Bone marrows from neuroblastoma patients: an excellent source for tumor genome analyses
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59537 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA255640
REPOSITORIES: GEO
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Project description:Background: Since the high relapse rate is considered to be responsible for the poor survival of stage M neuroblastoma patients, we tested whether the genomic information of bone marrow-derived disseminated tumor cells (DTCs) would help to better understand tumor evolution and to characterize the relapse-seeding clone. Methods: Seven samples from different regions of a primary tumor of a stage M neuroblastoma patient, corresponding DTCs at diagnosis, and DTCs and a metastatic tumor at relapse were analyzed by a high-density SNP array. Relapse-associated chromosomal aberrations found in this case were then validated in DTCs and tumor samples of 154 stage M neuroblastoma patients. Findings: In this case study, unique aberrations were evident in certain tissue/time points aside from a high concordance of genomic aberrations between all analyzed samples. Surprisingly, DTCs at diagnosis, and DTCs and the metastatic tumor at relapse all displayed a terminal deletion in 1q which was not detected in any of the primary tumor samples. In the validation cohort, 1q terminal deletions were found with a higher frequency in DTCs at diagnosis (17.8%) and at relapse (27.5%) compared to primary tumors (11%). 1q deletions were significantly associated with 19q and ATRX deletions. The presence of each individual aberration in the diagnostic DTCs was associated with an increased likelihood of an adverse event and in case of 19q deletion with a decreased overall survival. Moreover, PTPRD deletion and loss of chromosome Y had significantly higher frequencies in the relapse samples compared to the diagnostic samples. Interpretation: These data strongly suggest a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. In addition, the higher frequency of relapse-associated genomic aberrations in the diagnostic DTCs compared to the primary tumors and their effect on the event-free survival rate indicate that analysis of DTCs at diagnosis may provide a higher probability for detecting the relapse-seeding clone compared to the primary tumor. Background: Since the high relapse rate is considered to be responsible for the poor survival of stage M neuroblastoma patients, we tested whether the genomic information of bone marrow-derived disseminated tumor cells (DTCs) would help to better understand tumor evolution and to characterize the relapse-seeding clone. Methods: Seven samples from different regions of a primary tumor of a stage M neuroblastoma patient, corresponding DTCs at diagnosis, and DTCs and a metastatic tumor at relapse were analyzed by a high-density SNP array. Relapse-associated chromosomal aberrations found in this case were then validated in DTCs and tumor samples of 154 stage M neuroblastoma patients. Findings: In this case study, unique aberrations were evident in certain tissue/time points aside from a high concordance of genomic aberrations between all analyzed samples. Surprisingly, DTCs at diagnosis, and DTCs and the metastatic tumor at relapse all displayed a terminal deletion in 1q which was not detected in any of the primary tumor samples. In the validation cohort, 1q terminal deletions were found with a higher frequency in DTCs at diagnosis (17.8%) and at relapse (27.5%) compared to primary tumors (11%). 1q deletions were significantly associated with 19q and ATRX deletions. The presence of each individual aberration in the diagnostic DTCs was associated with an increased likelihood of an adverse event and in case of 19q deletion with a decreased overall survival. Moreover, PTPRD deletion and loss of chromosome Y had significantly higher frequencies in the relapse samples compared to the diagnostic samples. Interpretation: These data strongly suggest a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. In addition, the higher frequency of relapse-associated genomic aberrations in the diagnostic DTCs compared to the primary tumors and their effect on the event-free survival rate indicate that analysis of DTCs at diagnosis may provide a higher probability for detecting the relapse-seeding clone compared to the primary tumor.
2017-08-31 | GSE84291 | GEO
Project description:Background: Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of stage M patients present with disseminated tumor cells (DTCs) in the bone marrow (BM). Although these cells represent a major obstacle in the treatment of neuroblastoma patients, their transcriptomic profile was not intensively analyzed so far. Results: RNA-Seq of stage M primary tumors, enriched BM-derived DTCs and the corresponding non-tumor mononuclear cells (MNCs) revealed that DTCs largely retained the gene expression signature of tumors. However, we identified 322 genes that were differentially expressed (q < 0.001, |log2FC|>2). Particularly genes encoded by mitochondrial DNA were highly up-regulated in DTCs, whereas e.g. genes involved in angiogenesis were down-regulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8x10-75 log2FC > 6). Interestingly, we found that the gene expression profiles of diagnostic DTCs largely resembled those of relapse DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log2FC| > 0.5). Notably, relapse DTCs showed a positional enrichment of 31 down-regulated genes encoded by chromosome 19, including five tumor suppressor genes (SIRT6, PUMA, STK11, CADM4 and GLTSCR2). Conclusion: This first RNA-Seq analysis of DTCs from neuroblastoma patients revealed their unique expression profile in comparison to the corresponding MNCs and tumor samples, and, interestingly, also expression differences between diagnostic and relapse DTCs preferentially affecting chromosome 19. As these alterations might be associated with treatment failure and disease relapse, they should be considered for further functional studies.
2017-08-21 | GSE94035 | GEO
Project description:The aim of this study was to establish a single-cell array comparative genomic hybridization (SCaCGH) method providing in-depth genomic analysis of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs). The robustness and resolution limits of the method were estimated with different cell amounts of the breast cancer cell line SKBR3 using 44k and 244k arrays. Subsequent adjustments of the method were conducted analyzing the copy number profiles of 28 CTCs in combination with four hematopoietic cell (HC) controls from eight metastatic patients and of 24 DTCs, three probable HCs, and five HC controls from seven breast cancer patients and one healthy donor. The frequency of the major genomic gains and losses of the analyzed DTC revealed similarities to primary breast tumor samples with some evident differences. Three of the patients had available profiles for DTC and the corresponding primary tumor. In 2/3 of the examined DTCs, equivalent genomic changes and common aberration breakpoints were disclosed, both to each other and to the corresponding primary tumors. Interestingly, similar copy number changes were found in DTCs taken at time of diagnosis or in DTCs collected at 3-years relapse-free follow up. Residual immunomorphological characterized tumor cells showed balanced profiles with only minor aberrations. Three cells with unclear morphological identification showed either balanced profiles (n=2) or aberrations comparable to the primary tumor and DTC (n=1). SCaCGH may be a powerful tool for molecular characterisation of immunostained and morphological identified CTCs and DTCs to explore the malignant potential, therapeutic targets and tumor heterogeneity of single tumor cells. 24 DTCs, 3 probable HCs, and 5 HCs from 7 early-stage breast cancer patients, 28 CTCs and 4 HCs from 8 metastatic breast cancer patients, and 1 healthy donor were analysed. Comparison with the primary tumor was done in 3 patients. The reference for the patients was DNA from multiple anonymous female donors. This submission does not include the SKBR3 data obtained from the 44k array.
2012-11-19 | E-GEOD-27574 | biostudies-arrayexpress
Project description:In this study, using a Patient Derived Xenograft (PDX) system established by transplanting primary tumors from pre-metastatic breast cancer patients we demonstrate that development of distant organ metastases correlates with the presence of Bone Marrow Disseminated Tumor Cells (BM DTCs) in the PDX mice. Comparative gene expression analysis of bone marrow (BM) from tumor bearing PDX mice which developed metastatic disease was carried out with BM from non-tumor bearing controls. In this dataset, BM from seven tumor bearing mice with metastatic tumors, two control mice, a primary tumor and a spleen metastatic tumor from one of the tumor bearing mice were included in this analysis. This study allowed the identification of novel gene expression patterns associated with DTCs present in the BM and supports the concept that DTCs present in the BM undergo epithelial to mesenchymal transition (EMT). Analysis of the gene array data identified several genes which are known oncogenes (ETS1, GNL3), metastatic regulators (MALAT1, ALCAM, CD44), or associated with EMT (SIP 1) expressed at significantly higher levels in the BM of PDX mice as compared to BM from control animals.
2018-01-12 | GSE57947 | GEO
Project description:The aim of this study was to establish a single-cell array comparative genomic hybridization (SCaCGH) method providing in-depth genomic analysis of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs). The robustness and resolution limits of the method were estimated with different cell amounts of the breast cancer cell line SKBR3 using 44k and 244k arrays. Subsequent adjustments of the method were conducted analyzing the copy number profiles of 28 CTCs in combination with four hematopoietic cell (HC) controls from eight metastatic patients and of 24 DTCs, three probable HCs, and five HC controls from seven breast cancer patients and one healthy donor. The frequency of the major genomic gains and losses of the analyzed DTC revealed similarities to primary breast tumor samples with some evident differences. Three of the patients had available profiles for DTC and the corresponding primary tumor. In 2/3 of the examined DTCs, equivalent genomic changes and common aberration breakpoints were disclosed, both to each other and to the corresponding primary tumors. Interestingly, similar copy number changes were found in DTCs taken at time of diagnosis or in DTCs collected at 3-years relapse-free follow up. Residual immunomorphological characterized tumor cells showed balanced profiles with only minor aberrations. Three cells with unclear morphological identification showed either balanced profiles (n=2) or aberrations comparable to the primary tumor and DTC (n=1). SCaCGH may be a powerful tool for molecular characterisation of immunostained and morphological identified CTCs and DTCs to explore the malignant potential, therapeutic targets and tumor heterogeneity of single tumor cells.
2012-11-19 | GSE27574 | GEO
Project description:Cancer patients presenting with surgically resectable disease often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate cells based on spatial grounds. We developed a photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size including solitary disseminated tumor cells (DTCs), which are largely inaccessible otherwise. In a mouse pancreatic cancer model, transcriptional profiling of spontaneously arising DTCs revealed considerable heterogeneity, functionally reduced propensity to proliferate and enrichment for inflammatory-response phenotype associated with NF-κB signaling.
2021-03-02 | GSE158078 | GEO
Project description:In this study, we assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer In this dataset, Primary breast tissue from stage II or III breast cancer patients were included in the analysis. This study allowed the identification of novel gene expression patterns associated with the presence of DTCs BM by IHC and supports the concept of epithelial to mesenchymal transition transition (EMT) of DTCs present in the BM .
2015-12-16 | E-GEOD-71258 | biostudies-arrayexpress
Project description:Circulating (CTCs) and disseminated (DTCs) tumor cells are of great interest to the field of cancer research as they provide a minimally-invasive window for assessing aspects of cancer biology including tumor heterogeneity, a means to discover biomarkers of disease behavior, and a way to identify and prioritize therapeutic targets in the emerging era of precision oncology. However, the rarity of CTC/DTC poses a significant challenge to the consistent success in analyzing the molecular features of these cells including genomic aberrations. Herein, we demonstrate our optimized and robust methods to reproducibly detect genomic copy number alterations in samples of 2-40 cells after whole-genome amplification using a high resolution SNP-array platform and refined computational algorithms. We have determined the limit of detection for heterogeneity within a sample as 50% and also demonstrated success in analyzing single cells. We validated the genes in genomic regions that are frequently amplified or deleted by qPCR and nCounter copy number quantification. We further applied these methods to DTCs isolated from individuals with advanced prostate cancer to confirm the highly aberrant nature of these cells. We compared copy number alterations of DTCs to matched metastatic tumors isolated from the same individual to gain biological insight. These developments provide high-resolution genomic profiling of single and rare cell populations, and should be applicable to a wide-range of sample sources.
2015-10-02 | GSE73180 | GEO
Project description:PURPOSE: Bone marrow (BM) is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern. EXPERIMENTAL DESIGN: DTCs were identified in BM from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and FISH analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases. RESULTS: Combination of DNA copy number profiles (array CGH) with gene expression profiles identified five chromosomal regions differentiating BM-negative from BM-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21 and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (p=0.018). FISH analyses on further primary lung tumor samples confirmed the association between loss of 4q and the BM-positive status. In BM-positive patients 4q was frequently lost (37% vs. 7%), whereas gains could be commonly found among BM-negative patients (7% vs. 17%). The same loss was also found to be common in brain metastases from both small and non-small-cell lung cancer patients (39%). CONCLUSIONS: Thus, our data indicates for the first time that early hematogeneous dissemination of tumor cells might be driven by a specific pattern of genomic changes.
2009-10-05 | GSE13191 | GEO
Project description:Prostate cancer (PCa) has a significant ability to disseminate and survive in the bone marrow (BM). Once there, disseminated tumor cells (DTCs) may lie dormant for years, but often eventually reactivate proliferative pathways, thus largely contributing to bone metastasis, disease progression, and relapse. Unfortunately, quiescent PCa cells are difficult to identify and target with treatment, in part because formerly identified relevant markers are intracellular and regulated by protein stability. We sought to address this problem by identifying a G0 marker that is expressed on the cell surface and therefore amenable to antibody binding for identification and therapeutic targeting. In doing so, we utilized stably transduced fluorescent markers for CDKN1B (p27) and CDT1 protein levels, which separate viable PCa cells into G0, G1, or combined S/G2/M populations (as described in PMID 34957090). We then performed FACS to collect G1 and G0 PC3 PCa cells, isolated membrane proteins, and subsequently used GC-MS proteomics to determine differences in protein abundance between G0 and G1. In total, 3,791 proteins were identified.
2023-03-03 | PXD037378 | Pride