Copy number analysis of liver metastases from colorectal cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63490 | GEO | 2016/07/11
SECONDARY ACCESSION(S): PRJNA268028
REPOSITORIES: GEO
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Project description:Colorectal cancer (CRC) patients suffer from the second highest mortality among all cancer entities. In half of all CRC patients, colorectal cancer liver metastases (CRLM) can be observed. Metastatic colorectal cancer is associated with poor overall survival and limited treatment options. Even after successful surgical resection of the primary tumor, metachronous liver metastases occur in one out of eight cases. The only available curative intended treatment is hepatic resection, but metachronous CRLM frequently recur after approximately one year. In this study, we performed a proteome analysis of three recurrent liver metastases of a single CRC patient by mass spectrometry. Despite surgical resection of the primary CRC and adjuvant chemotherapy plus cetuximab treatment, the patient developed three metachronous CRLM which occurred consecutively after 9, 21 and 31 months. We identified a set of 1,132 proteins expressed in the three metachronous CRLM, of which 481 were differentially regulated, including 81 proteins that were associated with the extracellular matrix (ECM). 56 ECM associated proteins were identified as upregulated in the third metastasis, 26 (46%) of which were previously described as negative prognostic markers in CRC, including tenascin C, nidogen 1, fibulin1 and vinculin. These data may reflect an ascending trend of malignancy from the first to the third metachronous colorectal cancer liver metastasis. Additionally, the results indicate different ECM phenotypes for recurrent metachronous metastasis, associated with different grades of malignancy and highlights the importance of individual analysis of molecular features in different, consecutive metastatic events in a single patient.
2021-09-09 | PXD020109 | Pride
Project description:Tumour heterogeneity has been the main obstacle to the clinical efficacy of targeted and immunotherapy in cancer. An accurate understanding and recognition of tumour heterogeneity is critical in the clinical management of cancer patients. Here, we utilised single-cell RNA sequencing (scRNA-seq) to uncover the intra- and inter-tumoural heterogeneity of liver metastases from a patient with metastatic uveal melanoma.
2021-09-12 | GSE176029 | GEO
Project description:About 50% of colorectal cancer patients develop liver metastases. Patients with metastatic colorectal cancer have 5-year survival rates below 20% despite new therapeutic regimens. Tumor heterogeneity has been linked with poor clinical outcome, but was so far mainly studied via bulk genomic analyses. In this study we performed spatial proteomics via MALDI mass spectrometry imaging on six patient matched CRC primary tumor and liver metastases to characterize interpatient, intertumor and intratumor hetereogeneity. We found several peptide features that were enriched in vital tumor areas of primary tumors and liver metastasis and tentatively derived from tumor cell specific proteins such as annexin A4 and prelamin A/C. Liver metastases of colorectal cancer showed higher heterogeneity between patients than primary tumors while within patients both entities show similar intratumor heterogeneity sometimes organized in zonal pattern. Together our findings give new insights into the spatial proteomic heterogeneity of primary CRC and patient matched liver metastases.
2023-02-17 | PXD039409 | Pride
Project description:At present, medical treatments of synchronous and metachronous liver metastases from colorectal cancer are not differentiated. The aim of the study was to analyze the gene expression profiling of synchronous and metachronous lesions in order to identify molecular signatures as possible basis for choice of systemic therapies. Fresh tissues specimens from metastases of 18 patients undergone liver surgery were collected (10 synchronous and 8 metachronous lesions). Gene expression profiling was studied using Affymetrix platform. Two different profiles were identified. Pathway related to the Epidermal Growth Factor receptor (EGFr) was upregulated in metachronous lesions whereas pathways mainly related to inflammation in synchronous lesions. Real Time-PCR, Western Blotting and ELISA confirmed that the metachronous lesions had the overexpression of EGFr, but the synchronous ones had the overexpression of Cyclo-oxygenase 2 (COX-2). These results suggest that synchronous or metachronous liver metastases from colorectal cancer could be differently treated on the basis of different molecular pathways. Keywords: disease state analysis
2008-12-22 | GSE10961 | GEO
Project description:In this comprehensive study, the authors have developed concise models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 Immune Checkpoint Blockade (ICB) treatment in individual tumors. It's important to note that their validation was performed in smaller, independent cohorts, constrained by data availability. The authors have developed two Logistic Regression based models for Ipilimumab treated and Ipilimumab naive patients with metastatic melanoma. The main predictive features for the Ipilimumab treated patients are MHC-II HLA, LDH at treatment initiation and the presence of lymph node metastases (LN met), chosen using forward selection methodology. The main predictive features for the Ipilimumab naive patients are tumor heterogeneity, tumor ploidy and tumor purity, chosen using forward selection methodology.
Please note that in these models, the output ‘1’ means progressive disease (PD) and ‘0’ means non-PD. The original GitHub repository can be accessed at https://github.com/vanallenlab/schadendorf-pd1
2023-11-17 | MODEL2310150001 | BioModels
Project description:Diversity within or between a tumour and metastases, known as intra-patient tumour heterogeneity develops during disease progression, and is a serious hurdle for therapy1,2,3. Metastasis is the fatal hallmark of cancer and mechanisms of colonization, the most complex step of the metastatic cascade4,5, remain ill-defined. Better understanding of cellular and molecular processes underlying intra-patient tumour heterogeneity and metastasis are pivotal for the success of personalized cancer treatment. Here, transcriptional profiling of tumours and matched metastases showed cancer site-specific phenotypes, and identified increased glucocorticoid receptor (GR) activity in the distant metastases. GR has been shown to mediate the effects of stress hormones and of their synthetic derivatives, widely used in the clinic as anti-inflammatory and immunosuppressive.
2019-03-25 | PXD009102 | Pride
Project description:Introduction: In cancer progression the development of distant metastases is the crucial adverse event. In colorectal cancer 70% of patients develop metastases in the liver. Within the BMBF-founded consortium MetastaSys, the role of the WNT and EGFR pathway in these metastases was investigated. In order to address the phenomenon of intermetastatic heterogeneity metastasis profiling was applied to several metastases of two patients. Methods: Four and two sequential liver metastases of two pilot cases, as well as corresponding normal liver tissue were comprehensively characterized in terms of clinical annotations, standardized histopathological and molecular subtyping. In all metastases the mutational status of KRAS, NRAS, BRAF and PIK3CA was assessed, as well as alterations in DNA mismatch repair enzymes and microsatellite instability. Fresh frozen samples were characterized by an experienced pathologist (tumor cell content, amount of stroma, inflammatory infiltrate and necrosis) to assure high quality of tissue. Samples were subsequently profiled via transcriptome sequencing (RNA-Seq) and proteomic profiling with Reverse-Phase-Protein-Arrays (RPPA). Results: A standardized data analysis pipeline for an integrated analysis of RNA-Seq and protein array data with clinical and genetic data was established. Dimensionality reduction of the transcriptome data revealed a distinct separation between normal tissue and metastases samples. Interestingly, the correlation between healthy samples of both patients was higher compared to the correlation between different metastatic samples of an individual patient. In different metastases of the same patient heterogeneous expression patterns were identified in the EGFR and the WNT pathway with relevant implication for clinical treatment approaches. Conclusion: High-throughput profiling of gene expression allows a clear discrimination between normal and metastatic liver tissue. Identified master regulators could identify drivers of intrapatient metastasis heterogeneity. Based on our findings and the positive validation of the established methodology including innovative high-throughput profiling and comprehensive bioinformatics approaches we started analyzing a large number of metastatic patient samples within the consortium.
2022-04-30 | GSE162960 | GEO
Project description:Cancer staging and treatment frequently assume a binary division of tumors into localized or metastatic cancers. We proposed a state of metastatic disease defined by the number of metastases termed oligometastases. Patients with oligometastatic disease may be cured with localized methods of cancer treatment. We analyzed miRNA expression from paraffin blocks of primary or metastatic tumor samples derived from oligometastatic (≤ 5 metastases) patients treated with high dose localized radiotherapy. We report patterns of miRNA expression in the metastatic and primary tumor samples that identify patients who failed to progress to widespread polymetastases. We created a model of oligometastases of human tumors in immune compromised mice. The miRNA patterns of gene expression derived from patients accurately identified oligometastatic patterns in the mouse model as compared to animals that developed widespread metastases. MiRNA signatures may identify patients most likely to benefit from aggressive curative treatment of limited metastatic disease. Tissues: We collected samples from 5 patients with both primary and metastatic tumors available for analysis, 20 patients with primary tumors only, and 9 patients with metastatic tumors only. Eleven of these patients were analyzed retrospectively, while 23 patients were included prospectively from a previously reported radiotherapy protocol for oligometastatsis. Total RNA were derived from FFPE primary and metastatic tissue samples.
2010-11-25 | E-GEOD-25552 | biostudies-arrayexpress
Project description:Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized. Sixty four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group). AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors. Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms. Introduction: Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized. Materials and methods: Sixty four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group). Results: AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors. Conclusions: Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms. Gene expression profiling of 15 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 21 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 21 metachronous metastatic/recurrent SynSa tumors (SynSa3 group); Agilent One-Color technology.
2014-07-31 | E-GEOD-54187 | biostudies-arrayexpress
Project description:Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma (PPGL) and medullary thyroid cancer (MTC), are caused by autosomal dominant mutations in a multitude of familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion but have undergone independent clonal evolution. Such tumours provide a unique opportunity to discover common co-operative changes required for tumorigenesis while controlling for the genetic background of the individual. We performed an in-depth genomic analysis of synchronous and metachronous tumours from five patients harbouring germline mutations in the genes SDHB, RET and MAX. Using whole exome sequencing and high-density SNP-arrays we analyzed between two and four primary tumours from each patient. Furthermore, we applied multi-regional sampling to assess intra-tumoral heterogeneity and clonal evolution in two cases involving PPGL and MTC, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary PPGL. Convergent events also occurred during clonal evolution of metastatic MTC. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour.
2017-02-02 | GSE94378 | GEO