Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE27560 | GEO | 2011/06/06
SECONDARY ACCESSION(S): PRJNA138397
REPOSITORIES: GEO
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Project description:Comment on published article "Massive genomic rearrangement acquired in a single catastrophic event during cancer development." by Stephens, P.J., Greenman, C.D., Beiyuan, F., Yang, F., Bignell, G.R., Mudie, L.J., Pleasance, E.D., Lau, K.W., Beare, D., Stebbings, L.A., et al. (2011). Cell 144, 27-40. [PMID: 21215367] 10 myeloma patients examined with high resolution genome-wide chip SUPPLEMENTARY FILE: Copy number table.
2011-06-06 | E-GEOD-27560 | biostudies-arrayexpress
Project description:Multiple myeloma (MM) develops from a premalignant plasma cell proliferative disorder, and with time can progress to a more aggressive disease in extramedullary locations. The gradually clinical evolution is supported by clonal expansion of cells that acquire genetic lesions over years. This model of cancer evolution based on ongoing genomic instability mechanism may apply to development of most MM cases. However, in a small fraction of newly diagnosed MM who relapse quickly and finally die within 2 years, the gradual model appears to be untenable. Analysis of high resolution copy number profiles obtained using single nucleotide polymorphism array data from 764 newly diagnosed MM identified large numbers of genomic rearrangements with the hallmarks of chromothripsis in 1.3% of samples. Moreover, this catastrophic event confers a poor outcome. Because chromothripsis appears to occur in a single crisis, our results suggest that high-risk MM patients use this novel way of cancer evolution.
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Project description: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.
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Project description:PurposeWhole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined.Experimental designIn this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis.ResultsNinety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs.ConclusionsOverall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis.
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Project description:The iperactivation of self-renewal mechanisms, like Hedgehog (HH) pathway, which govern the refuel of Multiple Myeloma neoplastic clone, is critical to relapse events. The bulk of current knowledge is mainly based on the CD138+ cells molecular characterization, but in the light of the recent evidences, which attributed growing relevance to immature precursor clones, we become aware that multiple myeloma disease heterogeneity have more deepen roots. Here, we report on a high-throughput transcriptome study of gene expression profiles in newly diagnosed MM patients analyzed both in the CD138+ plasmacell fraction and in the CD19+ B cells compartment. Resulted data demonstrated that Hedgehog pathway, and in particular, a 10 HH-genes signature was heterogeneously expressed among MM patients, both in mature plasmacells and also in B cells at transcriptional level. Interestingly, this signature divide patients in two subgroups, and it seems that exists a sort of “ying-yang effect” between mature and immature cell compartments that are tightly regulate in order to express this relevant self-renewal pathway according to their maturation state.
2016-05-31 | GSE68891 | GEO
Project description:The iperactivation of self-renewal mechanisms, like Hedgehog (HH) pathway, which govern the refuel of Multiple Myeloma neoplastic clone, is critical to relapse events. The bulk of current knowledge is mainly based on the CD138+ cells molecular characterization, but in the light of the recent evidences, which attributed growing relevance to immature precursor clones, we become aware that multiple myeloma disease heterogeneity have more deepen roots. Here, we report on a high-throughput transcriptome study of gene expression profiles in newly diagnosed MM patients analyzed both in the CD138+ plasmacell fraction and in the CD19+ B cells compartment. Resulted data demonstrated that Hedgehog pathway, and in particular, a 10 HH-genes signature was heterogeneously expressed among MM patients, both in mature plasmacells and also in B cells at transcriptional level. Interestingly, this signature divide patients in two subgroups, and it seems that exists a sort of âying-yang effectâ between mature and immature cell compartments that are tightly regulate in order to express this relevant self-renewal pathway according to their maturation state. 144 samples have been analyzed: 126 BM-CD138+, 7 BM-B cells and 11 PBL-B cells; the homogeneity of samples has been ensured by the immunomagnetic enrichment procedure: only >90% pure cells have been employed.
2016-05-31 | E-GEOD-68891 | biostudies-arrayexpress