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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49666 | GEO | 2013/11/03

SECONDARY ACCESSION(S): PRJNA214694

REPOSITORIES: GEO

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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. Illumina 450k methylation array profiling performed on wild-type (n=23) and mutant (n=9) CCA (cholangiocarcinoma) samples, with adjacent normal tissue (n=4)

2013-10-20 | E-GEOD-49656 | biostudies-arrayexpress

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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.

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Genome wide binding sites of BAP1, HCF1 and OGT

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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.

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