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

Abstract

Summary 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.

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

“…Among the spectrum of tumor-specific genomic aberrations, we identified multiple samples with likely loss-of-function mutations or deletions in tumor suppressor genes found to be frequently mutated in previous genomic studies of ICC and other cholangiocarcinomas (Chan-On et al 2013;Jiao et al 2013;Zou et al 2014;Nakamura et al 2015;Farshidfar et al 2017;Jusakul et al 2017). Examples include the tumor suppressor genes ARID1A, BAP1, and PBRM1, which encode chromatin remodeling factors (Thompson 2009;Scheuermann et al 2010;Wilson and Roberts 2011;Wu and Roberts 2013).…”

Molecular genomic landscapes of hepatobiliary cancer

“…27 The Cancer Genome Atlas CCA project analyzed 34 CCA samples that were fluke-negative and HBV/HCV-negative. 28 Due to the limited size of the cohort, frequencies of driver genes were variable compared to other large-scale studies; however, notably, this cohort F I G U R E 4 Specific driver genes across anatomical subtypes of biliary tract cancer (BTC), and comparison with core driver genes in hepatocellular carcinoma (HCC) and pancreatic cancer. ECC, extrahepatic cholangiocarcinoma; GB, gallbladder cancer; ICC, intrahepatic cholangiocarcinoma represented a higher frequency of IDH1 (13%) and IDH2 (5%) mutations compared to Asian cohorts.…”

“…25,31,33 The FGFR2 fusion gene is one of characteristic molecular signatures of CCA with a frequency of approximately 10% of cases. 25,28,[34][35][36] Previous studies reported at least 19 different fusion partners, and various types of structural alterations, including intrachromosomal (inversion and interstitial deletion) or interchromosomal (translocation) rearrangements, are involved ( Figure 5). Invariably, fusion partners replace the last exon of the FGFR2 gene, which encodes C-terminal protein and 3 0 -UTR.…”

“…The Cancer Genome Atlas CCA group more clearly isolated a subtype enriched with IDH1/2-mutated tumors, which showed a unique methylation pattern and upregulation of mitochondrial gene expression signatures. 28 24,27,30,43 are summarized. Subtypes colored green showed better prognosis; those colored orange showed poorer prognosis.…”

A Molecular Diagnosis of Cholangiocarcinoma suggested using Cell-free DNA following Multiple Unsuccessful Attempts at Obtaining a Tissue Diagnosis.

“…Other frequently mutated genes in cholangiocarcinomas were also studied (see above), although BAP1 (which is commonly mutated in cholangiocarcinoma) was not (8,9,10,11).In this case, the TP53 (C141fs), IDH2 (R140Q), NF1 (Q83*) and ATM (R3008) alterations were detected using cfDNA NGS testing. These alterations are thought to be somatic driver mutations, given the known oncogenic or lost tumor suppressor gene activity resulting from the mutated gene.…”