RNA over-editing leads to aggressiveness of intrahepatic cholangiocarcinoma [SNP]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119335 | GEO | 2018/12/12
REPOSITORIES: GEO
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Project description:Alteration in RNA editing has been connected to tumor progression and many other important human diseases. However, the role of RNA editing in intrahepatic cholangiocarcinoma (ICC) remains unclear. Here we conducted a transcriptome-wide investigation in ICCs, and revealed ADAR-associated over-editing occurred uniformly in ICCs. Collectively, these results reveal a previously unrecognized role of RNA editing in malignant transformation into ICC, and ADAR1 inhibition may obviate progression and relapse of this malignancy.
2018-12-12 | GSE119336 | GEO
Project description:Background & Aims: Intrahepatic cholangiocarcinoma (ICC) is known to heterogeneous with diverse etiology, morphology, and clinical outcomes. Recently, cholangiolar differentiation of ICC has been suggested to associate with prognostic outcomes, however, its molecular patho-biological features and clinical significances were not evaluated extensively. Methods:Integrative analysis was performed using transcriptomic profiles (n=27) and tissue microarrays (n=142) from ICC specimens. Results:ICCs were classified into ICC with cholangiolar differentiation (ICC-CD, n=20) and ICC with bile duct differentiation (ICC-BD, n=122). ICC-CD showed favorable overall survival (OS) compared to ICC-BD (Hazard Ratio=0.38, P=0.020, log-rank test). Transcriptomic profiling of ICC-CD and ICC-BD revealed a cholangiolar differentiation signature (CD signature, n=794), which could predict prognostic outcomes of ICC in an independent data. Interestingly, the expression of CD signature demonstrated that the ICC-BD but not ICC-CD harbored pancreatic ductal adenocarcinoma (PDAC) like expression trait, implying its cellular origin from multipotent biliary tree stem cells or the cells committed to differentiate into pancreatic lineage cells. The CD signature might be a key determinant for ICC heterogeneity indicating spectral continuum of cellular differentiation of ICC-CD → ICC-BD → PDAC. In addition, we identified four genes (i.e., CRP, CDH2, TFF1, and S100P) from integrated analysis of tissue microarrays and transcriptome profiles as prognostic as well as differential histologic markers for ICC-CD and ICC-BD. Strikingly, combined expression status of the four genes were more beneficial in predicting prognostic outcomes of ICC. Conclusions:Our integrative genomic-pathologic analysis could reveal new molecular and clinical significance of cholangiolar differentiation in association with PDAC-like expression traits, which might play pivotal roles in heterogeneous progression of ICC.
2017-07-01 | GSE66255 | GEO
Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform. RNA-seq expression profiling in Adar1 and Adar1/Mavs knockout mice embryos.
2014-12-19 | E-GEOD-62917 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations (CNV) were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. CNV-based clustering was able to further refine these molecular groups. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. Gene-expression profiling was performed using formalin-fixed, paraffin-embedded intrahepatic cholangiocarcinoma tissues obtained at the time of surgical resection.
2013-01-24 | E-GEOD-32225 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations (CNV) were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. CNV-based clustering was able to further refine these molecular groups. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. DNA copy number profiling was performed using formalin-fixed, paraffin-embedded intrahepatic cholangiocarcinoma tissues obtained at the time of surgical resection.
2013-01-24 | E-GEOD-33326 | biostudies-arrayexpress
Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFM-NM-2) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFM-NM-22 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFM-NM-22 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. 20 RNA samples were analyzed, from 10 patients with ICC. For each patient, RNA were isolated from laser capture microdissected (LCM) stroma from tumor and non tumor areas.
2013-06-21 | E-GEOD-45001 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations (CNV) were identified by GISTIC analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). RESULTS: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. CNV-based clustering was able to further refine these molecular groups. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-01-24 | E-GEOD-33327 | biostudies-arrayexpress
Project description:Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficulty in diagnosis, and overall poor prognosis. We performed comprehensive genomic and transcriptomic characterization of treatment-naive iCC. Whole transcriptome analyses identified two prognostic subtypes, concordant with previous reports. This study reports a large-scale multiomics analysis of iCC. The findings could assist in patient stratification with iCCs and in developing rational therapeutic strategies.
| EGAS00001006007 | EGA
Project description:MicroRNA expression profiles were sucessfully contructed in 63 patients with ICC and 9 normal intrahepatic bile ducts using a custom microarray containing probes for 1094 miRNAs and an outcome prediction of miRNA signature was successfully identified for predicting prognosis in ICC.
2015-03-06 | GSE53870 | GEO
Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFβ2 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression.
2013-06-21 | GSE45001 | GEO