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Comparing miRNA Signature of Colon Cancer Primary Tumors to Metastases Formed in the Liver

ABSTRACT: Genome wide miRNA expression profiling was performed using Affymetric miRNA v. 3.0 Array on 48 samples which included paired FFPE colon tuomor and metastisized liver and paired normal colon, normal liver). The data set was divided into two categories and identified by tissue source and patient demographics: Tissue (Colon, Liver), Source (Colon Tumor Liver Met, Colon Normal, Liver Normal), Sex (Male, Female), Patient Pair. microRNAs (miRs) are frequently dysregulated in colorectal cancer (CRC) and subsets are correlated with advanced tumor stage and metastasis. Despite this, the development of prognostic biomarkers that predict metastatic potential remain limited. Our study was designed to identify, validate, and elucidate underlying biology imposed by a miR signature that defines and predicts metastatic disease. Genome-wide miR expression profiling was performed on fourteen patient-matched stage IV primary CRC tumors and corresponding liver metastases using microRNA array technology. Based on these results, this miR panel was then validated and evaluated in normal colon tissue (N = 5), early stage (I & II, N = 11) and late stage (Stage III & IV, N = 14) colorectal primary tumors via qRT-PCR.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE98406 | GEO | 2017/05/02

SECONDARY ACCESSION(S): PRJNA385008

REPOSITORIES: GEO

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Project description:Abstract: Altered expression of microRNAs (miRNAs) is associated with development and progression of various human cancers by regulating the translation of oncogenes and tumor suppressor genes. In colorectal cancer (CRC), these regulators complement the Vogelstein multi-step model of pathogenesis and have the potential of becoming a novel class of tumor biomarkers and therapeutic targets. Using QRT-PCR, we measured the expression of 621 mature miRNAs in 40 CRCs and their paired normal tissues and identified 23 significantly deregulated miRNAs. We subsequently evaluated their association with clinical characteristics of the samples and presence of alterations in the molecular markers of CRC progression. Expression levels of miR-31 were correlated with CA19-9 and miR-18a, miR-21 and miR-31 were associated with mutations in APC gene. To investigate the downstream regulation of the differentially expressed miRNAs identified we integrated putative mRNA target predictions with the results of a meta-analysis of seven public gene expression datasets of normal and tumor samples of CRC patients. Many of the CRC deregulated miRNAs computationally map to targets involved in pathways related to progression. Here one promising candidate pair (miR-1 and MET) was studied and functionally validated. We show that miR-1 can have a tumor suppressor function in CRC by directly down-regulating MET oncogene both at RNA and protein level and that re-expression of miR-1 leads to MET driven reduction of cell proliferation and motility, identifying the miR-1 down-modulation as one of the events that could enhance CRC progression. Note: Each sample has the following information: Type - tissue type (T : Tumor or N: Normal), Patient - patient identifier, Stage - tumor stage (I - IV), Status - disease status at last check-up (ED: evident disease, NED: non-evident disease), CEA - carcinoembryonic antigen (continuous), CA199 - carbohydrate antigen 19-9 (continuous), APC - mutation status of APC gene (0: wild-type, 1: mutated), KRAS - mutation status of KRAS gene (0: wild-type, 1: mutated), chr18qLOH - LOH status of 18q (0: no LOH, 1: LOH), TP53 - mutation status of TP53 gene (0: wild-type, 1: mutated). Tumor and normal counter-parts of 40 colorectal cancer patients (10 of each Stage I to IV) where profiled using TaqMan(r) Array Human MicroRNA A+B Cards v2.0

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.

Project description:The alteration of metabolism is essential for the initiation and progression of numerous types of cancer, including colorectal cancer (CRC). Metabolomics has been used to study CRC. At present, the reprogramming of the metabolism in CRC remains to be fully elucidated. In the present study, comprehensive untargeted metabolomics analysis was performed on the paired CRC tissues and adjacent normal tissues from patients with CRC (n=35) using ultra‑high‑performance liquid chromatography‑mass spectrometry. Subsequently, bioinformatic analysis was performed on the differentially expressed metabolites. The changes in these differential metabolites were compared among groups of patients based on sex, anatomical tumor location, grade of tumor differentiation and stage of disease. A total of 927 metabolites were detected in the tissue samples, and 24 metabolites in the CRC tissue were significantly different compared with the adjacent normal tissue. The present study revealed that the levels of three amino acid metabolites were increased in the CRC tissue, specifically, N‑α‑acetyl‑ε‑(2‑propenal)‑Lys, cyclo(Glu‑Glu) and cyclo(Phe‑Glu). The metabolites with decreased levels in the CRC tissue included quinaldic acid (also referred to as quinoline‑2‑carboxilic acid), 17α‑ and 17β‑estradiol, which are associated with tumor suppression activities, as well as other metabolites such as, anhydro‑β‑glucose, Asp‑Arg, lysophosphatidylcholine, lysophosphatidylethanolamine (lysoPE), lysophosphatidylinositol, carnitine, 5'‑deoxy‑5'‑(methylthio) adenosine, 2'‑deoxyinosine‑5'‑monophosphate and thiamine monophosphate. There was no difference in the levels of the differential metabolites between male and female patients. The differentiation of CRC also showed no impact on the levels of the differential metabolites. The levels of lysoPE were increased in the right side of the colon compared with the left side of the colon and rectum. Analysis of the different tumor stages indicated that 2‑aminobenzenesulfonic acid, P‑sulfanilic acid and quinoline‑4‑carboxylic acid were decreased in stage I CRC tissue compared with stage II, III and IV CRC tissue. The levels of N‑α‑acetyl‑ε‑(2‑propenal)‑Lys, methylcysteine and 5'‑deoxy‑5'‑(methylthio) adenosine varied at different stages of tumorigenesis. These differential metabolites were implicated in multiple metabolism pathways, including carbohydrate, amino acid, lipid, nucleotide and hormone. In conclusion, the present study demonstrated that CRC tumors had altered metabolites compared with normal tissue. The data from the metabolic profile of CRC tissues in the present study provided supportive evidence to understand tumorigenesis.

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Comparing miRNA Signature of Colon Cancer Primary Tumors to Metastases Formed in the Liver

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