Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores – mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.

Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

“…As such, we set to investigate the utility of an already implemented NGS gene panel. We found that ARID1A was predominantly mutated in eCCA, which is in discrepancy with data earlier reported ; however, this may be due to our relatively small cohort. ARID1A aberrations were found in 33% which has previously been reported with lower frequencies by Nepal et al (9.9%) and Wardell et al (6%) but closer by Nakamura et al (17%) , Jiao et al (19%) and in our database reference, likely reflective of heterogeneous patient populations (Table ).…”

Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

“…Linking a distinct molecular footprint of iCCA to a specific causative etiology also has important implications with respect to potentially establishing whether the tumor developed as a result of past exposures to an extrinsic carcinogen or to an intrinsic genetic alteration independent of an environmental risk factor. Here, the recently reported results of an international team using an integrated genomic, epigenetic, and transcriptomic analysis of over 400 iCCA cases from 10 different countries identified a liver fluke–associated iCCA subtype uniquely enriched in ERBB2 amplifications and TP53 mutations . This finding is noteworthy because it exemplifies how assessment of whole‐genome and epigenomic landscapes of distinct subtypes of iCCA may be of potential value in distinguishing extrinsic from intrinsic carcinogenic processes.…”

Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma

“…Arguably the greatest obstacle in the development of therapeutic strategies for CCA is its extensive molecular heterogeneity, further confounded by mixed patient cohorts of varied clinical and pathological features. Previous efforts have identified individual genomic events responsible for specific therapeutic sensitivities (e.g., IDH mutations and FGFR2 fusions) and broad clusters of patients with diverse characteristic pathobiological properties . What remains unclear are the broader network implications of such individual events and the molecular origins of these clusters.…”