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Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Published on Dec 1, 2019in Nature Communications11.878
路 DOI :10.1038/s41467-019-11680-1
Francesco Maura13
Estimated H-index: 13
(University of Milan),
Niccolo Bolli2
Estimated H-index: 2
(University of Milan)
+ 25 AuthorsPeter J. Campbell95
Estimated H-index: 95
Abstract
The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients. Multiple myeloma evolves continuously. Here the authors chronologically reconstruct driver events in multiple myeloma, noting a limited repertoire of initiating driver events that shape the evolutionary trajectory of the disease.
  • References (54)
  • Citations (8)
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References54
Newest
#1Brian A Walker (University of Arkansas for Medical Sciences)H-Index: 36
#2Konstantinos Mavrommatis (Celgene)H-Index: 4
Last. Gareth J Morgan FRCPath (University of Arkansas for Medical Sciences)H-Index: 94
view all 39 authors...
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part...
26 CitationsSource
#1Brian A Walker (University of Arkansas for Medical Sciences)H-Index: 36
In this issue of Blood , Chapman et al 1 have derived a 7-gene expression signature that predicts whether a newly diagnosed myeloma patient will respond to treatment with bortezomib when autologous stem cell transplant (ASCT) is not considered as part of the upfront therapy.
7 CitationsSource
#1Jacob Grinfeld (University of Cambridge)H-Index: 6
#2Jyoti Nangalia (University of Cambridge)H-Index: 18
Last. Peter J. Campbell (University of Cambridge)H-Index: 95
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Abstract Background Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment. Methods We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations ...
39 CitationsSource
#1Niccolo Bolli (University of Milan)H-Index: 29
#2Francesco Maura (University of Milan)H-Index: 13
Last. Nikhil C. Munshi (Harvard University)H-Index: 117
view all 24 authors...
We analyzed whole genomes of unique paired samples from smoldering multiple myeloma聽(SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a 鈥渟tatic progression model鈥, where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects ...
11 CitationsSource
#1Brian A Walker (University of Arkansas for Medical Sciences)H-Index: 36
#2Konstantinos Mavrommatis (Celgene)H-Index: 4
Last. Gareth J Morgan FRCPath (University of Arkansas for Medical Sciences)H-Index: 94
view all 39 authors...
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1 , IDH2 , HUWE1 , KLHL6 , and PTPN11 . Oncogene mutations are significantly more clonal than tumor suppresso...
39 CitationsSource
#1Thomas J. Mitchell (University of Cambridge)H-Index: 13
#2Samra Turajlic (National Health Service)H-Index: 23
Last. Peter J. Campbell (University of Cambridge)H-Index: 95
view all 47 authors...
The work presented in this manuscript was funded by EU FP7 (project PREDICT ID number 259303) and the Wellcome Trust and Cancer Research UK. S.T. is funded by Cancer Research UK (C50947/A18176). S.T., J.L., and M.G. receive funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.H.R.F. and A.G.L. were supported by the University of Cambridge, Cancer Research UK (C14303/A17197), and Hutchiso...
63 CitationsSource
#1Phuc H. Hoang (ICR: Institute of Cancer Research)H-Index: 2
#2Sara E. Dobbins (ICR: Institute of Cancer Research)H-Index: 24
Last. Richard S. Houlston (ICR: Institute of Cancer Research)H-Index: 93
view all 7 authors...
Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naive B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alter...
13 CitationsSource
#1Michael SeilerH-Index: 15
#2Shouyong PengH-Index: 4
Last. Lihua YuH-Index: 12
view all 734 authors...
Summary Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-l...
53 CitationsSource
#1Francesco Maura (University of Milan)H-Index: 13
#2Mia Petljak (Wellcome Trust Sanger Institute)H-Index: 9
Last. Niccolo Bolli (University of Milan)H-Index: 29
view all 25 authors...
Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines
11 CitationsSource
#1Niccolo Bolli (University of Milan)H-Index: 29
#2Giulia Biancon (University of Milan)H-Index: 3
Last. Nikhil C. Munshi (Harvard University)H-Index: 117
view all 27 authors...
In multiple myeloma, next-generation sequencing (NGS) has expanded our knowledge of genomic lesions, and highlighted a dynamic and heterogeneous composition of the tumor. Here we used NGS to characterize the genomic landscape of 418 multiple myeloma cases at diagnosis and correlate this with prognosis and classification. Translocations and copy number abnormalities (CNAs) had a preponderant contribution over gene mutations in defining the genotype and prognosis of each case. Known and novel inde...
12 CitationsSource
Cited By8
Newest
ABSTRACTIntroduction: Multiple Myeloma (MM) is a very heterogeneous clonal plasma cell hematological malignancy for which new therapies and transplantation effectively improve Progression-free surv...
Source
#1Kez Cleal (Cardiff University)H-Index: 4
#2Duncan Martin Baird (Cardiff University)H-Index: 29
When cells progress to malignancy, they must overcome a final telomere-mediated proliferative lifespan barrier called replicative crisis. Crisis is characterized by extensive telomere fusion that drives widespread genomic instability, mitotic arrest, hyperactivation of autophagy, and cell death. Recently, it has become apparent that that the resolution of dicentric chromosomes, which arise from telomere fusions during crisis, can initiate a sequence of events that leads to chromothripsis, a form...
Source
#1Bachisio Ziccheddu (UNITO: University of Turin)H-Index: 1
#2Giulia Biancon (University of Milan)H-Index: 3
Last. Marialuisa SensiH-Index: 23
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In multiple myeloma, novel treatments with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) have prolonged survival but the disease remains incurable. At relapse, next-generation sequencing has shown occasional mutations of drug targets but has failed to identify unifying features that underlie chemotherapy resistance. We studied 42 patients refractory to both PIs and IMiDs. Whole-exome sequencing was performed in 40 patients, and RNA sequencing (RNA-seq) was performed in 27. We f...
Source
#1Francesco Maura (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 13
#2Niccolo Bolli (University of Milan)H-Index: 2
Last. Ola Landgren (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 65
view all 6 authors...
Importance All patients who develop multiple myeloma have a preceding asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM). During the past decade, significant progress has been made in the classification and risk stratification of SMM. Observations This review summarizes current clinical challenges and discusses available models for risk stratification in the context of SMM. Owing to sever...
3 CitationsSource
#1Heather Landau (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 19
#2Venkata Yellapantula (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
Last. Yangyu Zhou (MSK: Memorial Sloan Kettering Cancer Center)
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The malignant progression of multiple myeloma is characterized by the seeding of cancer cells in different anatomic sites followed by their clonal expansion. It has been demonstrated that this spatial evolution at varying anatomic sites is characterized by genomic heterogeneity. However, it is unclear whether each anatomic site at relapse reflects the expansion of pre-existing but previously undetected disease or secondary seeding from other sites. Furthermore, genomic evolution over time at spa...
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#1Niccolo BolliH-Index: 2
#2Elisa GenuardiH-Index: 8
Last. Carolina TerragnaH-Index: 23
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Personalized treatment is an attractive strategy that promises increased efficacy with reduced side effects in cancer. The feasibility of such an approach has been greatly boosted by next-generation sequencing (NGS) techniques, which can return detailed information on the genome and on the transcriptome of each patient's tumor, thus highlighting biomarkers of response or druggable targets that may differ from case to case. However, while the number of cancers sequenced is growing exponentially, ...
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#1Vanessa Pinto (UC: University of Coimbra)
Last. M. Helena VasconcelosH-Index: 25
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Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resist...
Source
#1Yusuke Furukawa (Jichi Medical University)H-Index: 40
#2Jiro Kikuchi (Jichi Medical University)H-Index: 22
The treatment outcome of multiple myeloma (MM) is worse than expected from the average numbers of non-synonymous mutations, which are roughly correlated with the prognosis of cancer patients. The refractoriness of MM may be ascribed to the complex genomic architecture and clonal behavior of the disease. In MM, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exis...
Source
#1Malin Hultcrantz (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 12
#2Venkata Yellapantula (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
Last. Even H Rustad (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 1
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Abstract Advances in technologies for genomic profiling, primarily with next generation sequencing, have lead to a better understanding of the complex genomic landscape in multiple myeloma. Integrated analysis of whole genome, exome and transcriptome sequencing has lead to new insights on disease drivers including translocations, copy number alterations, somatic mutations, and altered gene expression. Disease progression in multiple myeloma is largely driven by structural variations including th...
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#1Kylee H. Maclachlan (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
#2Benjamin Diamond (MSK: Memorial Sloan Kettering Cancer Center)
Last. Dickran Kazandjian (NIH: National Institutes of Health)H-Index: 11
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Abstract The changing landscape of treatment options for multiple myeloma has led to a higher proportion of patients achieving deep, long-lasting responses to therapy. With the associated improvement in overall survival, the development of subsequent second malignancies has become of increased significance. The risk of second malignancy after multiple myeloma is affected by a combination of patient-, disease- and therapy-related risk factors. This review discusses recent data refining our knowle...
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