Abstract PL02-04: Genomic and epigenomic studies of cholangiocarcinoma in diverse populations
Authors: Teh Bin Tean 
Published: August 2019

Abstract
It is well-known that Asian prevalent cancers are often associated with a pathogen or carcinogen. For example, hepatocellular carcinoma is driven by hepatitis B and C viruses, gastric cancer by Helicobacter pylori, and nasopharyngeal cancer by Epstein-Barr virus. In this presentation, we focus on biliary tract cancer or cholangiocarcinoma (CCA) of different etiologies which are associated with chronic carcinogenic exposures leading to distinct genomic and epigenomic changes. CCA is a malignant tumor of bile duct epithelial cells with very poor prognosis which accounted for approximately 5% of all primary liver cancers diagnosed worldwide. It is broadly divided into intrahepatic, perihilar, and distal CCAs which may differ in their spectrum and frequency of genetic alterations, possibly reflecting differences in cell of origin and tumorigenic process. CCA displays distinct molecular mechanisms that require different therapeutic regimes for effective treatment representing an important unmet clinical need. Similarly, the genomic and epigenomic changes may serve as effective biomarkers for disease detection and monitoring.
Risk factors for CCA are related to geography and etiology. In Western countries, primary sclerosing cholangitis (PSC) is the most common risk factor of CCA, and other risk factors include hepatolithiasis, choledochal cysts, cirrhosis, diabetes, obesity, alcohol consumption and smoking. On the other hand, in the northeast region of Thailand, Laos and Cambodia, infestation of liver fluke called Opisthorchis viverrini (OV) has been associated with the highest incidence of CCA, with approximately 20,000 cases annually. Once ingested, OV can inhabit the biliary tract within the human host for over 10 years, promoting carcinogenesis potentially via 1) mechanical damage to the biliary epithelia caused by the feeding activities of the parasites, 2) immunopathology because of infection-related inflammation, 3) the toxic effects of parasite excretory/secretory molecules and 4) the disruption of the bile homeostasis. Furthermore, we and others have recently identified a potentially new risk factor for CCA, especially in China, Taiwan, South Korea and Singapore. Through mutation signature analysis on somatic genomic data, we observed an association of CCA with the herbal carcinogen Aristolochic Acid (AA), which is a natural compound exclusively found in plants of the Aristolochia genus used in traditional remedies for numerous indications.
With the goal of better understanding the underlying oncogenic mechanisms in CCA, we characterized and compared the genetic and epigenetic changes in OV and non-OV driven and AA-related CCAs from different populations. We found that in non-OV driven CCA, mutations in epigenetic modifier genes including IDH1/2 and BAP1 are the main drivers whereas OV-infected tumors are characterized by frequent p53 mutations. These mutational differences set the stage for more in-depth epigenomic characterization and mechanistic dissection of the tumorigenic process. Our recent data indicate that OV driven CCAs display predominantly CpG Island DNA hypermethylation whereas non-OV driven CCAs are predominantly CpG Shore DNA hypermethylated. OV and non-OV CCAs also differ in their enhancer landscape: OV CCAs exhibit widespread activation of inflammatory response genes, while genes involved in maintenance of cell junction are disrupted in non-OV CCAs. Several lines of evidence also support that chronic inflammation can lead to aberrant DNA methylation and de novo enhancer activity. Consequently, chronic inflammation associated with OV infection may play a key role in setting up divergent enhancer landscapes between OV-related and non-OV CCAs.
Other than OV and non-OV driven CCAs, AA represents a profound public health risk in Asia due to its wide use in herbal remedies. We found that AA exposure causes unique mutational signature of A:T to T:A transversion, with an antisense strand bias.
We recently detected AA signature in many CCA cases, especially from Asian countries. At present, we are conducting epigenomics studies on AA-related CCAs to understand how AA may impact the epigenomic landscape of CCA.
Our multi-omics analysis reflects the contrasting etiologies of CCA, strongly positing that the same disease manifestation can be in fact driven by vastly different molecular circuitries and that each patient should be treated with appropriately targeted therapy. These findings will deepen our understanding of early transformation events in CCA, which may lead to the development of relevant biomarkers and treatment regimens for each subgroup of CCA. As such, our study illustrates the value of investigating specific cancers in the context of diverse populations and etiologies.
Citation Format: Bin Tean Teh. Genomic and epigenomic studies of cholangiocarcinoma in diverse populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr PL02-04.