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Browsing by Author "Landgren, Ola"
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Item 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 MedicineDeciphering 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.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.Item The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states(Springer, 2022-08-03) Rasche, Leo; Schinke, Carolina; Maura , Francesco; Bauer , Michael A.; Ashby, Cody; Deshpande , Shayu; Poos , Alexandra M.; Zangari , Maurizio; Thanendrarajan, Sharmilan; Davies, Faith E.; Walker, Brian A.; Barlogie, Bart; Landgren, Ola; Morgan, Gareth J.; van Rhee, Frits; Weinhold , Niels; Medicine, School of MedicineDeciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.Item Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities(Springer Nature, 2021-03-25) Oben, Bénedith; Froyen, Guy; Maclachlan, Kylee H.; Leongamornlert, Daniel; Abascal, Federico; Zheng-Lin, Binbin; Yellapantula, Venkata; Derkach, Andriy; Geerdens, Ellen; Diamond, Benjamin T.; Arijs, Ingrid; Maes, Brigitte; Vanhees, Kimberly; Hultcrantz, Malin; Manasanch, Elisabet E.; Kazandjian, Dickran; Lesokhin, Alexander; Dogan, Ahmet; Zhang, Yanming; Mikulasova, Aneta; Walker, Brian; Morgan, Gareth; Campbell, Peter J.; Landgren, Ola; Rummens, Jean-Luc; Bolli, Niccolò; Maura, Francesco; Medicine, School of MedicineMultiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient’s life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.