composition in the eBL samples. However, we did not find any significant associations regarding initial patient outcome or anatomical presentation. Gene ontology analysis and pathway enrichment of previously validated targets of miR-10a-5p suggest that it can promote tumor cell survival as well as aid in evasion of apoptosis. To examine miR-10a-5p regulatory effect on gene expression in eBL, we performed a pairwise correlation coefficient analysis on the expression levels of all its validated targets. We found a significant enrichment of correlated target genes consistent with miR-10a-5p impacting expression. The functions of genes and their correlation fit with multiple target genes impacting tumor resilience. The observed downregulation of miR-10a and associated genes suggests a role for miRNA in eBL patient outcomes and has potential as a predictive biomarker that warrants further investigation.
authors.affiliation: Center for Global Health Research, Kenya Medical Research InstituteKisumu, Kenya; Department of Biomedical Sciences and Technology, Maseno UniversityMaseno, Kenya.
authors.forename: Cliff I
authors.initials: CI
authors.lastname: Oduor
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School Worcester, MA, USA.
authors.forename: Mercedeh
authors.initials: M
authors.lastname: Movassagh
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School Worcester, MA, USA.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Kaymaz
authors.affiliation: Department of Biomedical Sciences and Technology, Maseno University Maseno, Kenya.
authors.forename: Kiprotich
authors.initials: K
authors.lastname: Chelimo
authors.affiliation: Jaramogi Oginga Odinga Teaching and Referral Hospital, Ministry of Medical Services Kisumu, Kenya.
authors.forename: Juliana
authors.initials: J
authors.lastname: Otieno
authors.affiliation: Center for Global Health Research, Kenya Medical Research Institute Kisumu, Kenya.
authors.forename: John M
authors.initials: JM
authors.lastname: Ong'echa
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School Worcester, MA, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Moormann
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical SchoolWorcester, MA, USA; Division of Transfusion Medicine, Department of Medicine, University of Massachusetts Medical SchoolWorcester, MA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bailey
keywords: EBV; RNAseq; endemic Burkitt lymphoma; miR-10a-5p; microRNA expression