Integrative Analysis of Transcriptional Regulatory Network and Copy Number Variation in Intrahepatic Cholangiocarcinoma

Abstract

BackgroundTranscriptional regulatory network (TRN) is used to study conditional regulatory relationships between transcriptional factors and genes. However few studies have tried to integrate genomic variation information such as copy number variation (CNV) with TRN to find causal disturbances in a network. Intrahepatic cholangiocarcinoma (ICC) is the second most common hepatic carcinoma with high malignancy and poor prognosis. Research about ICC is relatively limited comparing to hepatocellular carcinoma, and there are no approved gene therapeutic targets yet.MethodWe first constructed TRN of ICC (ICC-TRN) using forward-and-reverse combined engineering method, and then integrated copy number variation information with ICC-TRN to select CNV-related modules and constructed CNV-ICC-TRN. We also integrated CNV-ICC-TRN with KEGG signaling pathways to investigate how CNV genes disturb signaling pathways. At last, unsupervised clustering method was applied to classify samples into distinct classes.ResultWe obtained CNV-ICC-TRN containing 33 modules which were enriched in ICC-related signaling pathways. Integrated analysis of the regulatory network and signaling pathways illustrated that CNV might interrupt signaling through locating on either genomic sites of nodes or regulators of nodes in a signaling pathway. In the end, expression profiles of nodes in CNV-ICC-TRN were used to cluster the ICC patients into two robust groups with distinct biological function features.ConclusionOur work represents a primary effort to construct TRN in ICC, also a primary effort to try to identify key transcriptional modules based on their involvement of genetic variations shown by gene copy number variations (CNV). This kind of approach may bring the traditional studies of TRN based only on expression data one step further to genetic disturbance. Such kind of approach can easily be extended to other disease samples with appropriate data.

Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer

“…Except for KIF7, for which no bands were detected, the remaining representatives certified the sequencing data in the investigated cell lines. While most of these proteins are components of pathways that are regulated by WWOX or AP-2α/γ (e.g., FGF [98,99], PI3K [31][32][33] and JAK/STAT [21,100] signaling), only regulation of GSK3B could be individually confirmed by literature data. Similar to observations from the current study, WWOX was found to repress GSK3B activity; such outcome results from direct binding of WWOX to GSK3B [101,102].…”

Role of the fibroblast growth factor receptor axis in cholangiocarcinoma

“…Despite these challenges, investments in clinical trials geared toward molecular subpopulations of CCA patients, such as the ongoing phase 2 study of BGJ398 in CCAs with FGFR alterations (NCT02150967), for now represent the best way to improve treatment prospects for these patients. Integrative genomic analyses have characterized two intrahepatic CCA subclasses, proliferative and inflammatory, that are distinguished by unique molecular signatures and clinical features; of these, the proliferative class is associated with poorer outcomes . In the future, these subclasses may be helpful to risk stratify patients for treatment and to develop more cohesive therapeutic strategies according to the patient's profile instead of individual biomarkers.…”

“…Integrative genomic analyses have characterized two intrahepatic CCA subclasses, proliferative and inflammatory, that are distinguished by unique molecular signatures and clinical features; of these, the proliferative class is associated with poorer outcomes. 11,12 In the future, these subclasses may be helpful to risk stratify patients for treatment and to develop more cohesive therapeutic strategies according to the patient's profile instead of individual biomarkers.…”

“…6,9 Copy number gains in chromosomal regions encoding ERBB2/Her-2, MEK2, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, and the JAK/STAT pathway have also been identified. 10,11 Activating KRAS mutations are frequent events in CCA, occurring in 45% to 50% and 10% to 15% of intrahepatic and extrahepatic tumors, respectively. 12,13 BRAF mutations have been reported in 0% to 22% of CCAs.…”

“…Mutations in KRAS , TP53 , DPC/SMAD4 , EGFR , PIK3CA , CDKN2A , and APC have been found in CCA . Copy number gains in chromosomal regions encoding ERBB2/Her‐2 , MEK2 , VEGFR2 , VEGFR3 , PDGFR α, PDGFR β, and the JAK/STAT pathway have also been identified . Activating KRAS mutations are frequent events in CCA, occurring in 45% to 50% and 10% to 15% of intrahepatic and extrahepatic tumors, respectively .…”