Timing the initiation of multiple myeloma Rustad, Even H; Yellapantula, Venkata; Leongamornlert, Daniel ...
Nature communications,
04/2020, Letnik:
11, Številka:
1
Journal Article
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The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma ...evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2
-3
decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.
Smoldering 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.
In this study we set out to investigate whether anti PDL1 or PD-1 treatment targeting the immune system could be used against multiple myeloma. DCs are important in regulating T cell responses ...against tumors. We therefore determined PDL1 and PDL2 expression on DC populations in bone marrow of patients with plasma cell disorders using multicolour Flow Cytometry. We specifically looked at CD141+ and CD141- myeloid and CD303+ plasmacytoid DC. The majority of plasma cells (PC) and DC subpopulations expressed PDL1, but the proportion of positive PDL1+ cells varied among patients. A correlation between the proportion of PDL1+ PC and CD141+ mDC was found, suggesting both cell types could down-regulate the anti-tumor T cell response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tracking of clonal immunoglobulin V(D)J rearrangement sequences by next generation sequencing is highly sensitive for minimal residual disease in multiple myeloma. However, previous studies have ...found variable rates of V(D)J sequence identification at baseline, which could limit tracking. Here, we aimed to define the factors influencing the identification of clonal V(D)J sequences. Bone marrow mononuclear cells from 177 myeloma patients underwent V(D)J sequencing by the LymphoTrack assays (Invivoscribe). As a molecular control for tumor cell content, we sequenced the samples using our in-house myeloma panel myTYPE. V(D)J sequence clonality was identified in 81% of samples overall, as compared with 95% in samples where tumor-derived DNA was detectable by myTYPE. Clonality was detected more frequently in patients with lambda-restricted disease, mainly because of increased detection of kappa gene rearrangements. Finally, we describe how the tumor cell content of bone marrow aspirates decrease gradually in sequential pulls because of hemodilution: From the initial pull used for aspirate smear, to the final pull that is commonly used for research. In conclusion, baseline clonality detection rates of 95% or higher are feasible in multiple myeloma. Optimal performance depends on the use of good quality aspirates and/or subsequent tumor cell enrichment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The emergence of SARS-CoV-2 variants of concern (VOC) is driven by mutations that mediate escape from neutralizing antibodies. There is also evidence that mutations can cause loss of T cell epitopes. ...However, studies on viral escape from T cell immunity have been hampered by uncertain estimates of epitope prevalence. Here, we map and quantify CD8 T cell responses to SARS-CoV-2-specific minimal epitopes in blood drawn from April to June 2020 from 83 COVID-19 convalescents. Among 37 HLA ligands eluted from five prevalent alleles and an additional 86 predicted binders, we identify 29 epitopes with an immunoprevalence ranging from 3% to 100% among individuals expressing the relevant HLA allele. Mutations in VOC are reported in 10.3% of the epitopes, while 20.6% of the non-immunogenic peptides are mutated in VOC. The nine most prevalent epitopes are conserved in VOC. Thus, comprehensive mapping of epitope prevalence does not provide evidence that mutations in VOC are driven by escape of T cell immunity.
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•Among 123 eluted or predicted SARS-CoV-2 HLA-ligands, 29 are CD8 T cell epitopes•Epitope immunoprevalence in non-vaccinated convalescents ranges from 3% to 100%•Epitope immunoprevalence and immunodominance is strongly correlated•Mutations in VOC are not driven by T cell escape
Meyer et al. identify peptide sequences from SARS-CoV-2 that are commonly recognized by CD8 T cells in convalescents. They demonstrate that these sequences are conserved in VOC. Thus, the emergence of VOC is not driven by escape from T cell immunity.
Abstract
Chromothripsis is detectable in 20–30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 ...NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.
Achieving minimal residual disease (MRD) negativity in the bone marrow is one of the strongest prognostic factors in multiple myeloma. Consequently, MRD testing is routinely performed in clinical ...trials and moving towards standard of care. This review focuses on the role of next generation sequencing (NGS) of tumor-specific immunoglobulin V(D)J sequences for MRD tracking. The immunoglobulin variable regions are ideal targets for tracking, because every tumor cell shares an identical gene sequence, which is stable over time and generally distinct from the immunoglobulin sequences of normal B-cells. Several excellent assays for NGS-based MRD testing are available, both commercial and community-based, including one that is FDA-approved. These assays can achieve the gold standard analytical sensitivity of one tumor cell per million (10−6), requiring a minimum input of 3 million bone marrow cells. On-going clinical trials will outline how MRD testing should be used to inform dynamic risk-adopted therapy.
Reconstructing the evolutionary history of multiple myeloma Maura, Francesco; Rustad, Even H.; Boyle, Eileen M. ...
Baillière's best practice and research in clinical haematology/Baillière's best practice & research. Clinical haematology,
03/2020, Letnik:
33, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Multiple myeloma is the second most common lymphoproliferative disorder, characterized by aberrant expansion of monoclonal plasma cells. In the last years, thanks to novel next generation sequencing ...technologies, multiple myeloma has emerged as one of the most complex hematological cancers, shaped over time by the activity of multiple mutational processes and by the acquisition of key driver events. In this review, we describe how whole genome sequencing is emerging as a key technology to decipher this complexity at every stage of myeloma development: precursors, diagnosis and relapsed/refractory. Defining the time windows when driver events are acquired improves our understanding of cancer etiology and paves the way for early diagnosis and ultimately prevention.
Duration of first remission is important for the survival of patients with multiple myeloma.
From the CoMMpass study (NCT01454297), 926 patients with newly diagnosed multiple myeloma, characterized ...by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD; time to progression, TTP ≤18 months).
After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP >18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared with patients with late PD, patients with early PD had a lower at least very good partial response rate (47% vs. 82%,
< 0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiD) and proteasome inhibitors (PI; 21% vs. 8%,
< 0.001). Patients with early PD were at higher risk of death compared with patients with late PD and no PD (HR, 3.65; 95% CI, 2.7-4.93;
< 0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the early PD risk were
mutation (OR, 3.78,
< 0.001), high lactate dehydrogenase levels (OR, 3.15,
= 0.006), λ-chain translocation (OR, 2.25,
= 0.033), and
mutation (OR, 2.15,
= 0.007). Carfilzomib-based induction (OR, 0.15,
= 0.014), autologous stem-cell transplantation (OR, 0.27,
< 0.001), and continuous therapy with PIs and IMiDs (OR, 0.34,
= 0.024) mitigated the risk of early PD.
Early PD identifies a high-risk multiple myeloma population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk.
The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low ...coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (
),
and
Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as
and
. Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
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