A complex seeding of multiple metastases in clear cell renal cell carcinoma (expression)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113204 | GEO | 2022/04/04
REPOSITORIES: GEO
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Project description:Tumor heterogeneity resulting from clonal evolution is a frequent feature in clear cell renal cell carcinoma (ccRCC) and could play a role in metastatic dissemination. However, the dynamics of metastatic evolution is not completely elucidated and could follow a complex seeding process. Using a unique experimental design with a rare matched primary-metastatic case prior to any medical treatment, we retraced the lineage of metastatic clones that showed a complex, multiple, polyphyletic seeding of two functionally interdependent subclonal populations originating from the primary tumor, in the direction of all metastatic sites.
2022-04-04 | GSE113205 | GEO
Project description:Bone invigorates metastatic seeding
| PRJNA675666 | ENA
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:Bone invigorates metastatic seeding [RNA-seq]
| PRJNA674386 | ENA
Project description:A complex seeding of multiple metastases in clear cell renal cell carcinoma
| PRJNA450416 | ENA
Project description:Following the removal of implanted mammary tumors, nude mice develop multiple-organ metastases at late stage. The metastases may originate from the primary tumors before the resection surgery, or alternatively, from some established metastases. By multiple approaches, we have proved that bone environment could invigorate cancer cells for further dissemination. this study aims to examine if metastatic dissemination from bone to other sites occurs in natural setting of metastatic spread. We herein apply the rapidly evolving barcode system using homing guide RNA/Cas9 to trace the metastases formation in mouse. hgRNA/Cas9 is a self-targeting Crispr system which allows the mutation occurs in the DNA sequence of guide RNA. Tumor cells wer labelled with doxycycline inducible evolving barcoding system. Upon doxycycline treatment the DNA sequence of hgRNA accumulate mutations with time. The diversity of barcodes in each lesion can infer the timeing of seeding while the mutation patterns of barcodes suggest the phylogenetic correlation of metastases. Several findings were made on this study. First, at the terminal stage, multi-organ metastases are not genetically grouped according to sites of metastases. Nonnegative Matrix Factorization (NMF) analysis of mutant barcodes suggested the early disseminated metastases, which have highest level of Shannon entropy, were featured with a common cluster of mutant barcodes irrespective of their locations. Second, most metastases are potentially multiclonal as indicated by multiple clusters of independent mutant barcodes. Third, when we use Shannon entropy as an index of metastasis age , putative parent-child relationship between metastases with unique mutant barcodes clearly exemplified secondary metastatic seeding from bone to other organs. Finally, we did not observe a clear correlation between tumor burden and Shannon entropy across different metastases, suggesting that putative parental metastases might remain small after seeding further metastases.
2021-04-29 | GSE161145 | GEO
Project description:A complex seeding of multiple metastases in clear cell renal cell carcinoma (expression)
| PRJNA450421 | ENA
Project description:A complex seeding of multiple metastases in clear cell renal cell carcinoma (CGH)
| PRJNA450420 | ENA
Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. BS-Seq of 4 patients (A13, A38, A124 and A125). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets). Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates. Patient A124 included 2 primary tumors and 1 normal pancreas.
2016-10-24 | E-GEOD-63123 | biostudies-arrayexpress
Project description:During pancreatic cancer progression, heterogeneous subclonal populations evolve in the primary tumor that possess differing capacities to metastasize and cause patient death. However, the genetics of metastasis reflects that of the primary tumor, and PDAC driver mutations arise early. This raises the possibility than an epigenetic process could be operative late. Using an exceptional resource of paired patient samples, we found that different metastatic subclones from the same patient possessed remarkably divergent malignant properties and global epigenetic programs. Global reprogramming was targeted to thousands of large chromatin domains across the genome that collectively specified malignant divergence. This was maintained by a metabolic shift within the pentose phosphate pathway, independent of KRAS driver mutations. Analysis of paired primary and metastatic tumors from multiple patients uncovered substantial epigenetic heterogeneity in primary tumors, which resolved into a terminally reprogrammed state in metastatic lesions. This supports a model whereby driver mutations accumulate early to initiate pancreatic tumorigenesis, followed by a period of subclonal evolution that generates sufficient intra-tumor heterogeneity for selection of epigenetic programs that may increase fitness during malignant progression and metastatic spread. To map the epigenomic landscape of pancreatic cancer progression as it evolves within patients. RNA-Seq of 2 patients (A13 and A38). Patient A38 included local peritoneal metastasis and 2 distant metastsis (liver and lung mets), and 6AN treated and DMSO control samples. Patient A13 included 2 primary tumors and 1 distant lung metastasis. Each sample has been done with replicates.
2016-10-24 | E-GEOD-63124 | biostudies-arrayexpress