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Browsing by Author "Deshpande, Shayu"
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Item The functional epigenetic landscape of aberrant gene expression in molecular subgroups of newly diagnosed multiple myeloma(BMC, 2020-08-06) Choudhury, Samrat Roy; Ashby, Cody; Tytarenko, Ruslana; Bauer, Michael; Wang, Yan; Deshpande, Shayu; Den, Judith; Schinke, Carolina; Zangari, Maurizio; Thanendrarajan, Sharmilan; Davies, Faith E.; van Rhee, Frits; Morgan, Gareth J.; Walker, Brian A.; Medicine, School of MedicineBackground Multiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease. Methods Alterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate. Results We identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes. Conclusions Therefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.Item The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma(Springer Nature, 2021-01-12) Boyle, Eileen M.; Deshpande, Shayu; Tytarenko, Ruslana; Ashby, Cody; Wang, Yan; Bauer, Michael A.; Johnson, Sarah K.; Wardell, Christopher P.; Thanendrarajan, Sharmilan; Zangari, Maurizio; Facon, Thierry; Dumontet, Charles; Barlogie, Bart; Arbini, Arnaldo; Rustad, Even H.; Maura, Francesco; Landgren, Ola; Zhan, Fenghuang; van Rhee, Frits; Schinke, Carolina; Davies, Faith E.; Morgan, Gareth J.; Walker, Brian A.; Medicine, School of MedicineSmoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.