Browsing by Author "Blaney, Patrick"

Now showing 1 - 4 of 4
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    Identifying 1q amplification and PHF19 expressing high-risk cells associated with relapsed/refractory multiple myeloma
    (Research Square, 2023-08-16) Johnson, Travis S.; Sudha, Parvathi; Liu, Enze; Blaney, Patrick; Morgan, Gareth; Chopra, Vivek S.; Dos Santos, Cedric; Nixon, Michael; Huang, Kun; Suvannasankha, Attaya; Abu Zaid, Mohammad; Abonour, Rafat; Walker, Brian A.; Biostatistics and Health Data Science, School of Medicine
    Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers have been identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and has already been studied using RNA-seq. In this study a massive (325,025 cells and 49 patients) single cell multiomic dataset was generated with jointly quantified ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identified an association between one plasma cell subtype with myeloma progression that we have called relapsed/refractory plasma cells (RRPCs). These cells are associated with 1q alterations, TP53 mutations, and higher expression of PHF19. We also identified downstream regulation of cell cycle inhibitors in these cells, possible regulation of the transcription factor (TF) PBX1 on 1q, and determined that PHF19 may be acting primarily through this subset of cells.
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    Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
    (Springer Nature, 2021-12-02) Ghamlouch, Hussein; Boyle, Eileen M.; Blaney, Patrick; Wang, Yubao; Choi, Jinyoung; Williams, Louis; Bauer, Michael; Auclair, Daniel; Bruno, Benedetto; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.; Medicine, School of Medicine
    Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.
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    Myeloma Genome Project Panel is a Comprehensive Targeted Genomics Panel for Molecular Profiling of Patients with Multiple Myeloma
    (American Association for Cancer Research, 2022) Sudha, Parvathi; Ahsan, Aarif; Ashby, Cody; Kausar, Tasneem; Khera, Akhil; Kazeroun, Mohammad H.; Hsu, Chih-Chao; Wang, Lin; Fitzsimons, Evelyn; Salminen, Outi; Blaney, Patrick; Czader, Magdalena; Williams, Jonathan; Zaid, Mohammad I. Abu; Ansari-Pour, Naser; Yong, Kwee L.; van Rhee, Frits; Pierceall, William E.; Morgan, Gareth J.; Flynt, Erin; Gooding, Sarah; Abonour, Rafat; Ramasamy, Karthik; Thakurta, Anjan; Walker, Brian A.; Medicine, School of Medicine
    Purpose: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. Experimental design: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations). Results: Canonical immunoglobulin heavy chain translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for 1 patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2 = 0.969. Variant allele frequency (VAF) for 74 mutations were compared between sequencing and ddPCR with concordance of R2 = 0.9849. Conclusions: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost-effective, comprehensive, clinically actionable, and can be routinely deployed to assist risk stratification at diagnosis or posttreatment to guide sequencing of therapies.
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    Structural variants shape the genomic landscape and clinical outcome of multiple myeloma
    (Springer Nature, 2022-05-30) Ashby, Cody; Boyle, Eileen M.; Bauer, Michael A.; Mikulasova, Aneta; Wardell, Christopher P.; Williams, Louis; Siegel, Ariel; Blaney, Patrick; Braunstein, Marc; Kaminetsky, David; Keats, Jonathan; Maura, Francesco; Landgren, Ola; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.; Medicine, School of Medicine
    Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis.