Single cell RNA sequencing of multiple myeloma II
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE110499 | GEO | 2018/05/24
REPOSITORIES: GEO
Similar Datasets
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:Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
2023-08-01 | GSE235783 | GEO
Project description:Little is known about the extent of intraclonal heterogeneity of CLL tumor cells. We performed longitudinal whole genome analysis in 22 CLL cases with evidence of clinical progression and/or clinical relapse post therapy. We demonstrate the striking and unanticipated presence of genetic clonal heterogeneity, with at least 27% of patients exhibiting clonal evolution and 18% showing evidence of multiple subclones. We show that CLL progression can occur with multiple genetic subclones evolving either in a linear or branching manner. The analysis reveals a shift in the relative dominance of subclones with the emergence of initially minor clones after therapy all of which were very resistant to secondary therapies. This study uncovers the clinical importance of tracking subclone diversity in CLL.
2012-06-30 | GSE30217 | GEO
Project description:Cancer evolves dynamically, as clonal expansions supersede or overlap one another, driven by shifting selective pressures, mutational processes and disrupted cancer genes. These processes mark the genome, such that a cancerÕs life history is encrypted in the timing, ploidy, clonality and patterns of somatic mutation. We developed bioinformatic algorithms to decipher this narrative, and applied them to 21 breast cancer genomes. We find that mutational processes evolve across the lifespan of a breast tumor, with cancer-specific signatures of point mutations and chromosomal instability often emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, providing insight into the dynamics of clonal expansion in breast cancer. Most point mutations are found in just a fraction of tumor cells, together with frequent variegation in chromosomal copy number. Every tumor studied here has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent lineages of cells that are capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
2012-06-16 | E-MTAB-1087 | biostudies-arrayexpress
Project description:Cancer evolves dynamically, as clonal expansions supersede or overlap one another, driven by shifting selective pressures, mutational processes and disrupted cancer genes. These processes mark the genome, such that a cancerÕs life history is encrypted in the timing, ploidy, clonality and patterns of somatic mutation. We developed bioinformatic algorithms to decipher this narrative, and applied them to 21 breast cancer genomes. We find that mutational processes evolve across the lifespan of a breast tumor, with cancer-specific signatures of point mutations and chromosomal instability often emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, providing insight into the dynamics of clonal expansion in breast cancer. Most point mutations are found in just a fraction of tumor cells, together with frequent variegation in chromosomal copy number. Every tumor studied here has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent lineages of cells that are capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
2012-06-29 | E-MTAB-1088 | biostudies-arrayexpress
Project description:Little is known about the extent of intraclonal heterogeneity of CLL tumor cells. We performed longitudinal whole genome analysis in 22 CLL cases with evidence of clinical progression and/or clinical relapse post therapy. We demonstrate the striking and unanticipated presence of genetic clonal heterogeneity, with at least 27% of patients exhibiting clonal evolution and 18% showing evidence of multiple subclones. We show that CLL progression can occur with multiple genetic subclones evolving either in a linear or branching manner. The analysis reveals a shift in the relative dominance of subclones with the emergence of initially minor clones after therapy all of which were very resistant to secondary therapies. This study uncovers the clinical importance of tracking subclone diversity in CLL. All patients had genome wide genetic analysis performed by aCGH on at least two sequential tumor samples >6 months apart. For the purposes of this study, we classified samples as; time point 1 (TP1) collected >6 months before starting first-line treatment for disease progression; time point 2 (TP2) consisting of tumor samples at the time of progression requiring treatment; and time point 3 (TP3) consisting of tumor samples collected >6 months after initial treatment but prior to subsequent treatments. Overall, aCGH assay was performed in 54 samples from 22 patients (2 to 4 time points analyzed per patient). Thus, 6 patients were analyzed at TP1 and TP2, 8 patients at TP2 and TP3, 2 patients at TP1 and TP3, and the remaining 6 patients were analyzed at TP1, TP2 and TP3. Keyword : array comparative genomic hybridization
2012-06-29 | E-GEOD-30217 | biostudies-arrayexpress
Project description:Single cell lineage analysis was used to assess clonal genetic heterogeneity and functional aspects of AML HSPCs derived at diagnosis and relapse. To address inherent limitations of single cell analysis, we developed a unique high-resolution technique capable of following single cell-derived subclones of different HSPC subpopulations during the AML course. Each of these subclones was evaluated for chemo-resistance, in-vivo leukemogenic potential in Nod Scid Gamma (NSG) mice, mutational profile, and the subclone cell of origin identified using retrospective cell lineage reconstruction.
2022-08-12 | E-MTAB-11884 | biostudies-arrayexpress
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72927 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72732 | GEO