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MiR expression profiles of paired primary colorectal cancerand metastases by next-generation sequencing

ABSTRACT: MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) o0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR o0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC

PROVIDER: EGAS00001001127 | EGA |

REPOSITORIES: EGA

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MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing.

Neerincx M M Sie D L S DL van de Wiel M A MA van Grieken N C T NC Burggraaf J D JD Dekker H H Eijk P P PP Ylstra B B Verhoef C C Meijer G A GA Buffart T E TE Verheul H M W HM

Oncogenesis 20151005

MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known ...[more]

PMID: 26436952

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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

Dataset Information

MiR expression profiles of paired primary colorectal cancerand metastases by next-generation sequencing

Publications

MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing.

Similar Datasets

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