Clariom D assay data from four colorectal cancer patients with tumor, metastasis and normal
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206800 | GEO | 2022/06/26
REPOSITORIES: GEO
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Project description:Colorectal cancer (CRC) is one of the most prevalent cancers, with over one million new cases per year. Overall, prognosis of CRC largely depends on the disease stage and metastatic status. As precision oncology for patients with CRC continues to improve, this study aimed to integrate genomic, transcriptomic, and proteomic analyses to identify significant differences in expression during CRC progression using a unique set of paired patient samples while considering tumour heterogeneity.We analysed fresh-frozen tissue samples prepared under strict cryogenic conditions of matched healthy colon mucosa, colorectal carcinoma, and liver metastasis from the same patients. Somatic mutations of known cancer-related genes were analysed using Illumina's TruSeq Amplicon Cancer Panel; the transcriptome was assessed comprehensively using Clariom D microarrays. The global proteome was evaluated by liquid chromatography-coupled mass spectrometry (LC‒MS/MS) and validated by two-dimensional difference in-gel electrophoresis. Subsequent unsupervised principal component clustering, statistical comparisons, and gene set enrichment analyses were calculated based on differential expression results.Although panomics revealed low RNA and protein expression of CA1, CLCA1, MATN2, AHCYL2, and FCGBP in malignant tissues compared to healthy colon mucosa, no differentially expressed RNA or protein targets were detected between tumour and metastatic tissues. Subsequent intra-patient comparisons revealed highly specific expression differences (e.g., SRSF3, OLFM4, and CEACAM5) associated with patient-specific transcriptomes and proteomes.Our research results highlight the importance of inter- and intra-tumour heterogeneity as well as individual, patient-paired evaluations for clinical studies. In addition to changes among groups reflecting CRC progression, we identified significant expression differences between normal colon mucosa, primary tumour, and liver metastasis samples from individuals, which might accelerate implementation of precision oncology in the future.
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Project description:(Purpose) Biological classification of colorectal cancer (CRC) can help to understand its heterogeneous background. The purpose of this study is to classify CRC based on gene expression profiles using formalin-fixed paraffin-embedded (FFPE) samples and to correlate subgroups of CRC with biological features and clinical outcomes. (Results) CRC was clustered into four subgroups by unsupervised hierarchical clustering method. These subgroups show different biological and clinical features. (Conclusion) Gene expression profiles of CRC using FFPE samples distinguish four subgroups that had different biological features and clinical outcomes. These subgroups may explain heterogeneity of CRC and be useful biomarker for clinical. Patients and Methods: One hundred patients with unresectable and advanced or recurrent CRC who underwent the surgical resection from 1998 to 2010 were enrolled in this study. RNA extracted from FFPE samples was subjected to gene expression microarray. After comprehensive gene expression analysis, CRC were classified by an unsupervised hierarchical clustering and a principle component analysis (PCA). Mutation analysis of KRAS, BRAF, PIK3CA and TP53 genes were performed by direct DNA sequencing. Correlation between the biological information, clinicopathological factors and clinical outcomes were analyzed.
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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.
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Project description:Clariom D assay data from four colorectal cancer patients with tumor, metastasis and normal
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Project description:(Purpose) Biological classification of colorectal cancer (CRC) can help to understand its heterogeneous background. The purpose of this study is to classify CRC based on gene expression profiles using formalin-fixed paraffin-embedded (FFPE) samples and to correlate subgroups of CRC with biological features and clinical outcomes. (Results) CRC was clustered into four subgroups by unsupervised hierarchical clustering method. These subgroups show different biological and clinical features. (Conclusion) Gene expression profiles of CRC using FFPE samples distinguish four subgroups that had different biological features and clinical outcomes. These subgroups may explain heterogeneity of CRC and be useful biomarker for clinical.
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Project description:The development of metastasis severely reduces the life expectancy of patients with colorectal cancer (CRC). Loss of SMAD4 is a key event in late-stage CRC resulting in the progression to metastatic CRC in 10-30% of the cases. However, the biological processes and underlying molecular mechanisms that it affects are not fully understood. Here, we applied a multi-omics approach to a CRC tumor progression organoid model that faithfully reflects the metastasis-inducing effects of SMAD4 inactivation. We show that loss of SMAD4 results in loss of differentiation and activation of pro-migratory and cell proliferation processes, which is accompanied by the disruption of several key oncogenic pathways, including the TGFB, WNT, and VEGF pathways. In addition, SMAD4 inactivation leads to increased secretion of proteins that are known to be involved in a variety of pro-metastatic processes. Finally, we show that one of the factors that is specifically secreted by metastatic organoids – DKK3 – reduces the anti-tumor effects of natural killer cells (NKCs). Altogether, our data provides promising new targets concerning the role of SMAD4 perturbation and metastatic disease in CRC.
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Project description:The development of metastasis severely reduces the life expectancy of patients with colorectal cancer (CRC). Loss of SMAD4 is a key event in late-stage CRC resulting in the progression to metastatic CRC in 10-30% of the cases. However, the biological processes and underlying molecular mechanisms that it affects are not fully understood. Here, we applied a multi-omics approach to a CRC tumor progression organoid model that faithfully reflects the metastasis-inducing effects of SMAD4 inactivation. We show that loss of SMAD4 results in loss of differentiation and activation of pro-migratory and cell proliferation processes, which is accompanied by the disruption of several key oncogenic pathways, including the TGFB, WNT, and VEGF pathways. In addition, SMAD4 inactivation leads to increased secretion of proteins that are known to be involved in a variety of pro-metastatic processes. Finally, we show that one of the factors that is specifically secreted by metastatic organoids – DKK3 – reduces the anti-tumor effects of natural killer cells (NKCs). Altogether, our data provides promising new targets concerning the role of SMAD4 perturbation and metastatic disease in CRC.
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Project description:Colorectal cancer (CRC) is the third most common cancer worldwide. Increased levels of C-reactive protein (CRP), which occur during local and systemic inflammation, have been linked to poor prognosis in CRC patients. on the other hand there are no biomarkers associated with 5 year survival of CRC patients. We divided the serum samples into either high (>30 mg/L) or low CRP (<30 mg/L) or long and short 5-year survival. In this study, we have quantified 256 proteins with two or more unique peptides. Data were further analyzed by ANOVA, principal component analysis (PCA), Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA)-modeling and OPLS-DA-associated S-plot. Pathway analysis was performed using Integrated Molecular Pathway Level Analysis (IMPaLa) and Ingenuity Pathway Analysis (IPA). We propose several proteins associated with prognosis and survival in patients with CRC.
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