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Distinct Mutational Patterns of Infection and Non-Infection-Related Bile Duct Cancers Revealed by Exome Sequencing

ABSTRACT: The impact of different carcinogenic exposures on the specific patterns of somatic mutations in human tumors remains unclear. To clarify this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by liver fluke Opisthorchis viverrini (OV)-infection and 101 cases due to non-OV etiologies. Whole-exome (N = 15) and prevalence screening (N = 194) revealed recurrent somatic mutations in BAP1 and ARID1A, neither of which has been previously reported to be mutated in CCA. Comparisons between intrahepatic OV and non-OV CCAs demonstrated statistically significant different mutation patterns: BAP1 and IDH1/2 were more frequently mutated in non-OV CCAs, while TP53 displayed the reciprocal pattern. Functional studies demonstrated tumor suppressive roles of BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations even within the same tumor type. Illumina 450k methylation array profiling performed on wild-type (n=23) and mutant (n=9) CCA (cholangiocarcinoma) samples, with adjacent normal tissue (n=4)

ORGANISM(S): Homo sapiens

SUBMITTER: Weng Khong Lim

PROVIDER: E-GEOD-49656 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Distinct Mutational Patterns of Infection and Non-Infection-Related Bile Duct Cancers Revealed by Exome Sequencing

Project description:The impact of different carcinogenic exposures on the specific patterns of somatic mutations in human tumors remains unclear. To clarify this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by liver fluke Opisthorchis viverrini (OV)-infection and 101 cases due to non-OV etiologies. Whole-exome (N = 15) and prevalence screening (N = 194) revealed recurrent somatic mutations in BAP1 and ARID1A, neither of which has been previously reported to be mutated in CCA. Comparisons between intrahepatic OV and non-OV CCAs demonstrated statistically significant different mutation patterns: BAP1 and IDH1/2 were more frequently mutated in non-OV CCAs, while TP53 displayed the reciprocal pattern. Functional studies demonstrated tumor suppressive roles of BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations even within the same tumor type. Affymetrix SNP6 arrays were performed according to the manufacturer's directions on DNA extracted from the 15 tumors and the 15 matched normal discovery samples.

2013-11-03 | E-GEOD-49666 | biostudies-arrayexpress

Distinct Mutational Patterns of Infection and Non-Infection-Related Bile Duct Cancers Revealed by Exome Sequencing

2013-10-20 | GSE49656 | GEO

Distinct Mutational Patterns of Infection and Non-Infection-Related Bile Duct Cancers Revealed by Exome Sequencing

2013-11-03 | GSE49666 | GEO

Genome wide binding sites of BAP1, HCF1 and OGT

Project description:We report the genome wide binding sites of BAP1, HCF1 and OGT in bone marrow derived macrophages. De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor–1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans. For BAP1, bone marrow derived macrophages were used differentiated from bone marrow cells of BAP1-3X Flag Tagged KI mice we generated. For OGT and HCF1, bone marrow derived macrophages were used from BAP1 WT mice.

2012-11-07 | E-GEOD-40723 | biostudies-arrayexpress

Therapeutic vulnerabilities in CCA from different etiologies identified using integrative multi-omics enhancer activity profiling

Project description:Through integrative analysis of enhancer and transcriptomic landscapes of CCA from diverse populations, we identified 3 distinct groups, associated with different etiologies, that were enriched in unique pathways. The first group (ESTRO) displayed aberrant enhancer activation in estrogen signaling, and were comprised of mostly fluke-associated CCAs. Another group (OXPHO) displayed activated oxidative phosphorylation pathways, and were associated with hypermethylated BAP1 and IDH-mutant CCAs. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype as well as CCA with aristolochic acid mutational signatures. Drug inhibitors of identified enriched pathways reduced tumor growth in in vitro and in vivo models.

| EGAS00001007309 | EGA

Genome wide binding sites of BAP1, HCF1 and OGT

2012-11-07 | GSE40723 | GEO

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress

The miRNAome of O. viverrini induced cholangiocarcinoma by microarray:

Project description:Cholangiocarcinoma is the second most common primary hepatic malignancy worldwide, with intrahepatic cholangiocarcinoma (ICC) a particularly significant public health problem in Southeast Asia, due to its strong association with the food-borne parasite Opisthorchis viverrini (OV). This manuscript represents the first comprehensive miRNA expression profiling by microarray of the three most common histological grades of OV-induced ICC: moderately differentiated, papillary, and well differentiated tumor tissue. No cohort of miRNAs emerged as commonly dysregulated among these histological grades of OV-induced ICC. Instead, each histological grade of ICC tissue showed a distinct miRNA profile. Moderately differentiated tumor tissue showed both the greatest number and the highest magnitude of miRNA dysregulation, followed by papillary ICC tumor tissue, and differentiated ICC tumor tissue. When ICC tumor tissue was compared to adjacent non-tumor tissue, a remarkable similarity in miRNA dysregulation was observed between these samples, indicative of intrahepatic metastasis. These findings indicate the possibility of determining the histological grade of ICC by profiling miRNA dysregulation, which not only would greatly enhance the molecular diagnosis of ICC, but could even lead to the personalized the treatment for ICC by the early classification of histological grade. A total of 46 unique liver tissue samples were analyzed on Agilent human miRNA microarray (miRBase Release 16.0). Of the 46 samples, 13 are from non-cancer healthy patients with gastric bypass surgery. The rest of 33 samples are CCA tumor tissue samples and their paired adjacent normal/necrotic tissue: 12 from well differentiated CCA, 17 from papillary CCA, 4 from moderately differentiated CCA.

2014-07-17 | E-GEOD-53992 | biostudies-arrayexpress

Proteomic characterization of Opisthorchis viverrini excretory/secretory products

Project description:O. viverrini infection is recognised by the WHO as a group 1 biological carcinogen because of its extremely strong link with cholangiocarcinoma (CCA), cancer of the bile ducts. The incidence of CCA associated with liver fluke infection, calculated as an age‐standardized rate, varies by geographical region and other risk factors but exceeds 100 per 100,000 in men and 40 per 100,000 in women in hotspots in northeast Thailand. Any attempts to control liver fluke infection, whether through mass drug administration or ultimately through vaccination requires specific and sensitive diagnostic tools that are readily deployable in the field and easy to use. It is imperative that methods to detect infection are appropriately sensitive and rapid in order to diagnose new cases, assess effectiveness of elimination measures and be applicable to large-scale disease surveillance. Indeed, the WHO recently highlighted the low sensitivity of current diagnostic methods as a barrier to controlling liver fluke infection. Herein, we have leveraged the O. viverrini soluble secreted proteome to help create the first O. viverrini protein microarray.

2024-09-20 | PXD056031 | Pride

Integrative genomic analyses of European intrahepatic cholangiocarcinoma: new ROS1 fusion gene and PBX1 as prognostic marker

Project description:Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis due to limited therapeutic options. Intrahepatic CCA (iCCA) is particularly rising worldwide and its molecular basis is just emerging. Environmental factors contribute to regional differences in mutation spectrum with European iCCA patients being underrepresented in systematic genomic and transcriptomic studies. Here we describe an integrated whole exome sequencing and transcriptomic study of 37 iCCAs of German patients. We observed as most frequently mutated genes ARID1A (14%) and IDH1, BAP1, TP53, KRAS, and ATM each in 8% of patients. We identified FGFR2::BICC1 fusions in two tumors and FGFR2::KCTD1 and TMEM106B::ROS1 as new fusions and therapeutic targets for iCCA. Using a data integration framework, we identified PBX1 as a new central regulatory gene for iCCA. We performed an extended screen by targeted sequencing of additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes and we found PBX1 to show copy gain in 20% of tumors. Considering other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs. Analyzing an additional European cohort of iCCA, we found PBX1 protein expression to be a marker for poor prognosis. Overall, our findings add insight into key molecular alterations of iCCA, reveal new targetable fusion genes, and suggest PBX1 as a new modulator of the disease.

| EGAS00001007525 | EGA

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