Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

Cell Reports: Volume 18, Issue 11, p2780 - 2794 DOI: http://dx.doi.org/10.1016/j.celrep.2017.02.033

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

Data in the GDC

• Download the GDC Manifest File [txt]

Supplemental Data

Reference Lists

• Participant List [txt]
• Sample List [txt]
• Data Freeze List [xlsx]
• BAM File List [xlsx]

Additional Publication Specific Data

• Curated Mutations
  • MC3 MAF File - MC3_MAF [txt]
• Reverse Phase Protein Array (RPPA) Expression
  • RPPA Core - CHOL_MDA_RPPA [txt]
  • RPPA Core MAGE-TAB - CHOL_MDA_RPPA_Core_MAGE-TAB [xml]

Additional Resources

• Broad Institute FireCloud (link is external) The Broad Institute
• cBioPortal for Cancer Genomics (link is external) Memorial Sloan-Kettering Cancer Center
• Regulome Explorer (link is external) Institute for Systems Biology
• Next-Generation Clustered Heat Maps (link is external) MD Anderson Cancer Center