Clonal selection and double hit events involving tumor suppressor genes underlie relapse from chemotherapy: myeloma as a model
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE82307 | GEO | 2017/06/01
SECONDARY ACCESSION(S): PRJNA324596
REPOSITORIES: GEO
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Project description:In order to gain insights into the mechanisms of disease progression in multiple myeloma (MM) patients treated with multi-agent and high-dose chemotherapy we have performed a longitudinal study of 33 patients entered into Total Therapy protocols using gene expression profiling, high resolution copy number analyses and whole exome sequencing. The results of this study show the importance of acquired mutations in MM driver genes, bi-allelic events affecting tumor suppressor genes and increased proliferation rates in driving relapse, which is enhanced by intra-clonal heterogeneity and Darwinian type clonal evolution. Branching was the most frequent evolution pattern, characterized by clonal loss and appearance of new clones. We found a higher number of lost and acquired copy number aberrations and an excess of bi-allelic inactivation of tumor suppressor genes in GEP70 high risk (HiR) cases, consistent with genomic instability being a key feature of HiR MM. In conclusion, our study further stresses the impact of known prognostic markers and driver genes on the fitness level of MM cells to survive multi-agent chemotherapy. The frequent bi-allelic loss of tumor suppressor genes in HiR cases and the potentially resulting failure of treatment with DNA damaging agents highlight the need for new therapies for HiR MM.
| EGAS00001001810 | EGA
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
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.
2013-02-13 | GSE37469 | GEO
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
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.
2013-02-13 | GSE25262 | GEO
Project description:We used copy number analysis of paired primary and relapse ovarian tumours to identify genes associated with acquired resistance
2012-06-21 | GSE38787 | GEO
Project description:Multiple myeloma is a genetically heterogeneous disease of plasma cells. The thalidomide analog lenalidomide is a mainstay in the treatment of multiple myeloma and is used in combination with other drugs such as corticosteroids, chemotherapy and proteasome inhibitors, achieving high remission rates. However, most patients relapse due to acquired resistance of the malignant cells. Genetic analyses have revealed mutations in CRBN, the target of all IMiDs, as a resistance mechanism in 10% of patients, while for the majority of cases, the mechanism of resistance is unknown. Here, we performed integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses revealed proteins highly upregulated at relapse, including TRIP13, RRM1 and CDK6, which was not reflected on the RNA expression level. Overexpression of CDK6 in multiple myeloma cell lines reduced sensitivity to lenalidomide and pomalidomide in a kinase-dependent fashion. CDK6 inactivation by palbociclib or a CDK6-specific proteolysis targeting chimera (PROTAC) plus lenalidomide or pomalidomide was highly synergistic. Proteomic analyses in cell lines revealed that CDK6 inhibition reverses a complex protein resistance signature including RRM1 and TRIP13 and in combination with IMiDs promotes metabolic remodeling and c-MYC downregulation . In conclusion, our global proteomic analyses identified CDK6 upregulation as a drug target to overcome lenalidomide resistance in multiple myeloma.
2021-12-14 | GSE162403 | GEO
Project description:The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include the maximisation of response and use of maintenance therapy. We used whole exome sequencing to study the genetics of paired presentation and relapse samples from 56 newly diagnosed patients, following induction therapy, randomised to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomisation. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterised by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumour suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response the evolutionary features were predominantly stable with a similar mutational and structural profile. There were no significant differences between patients relapsing after maintenance lenalidomide vs observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse.
| EGAS00001003539 | EGA
Project description:A SNP microarray and FISH-based procedure to detect allelic imbalances in multiple myeloma: an integrated genomics approach reveals a wide dosage effect on gene and microRNA expression Multiple myeloma (MM) is characterized by marked genomic instability. Beyond structural rearrangements, a relevant role in its biology is represented by allelic imbalances leading to significant variations in ploidy status. To better elucidate the genomic complexity of MM, we analyzed a panel of 45 patients using combined FISH and microarray approaches. Using a self-developed procedure to infer exact local copy numbers for each sample, we identified a significant fraction of patients showing marked aneuploidy. A conventional clustering analysis showed that aneuploidy, chromosome 1 alterations, hyperdiploidy and recursive deletions at 1p and chromosomes 13, 14 and 22 were the main aberrations driving samples grouping. Then, we integrated mapping information with gene and microRNAs expression profiles: a multiclass analysis of the identified clusters showed a marked gene-dosage effect, particularly concerning 1q transcripts, also confirmed by correlating gene expression levels and local copy number alterations. A wide dosage effect affected also microRNAs, indicating that structural abnormalities in MM closely reflect in their expression imbalances. Finally, we identified several loci in which genes and microRNAs expression correlated with loss-of-heterozygosity occurrence. Our results provide insights into the composite network linking genome structure and gene/microRNA transcriptional features in MM. Keywords: Integrated genomics approach based on SNP microarray and FISH procedures to detect allelic imbalances in multiple myeloma. Pathological bone marrow specimens from 41 MM and four plasma cell leukemia (PCL) patients at diagnosis. 250 nanograms of genomic DNA was processed and, in accordance with the manufacturer's protocols, 40 micrograms of fragmented biotin-labelled DNA were hybridized on GeneChip Human Mapping 50K XbaI Arrays (Affymetrix Inc.). The arrays were scanned using the GeneChip Scanner 3000 7G. The images were acquired using Affymetrix GeneChip® Operating Software (GCOS version 1.4). Copy number values for individual SNPs were extracted and converted from CEL files into signal intensities using GTYPE 4.1 and Affymetrix Copy Number Analysis Tool (CNAT 4.0.1) softwares. Genomic Smoothing analysis was performed by using the smoothing window of 0 Mb, and inferred copy number states were derived from a Hidden Markov Model (HMM) based algorithm implemented in CNAT 4.0.1. Circular Binary Segmentation (Ohlsen et al., 2004) was applied using DNAcopy package for R Bioconductor on raw data. FBN procedure was finally applied to infer exact local copy number as described in the mentioned Reference.
2009-05-16 | E-GEOD-16121 | biostudies-arrayexpress
Project description:We used copy number analysis of paired primary and relapse ovarian tumours to identify genes associated with acquired resistance Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from ovarian tumours. Copy number profiles of 22 primary and matched ascites samples. Multiple biopsies of four samples were also profiled to assess the intra tumour heterogeneity in samples.
2012-06-20 | E-GEOD-38787 | biostudies-arrayexpress