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Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Wilfried Gouraud

PROVIDER: E-GEOD-27560 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients.

Magrangeas Florence F Avet-Loiseau Hervé H Munshi Nikhil C NC Minvielle Stéphane S

Blood 20110531 3

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 with ...[more]

PMID: 21628407

Similar Datasets

Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients

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]

2011-06-06 | GSE27560 | GEO

Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients.

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.

| S-EPMC3142904 | biostudies-literature

Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma.

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.

| S-EPMC8397708 | biostudies-literature

Genetic adaptability of cancer cells under treatment selection pressure in multiple myeloma patients.

Project description:Purpose Despite advances and significant improvement in survival, multiple myeloma (MM) remains incurable and nearly all patients relapse after treatment. Previous studies have shown a complex spectrum of diverse genetic alterations in almost all patients, but evolution of genomic rearrangements throughout myeloma life cycle has not been investigated. Patients and Methods We performed genomic analysis integrating copy number, allele specific copy number, allele ratio calculations, breakpoint sequencing and rearrangement PCR genotyping on matched diagnosis and relapse samples from 24 MM patients either treated with proteasome inhibitor (bortezomib)-based induction regimen or conventional chemotherapeutic agents. Results All relapse samples have a clear relationship to the diagnosis clone with significant increase of copy number abnormalities (CNAs). Despite a wide diversity of CNAs acquired at relapse, regulators of NF-kB activity were targeted in 25% of the patients. Relapse-associated lesions either appeared as new acquisition or were selected from minor subpopulations at diagnosis. In one third of the patients, we found loss of abnormities containing loss of heterozygosity (LOH) providing evidence that the relapse clone derived from an ancestral clone shared with the dominant diagnosis clone. Remarkably, re-emergence of ancestral clones was almost exclusively found in patients treated with bortezomib, attested to a remarkable adaptability of myeloma cells under targeted drug selection pressure. Conclusion These data suggest that genomic instability and clonal selection are the main forces that drive adaptive changes in MM under drug selection pressure, and they support the proposal to combine several anti-myeloma drugs upfront in order to obtain long-term remissions. [SNP genotyping] 24 myeloma patients at diagnosis and relapse examined with high resolution genome-wide chip

2013-02-13 | E-GEOD-25262 | biostudies-arrayexpress

Impact of Rare Structural Variant Events in Newly Diagnosed Multiple Myeloma.

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.

| S-EPMC10841766 | biostudies-literature

Minor clone provides a reservoir for relapse in multiple myeloma

Project description:In this study we addressed subclonal evolutionary process after treatment and subsequent relapse in multiple myeloma (MM) in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. Because MM is a highly heterogeneous disease coupled with a large number of DNA copy number alterations (CNAs) and loss of heterozygosity (LOH), we focused our study on the secondary genetic events: 1q21 gain, NF-kB activating mutations, RB1 and TP53 deletions, that seem to reflect progression. By using genome-wide high resolution SNP arrays we identified subclones with nonlinear complex evolutionary histories in a third of patients with myeloma, the relapse clone apparently derived from a minor subclone at diagnosis. Such reordering of the spectrum of genetic lesions during therapy is likely to reflect selection of genetically distinct subclones not initially competitive against the dominant population that survived chemotherapy, thrived and acquired new anomalies. In addition we found that emergence of minor subclones at relapse was significantly associated with bortezomib treatment. Altogether, these data support the idea of new strategy of future clinical trials in MM that would combine targeted therapy and subpopulations control to eradicate all myeloma subclones in order to obtain long-term remission. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-02-13 | E-GEOD-37469 | biostudies-arrayexpress

Constitutional Chromothripsis on Chromosome 2: A Rare Case with Severe Presentation.

Project description:Chromothripsis is characterized by shattering and subsequent reassembly of chromosomes by DNA repair processes, which can give rise to a variety of congenital abnormalities and cancer. Constitutional chromothripsis is a rare occurrence, reported in children presenting with a wide range of birth defects. We present a case of a female child born with multiple major congenital abnormalities including severe microcephaly, ocular dysgenesis, heart defect, and imperforate anus. Chromosomal microarray and mate pair sequencing identified a complex chromosomal rearrangement involving the terminal end of the long arm of chromosome 2, with two duplications (located at 2p25.3-p25.1 and 2q35-q37.2 regions) and two deletions (located at 2q37.2-q37.3 and 2q37.3 regions) along with structural changes including inverted segments. A review of the literature for complex rearrangements on chromosome 2 revealed overlapping features; however, our patient had a significantly more severe phenotype which resulted in early death at the age of 2 years. Breakpoints analysis did not reveal the involvement of any candidate genes. We concluded that the complexity of the genomic rearrangement and the combined dosage/structural effect of these copy number variants are likely explanations for the severe presentation in our patient.

| S-EPMC10846923 | biostudies-literature

Comparison between newly diagnosed hypertension in diabetes and newly diagnosed diabetes in hypertension.

Project description:BackgroundHypertension and diabetes mellitus are often jointly present, especially in early onset cases of either disease. We investigated clinical characteristics of hypertensive patients with newly diagnosed diabetes and diabetic patients with newly diagnosed hypertension.MethodsOur study subjects were recruited in a China nationwide multicenter registry of hypertension and diabetes (n = 2510). We performed logistic regression to compare patients seen for hypertension in cardiology, with newly diagnosed diabetes (n = 137) and patients seen for diabetes mellitus in endocrinology, with newly diagnosed hypertension (n = 155). Albuminuria was defined as a urinary albumin-to-creatinine ratio of ≥ 30 mg/g, and left ventricular hypertrophy according to the Cornell product index.ResultsThese two groups of patients with both hypertension and diabetes mellitus were similar in most of the characteristics (P ≥ 0.06). However, hypertensive patients with newly diagnosed diabetes, compared to diabetic patients with newly diagnosed hypertension, had a significantly greater body mass index (26.3 vs. 25.4 kg/m2, P = 0.03) and slower heart rate (73.7 vs. 78.1 beats/min, P = 0.01). In logistic regression analyses adjusted for sex (48.3% women) and age (mean 60.0 ± 11.5 years), the odds ratio for newly diagnosed diabetes mellitus versus newly diagnosed hypertension was 1.27 (95% CI 1.03-1.56) and 0.80 (95% CI 0.66-0.96) for body mass index (+ 3 kg/m2) and heart rate (+ 10 beat/min), respectively. Hypertensive patients with newly diagnosed diabetes also had a lower prevalence of albuminuria (16.0% vs. 30.1%, P = 0.02) and slightly and non-significantly higher prevalence of left ventricular hypertrophy (5.1% vs. 1.9%, P = 0.14) than diabetic patients with newly diagnosed hypertension.ConclusionsEarlier or later onset of hypertension than diabetes mellitus may have different risk factors and organ damage.

| S-EPMC6708242 | biostudies-literature

Single cell analysis of newly diagnosed AML patients

Project description:Acute Myeloid Leukemia (AML) is a heterogenous disease characterized by immature blasts at different maturation stage. We used single cell sequencing technique to analyze newly diagnosed AML patients.

2023-12-18 | GSE239721 | GEO

Hydroxymethylation in newly diagnosed Multiple Myeloma

Project description:DNA Hydroxymethylation is Associated with Disease Severity and Persists at Enhancers of Oncogenic Regions in Multiple Myeloma

| PRJEB32800 | ENA