Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Frequent Evolution of Copy Number Alterations Following First‑line Treatment with FC(R) is Enriched with TP53 Alterations which Impact Long Term Survival – Results from the CLL8 Trial

ABSTRACT: To define clonal evolution of somatic copy number alterations (CNAs) in chronic lymphocytic leukemia (CLL), sequential samples of 103 individuals were investigated by SNP-array analysis for appearance of novel CNAs. Patients were enrolled on the CLL8 trial and uniformly received fludarabine, cyclophosphamide +/- rituximab (FC/FCR). Comparing two sequential samples prior to therapy (N=27, a median of 2.9 years apart), CNA evolution occurred in 19% of cases. In contrast, when comparing treatment‑initiation and relapse genomic profiles (a median of 3.6 years apart), CNA evolution was seen in 40% of cases. This suggested association of FC(R) treatment with higher rate of CNA evolution. The only clinical feature significantly associated with CNA evolution was FCR therapy compared with FC (OR=2.806, p=0.024). As this might be related to narrower evolutionary bottlenecks imposed by the more effective FCR therapy, which could execute more selection pressure, we examined matched minimal residual disease data. We found CNA evolution more frequently in cases with CLL cell numbers rapidly receding in early phases of treatment. Finally, we observed frequent rises of TP53 mutant/deficient clones with therapy (N=19, 22%) that were associated with decreased overall survival (p=0.016). These results demonstrated that re-examination of TP53 status upon relapse provides important information.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83566 | GEO | 2017/08/25

SECONDARY ACCESSION(S): PRJNA326400

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Sequential gene expression profiling in CLL during treatment

Project description:Purpose: Accurate prediction of clinical response is the prerequisite for individualized therapy in chronic lymphocytic leukemia (CLL). We hypothesized that sequential assessment of gene expression changes early during therapy may well reflect behaviour of the leukemic clone in response to specific drugs. Patients and Methods: Gene expression profiles (GEP) were determined in CD19+ selected B-cells from 20 patients treated with fludarabine and cyclophosphamide (FC) (N=10) or FC plus rituximab (FCR) (N=10). Samples were collected in the first cycle before and within 48hours after initiation of treatment. GEP analysis was stratified by clinical response 3 months after start of therapy. Results: GEP before treatment detected high expression of 34 genes correlated with response and 32 genes correlated with resistance to therapy. These genes were related to regulation of apoptosis, cell cycle, cell adhesion, and signal transduction. Different results were obtained with sequential GEP: Sixteen genes were up-regulated after rituximab infusion in non-responders. Rituximab therapy resulted in down-regulation of AKT1 indicating involvement of the PI3-kinase pathway in CD20-signaling. Up-regulation of 24 genes after FC (including ITPKB (inositol 1,4,5-trisphosphate 3-kinase) and CD44) and of 36 genes after FCR (including CD49d) was associated with resistance. Down-regulation of CTLA4 correlated with poor response to FC. CD44, CD49d and the PI3-kinase signaling pathway were confirmed as potential therapeutic targets to overcome resistance by (protein analysis) or functional experiments. Conclusion Sequential GEP provides rapid and relevant information for prediction of response and resistance. This approach could be used to guide and adapt individualized therapy in CLL. 50 Samples from CD19 selected B-cells, three treatments (rituximab, FC and RFC), 10 replicates for each treatment, 20 replicates for control condition

2011-03-01 | E-GEOD-15490 | biostudies-arrayexpress

Sequential gene expression profiling in CLL during treatment

2011-03-01 | GSE15490 | GEO

Genomic Alterations in High-risk CLL Frequently Affect Cell Cycle Key Regulators and NOTCH1‑regulated Transcription.

Project description:To identify genomic alterations contributing to the pathogenesis of high‑risk chronic lymphocytic leukemia (CLL) beyond the well‑established role of TP53 aberrations, we comprehensively analyzed 146 high‑risk CLL cases by single‑nucleotide polymorphism (SNP)‑arrays and targeted next‑generation sequencing including 75 relapsed/refractory and 71 treatment‑naïve high‑risk cases from prospective clinical trials. Increased genomic complexity was a hallmark of relapsed/refractory and treatment‑naïve high‑risk CLL, and was associated with TP53 and ATM dysfunction. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both of these copy number alterations (CNAs) affected key regulators of cell cycle progression, namely c‑MYC and CDKN2A/B. Gains in 8q24.21 were either focal gains in a c‑MYC enhancer region or larger gains directly affecting the c‑MYC locus, but only the latter type was highly enriched in relapsed/refractory CLL (17%). Loss of CDKN2A/B was found frequently to co‑occur with gain of c‑MYC and in this combination it was likely associated with Richter transformation. In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 target genes. We investigated the functional impact of these alterations on HES1, DTX1 and c‑MYC gene transcription and found de‑repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the pathogenesis of high‑risk CLL by defining novel recurrent CNAs and identifying alterations that likely contribute to disease refractoriness.

2020-05-06 | GSE131114 | GEO

APOBEC mutagenesis and copy number alterations are drivers of proteogenomic tumor evolution and heterogeneity in metastatic thoracic tumors

Project description:Intratumor mutational heterogeneity has been documented in primary non-small cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC-mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk germline APOBEC3 variant, strongly correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN- induced expression of APOBEC3B in lung adenocarcinoma cells in culture suggesting a role for the immune microenvironment in the generation of mutational heterogeneity. CNA occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.

2019-05-07 | PXD012845 | Pride

Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia

Project description:The identification of gene mutation and structural genomic aberrations that are critically involved in CLL pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL proliferation, apoptosis thresholds, or chemotherapy resistance should increase in frequency over time when measured sequentially in a large CLL cohort. We sequentially sampled a large, well-characterized CLL cohort at a mean of 4 years between samplings. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies. Results: we identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients that did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations prior to therapy. Further, we provide evidence that therapy of CLL with preexisting TP53 mutations results in the outgrowth of genomically very complex clones which dominate at relapse. Using complementary technologies directed at the detection of genomic events that are present in substantial proportions of of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs, and TP53 mutations. Data from 156 paired samples (enrollment and one longitudinal sample) are included in this data set. Of these, 27 patients were assayed at two (or, rarely, more than two) time points. Please note: normal DNA and enrollment date tumor DNA CEL files and SNP call files will be found in a separate GEO data submission: GSE30777

2013-04-19 | E-GEOD-45565 | biostudies-arrayexpress

Paired copy number analysis of DLBCL Diffuse Large B Cell Lymphoma [SNP 6.0 Array]

Project description:Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected a total of 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20% of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5%) and 17p13.1 (2.5%) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains, which includes ETS1 and FLI1 genes. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.

2016-01-22 | GSE71389 | GEO

Paired copy number analysis of Diffuse Large B Cell Lymphoma [OncoScan]

2016-01-22 | GSE71386 | GEO

Longitudinal Genome Wide Analysis of Chronic Lymphocytic Leukemia Reveals Complex Evolution of Clonal Architecture at Disease Progression and at the Time of Relapse

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

Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia

2013-04-19 | GSE45565 | GEO

Longitudinal Genome Wide Analysis of Chronic Lymphocytic Leukemia Reveals Complex Evolution of Clonal Architecture at Disease Progression and at the Time of Relapse

2012-06-30 | GSE30217 | GEO