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Integrated mRNA and lncRNA expression profiling for exploring metastatic biomarkers of human intrahepatic cholangiocarcinoma.

ABSTRACT: Long noncoding RNAs (lncRNAs) is crucial for various human cancers, but the function and mechanism of lncRNAs is largely unknown in human intrahepatic cholangiocarcinoma (ICC), the second most common liver cancer. In this study, we performed transcriptomic profiling of ICC and normal tissues, and found 2148 lncRNAs and 474 mRNAs were significantly upregulated, whereas 568 lncRNAs and 409 mRNAs were downregulated in ICC tissues. Enrichment analysis suggests these differentially expressed genes mainly focus on response to stimulus, development, and cell proliferation. Further, potential lncRNAs involved in five signaling pathways (ERBB, JAK/STAT, MAPK, VEGF and WNT) were constructed by highly co-expressed with mRNAs in these signaling pathways. The differentially expressed lncRNA-mRNA co-regulated signaling pathways in ICC were further confirmed by lncRNA target prediction. Finally, the differentially expressed lncRNAs were confirmed by quantitative real-time PCR in 32 paired ICC and adjacent tissues. The correlation analysis between the expression levels of lncRNAs and clinicopathologic characteristics showed that EMP1-008, ATF3-008, and RCOR3-013 were observed significantly downregulated in ICC with tumor metastasis. These findings suggested that lncRNA expression profiling in ICC is profoundly different from that in noncancerous tissues, and lncRNA may be used as a potential diagnostic and prognostic biomarker for ICC metastasis.

SUBMITTER: Lv L

PROVIDER: S-EPMC5385652 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Integrated mRNA and lncRNA expression profiling for exploring metastatic biomarkers of human intrahepatic cholangiocarcinoma.

Lv Lisheng L Wei Miaoyan M Lin Peiyi P Chen Zhisheng Z Gong Peng P Quan Zhiwei Z Tang Zhaohui Z

American journal of cancer research 20170301 3

Long noncoding RNAs (lncRNAs) is crucial for various human cancers, but the function and mechanism of lncRNAs is largely unknown in human intrahepatic cholangiocarcinoma (ICC), the second most common liver cancer. In this study, we performed transcriptomic profiling of ICC and normal tissues, and found 2148 lncRNAs and 474 mRNAs were significantly upregulated, whereas 568 lncRNAs and 409 mRNAs were downregulated in ICC tissues. Enrichment analysis suggests these differentially expressed genes ma ...[more]

PMID: 28401021

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Project description:IntroductionIntrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.Case presentationWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.ConclusionThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

Project description:Recent studies show that long non-coding RNAs (lncRNAs) play crucial roles in human cancers. However, functional lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of intrahepatic cholangiocarcinoma (ICC) and its progression. In the present study, we performed transcriptomic profiling of five ICC and paired adjacent noncancerous tissues (N) using lncRNA and mRNA microarrays to identify relevant biomarkers in ICC. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the microarray results. We sought correlations between the expression levels of lncRNAs and those of target genes. Clinicopathological characteristics and overall survival were compared using the t-test and the Kaplan–Meier method, respectively. A total of 3,054 and 2,111 lncRNAs were significantly up- and down-regulated(fold change?2, p?0.05) in ICC tissues compared to the adjacent NT samples. Bioinformatic analysis indicated that most such genes were related to carcinogenesis, hepatic system disease, and signal transduction. Positive correlations were evident between four pairs of lncRNAs and target mRNAs (RNA43085 and SULF1, RNA47504 and KDM8, RNA58630 and PCSK6, and RNA40057 and CYP2D6). In addition, some lncRNAs and mRNAs were significantly associated with clinicopathological characteristics. The cumulative overall survival rate was significantly associated with low-level expression of CYP2D6 (p=0.005) and PCSK6 (p=0.038). And patients with high expression levels of CYP2D6 and RNA40057 have significant better prognosis (p=0.014). Our results suggested that lncRNA expression profile in ICC tissues is profoundly different from that in NT samples. The lncRNA signature could be used as a biomarker for the prognosis of patients with ICC. Furthermore, the combination of lncRNA and mRNA can reliably predict the survival. The lncRNA expression profiles of cancer and adjacent normal tissues form 5 ICC patients were studied by microarray and an combination of lncRNA and mRNA could be used as a biomarker for the prognosis of patients with ICC

Project description:Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer arising from the bile ducts with a need for earlier diagnosis and a greater range of treatment options. KRAS/NRAS mutations are common in ICC tumours and 6-32% of patients also have isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations associated with metabolic changes. This feasibility study investigated sequencing circulating tumour DNA (ctDNA) combined with metabolite profiling of plasma as a method for biomarker discovery in ICC patients. Plasma was collected from four ICC patients receiving radio-embolisation and healthy controls at multiple time points. ctDNA was sequenced using Ampliseq cancer hotspot panel-v2 on Ion Torrent PGM for single nucleotide variants (SNV) detection and with Illumina whole genome sequencing for copy number variants (CNV) and further targeted examination for SNVs. Untargeted analysis of metabolites from patient and control plasma was performed using liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS). Metabolite identification was performed using multi-parameter comparisons with analysis of authentic standards, and univariate statistical analysis was performed to identify differences in metabolite abundance between patient and control samples. Recurrent somatic SNVs and CNVs were identified in ctDNA from three out of four patients that included both NRAS and IDH1 mutations linked to ICC. Plasma metabolite analysis revealed biomarker metabolites associated with ICC and in particular 2-hydroxyglutarate (2-HG) levels were elevated in both samples from the only patient showing a variant allele in IDH1. A reduction in the number of CNVs was observed with treatment. This study demonstrates that ctDNA and metabolite levels can be identified and correlated in ICC patient blood samples and differentiated from healthy controls. We conclude that combining genomic and metabolic analysis of plasma offers an effective approach to biomarker identification with potential for disease stratification and early detection studies.

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Integrated mRNA and lncRNA expression profiling for exploring metastatic biomarkers of human intrahepatic cholangiocarcinoma.

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Integrated mRNA and lncRNA expression profiling for exploring metastatic biomarkers of human intrahepatic cholangiocarcinoma.

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