Dataset Information

Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations.

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is a biliary tree-origin epithelial malignancy in liver with unfavorable clinical outcomes. Systematic genome analyses may advance our understanding of ICC pathogenesis also improving current diagnostic and therapeutic modalities. In this study, we analyzed 17 ICC tumor-vs-matched normal pairs using either whole-exome (n = 7), transcriptome sequencing (n = 7) or both platforms (n = 3). For somatic mutations, we identified recurrent mutations of previously reported genes such as KRAS, TP53, APC as well as epigenetic regulators and those of TGF? signaling pathway. According to the abundance of somatic mutations and DNA copy number alterations (CNA), ten ICC exome cases were distinguished into two classes as those primarily driven by either somatic mutations (M class) or CNAs (C class). Compared to M class ICCs (92-147 somatic mutations; n = 5) with a relative deficit of CNAs, C class ICCs (54-84 mutations; n = 5) harbor recurrent focal CNAs including deletions involving CDKN2A, ROBO1, ROBO2, RUNX3, and SMAD4. We also show that transcriptome sequencing can be used for expression-based ICC categorization but the somatic mutation calling from the transcriptome can be heavily influenced by the gene expression level and potentially, by posttranscriptional modification such as nonsense mediated decay. Along with a substantial level of mutational heterogeneity of ICC genomes, our study reveals previously unrecognized two ICC classes defined by relative abundance of somatic mutations over CNAs or vice versa, which should be considered in the selection of genotyping platforms and sensitive screening of targets for ICC therapeutics.

SUBMITTER: Kim YH

PROVIDER: S-EPMC5029666 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations.

Kim Young-Ho YH Hong Eun-Kyung EK Kong Sun-Young SY Han Sung-Sik SS Kim Seoung-Hoon SH Rhee Je-Keun JK Hwang Soo-Kyung SK Park Sang-Jae SJ Kim Tae-Min TM

Oncotarget 20160401 17

Intrahepatic cholangiocarcinoma (ICC) is a biliary tree-origin epithelial malignancy in liver with unfavorable clinical outcomes. Systematic genome analyses may advance our understanding of ICC pathogenesis also improving current diagnostic and therapeutic modalities. In this study, we analyzed 17 ICC tumor-vs-matched normal pairs using either whole-exome (n = 7), transcriptome sequencing (n = 7) or both platforms (n = 3). For somatic mutations, we identified recurrent mutations of previously re ...[more]

PMID: 27009864

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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.

Project description:Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients.We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic 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 were identified by Genomic Identification of Significant Targets in Cancer (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).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. Copy number variation-based clustering was able to refine these molecular groups further. 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 < .001).We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.

Dataset Information

Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations.

Publications

Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations.

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