Epigenome Remodeling in Cholangiocarcinoma

Sequencing data have recurrently identified mutations in epigenetic regulators in CCA. However, the epigenome-wide consequences of these genetic insults remain largely unclarified in these dismal malignancies. Epigenomic profiling holds considerable potential to advance our understanding of fundamental aspects of CCA pathobiology, including molecular heterogeneity, diverse cells of origin, and prominent tumor microenvironments. The causes of epigenomic dysregulation in CCA are diverse and likely include mutations in epigenetic regulators, alterations in chromatin accessibility, aberrations in metabolic substrates required for normal epigenome regulator functions, and protumorigenic microenvironmental signaling. While evidence of direct causative roles of specific epigenetic lesions in CCA is lacking, exploitation of recurrent epigenetic alterations may enable development of sensitive biomarker panels to improve diagnosis, prognosis, and monitoring of treatment response, as well as afford therapeutic opportunities. Cholangiocarcinoma (CCA) comprises a heterogeneous collection of malignancies arising within the biliary tract, characterized by late diagnosis, innate chemoresistance, and abysmal prognosis. Sequencing data have uncovered recurrent mutations in diverse epigenetic regulators, implicating epigenetic destabilization at the root of these tumors. However, few studies have characterized biliary tumor epigenomes. In this Opinion article, we argue that an epigenome-oriented approach to CCA could establish diverse interconnections between many key aspects of research on this disease, including molecular heterogeneity, diverse cells of origin, and prominent tumor microenvironments. Moreover, we discuss plausible causes of epigenome dysregulation in biliary tumors, including genetic, epigenetic, metabolic, microenvironmental, and physiological factors. Lastly, we assess the translational potential of epigenomics in CCA to uncover robust biomarkers and therapeutic opportunities for this growing group of patients with limited treatment options. Cholangiocarcinoma (CCA) comprises a heterogeneous collection of malignancies arising within the biliary tract, characterized by late diagnosis, innate chemoresistance, and abysmal prognosis. Sequencing data have uncovered recurrent mutations in diverse epigenetic regulators, implicating epigenetic destabilization at the root of these tumors. However, few studies have characterized biliary tumor epigenomes. In this Opinion article, we argue that an epigenome-oriented approach to CCA could establish diverse interconnections between many key aspects of research on this disease, including molecular heterogeneity, diverse cells of origin, and prominent tumor microenvironments. Moreover, we discuss plausible causes of epigenome dysregulation in biliary tumors, including genetic, epigenetic, metabolic, microenvironmental, and physiological factors. Lastly, we assess the translational potential of epigenomics in CCA to uncover robust biomarkers and therapeutic opportunities for this growing group of patients with limited treatment options. a model of biliary transformation in which committed cholangiocytes act as the cell-of-origin for epigenetic alteration- and mutation-mediated tumorigenesis. epigenetic classification of a gene that plays a functional role in stemness or survival and is recurrently targeted by epigenetic alterations in cancer, for example, SOX17 in CCA. epigenetic classification of a gene that is recurrently altered in cancer by mutations or epigenetic alterations, triggering epigenomic reprogramming, for example, IDH1/2 in CCA. epigenetic classification of a gene that plays a functional role as an epigenetic writer, reader, or eraser enzyme whose normal function becomes compromised by recurrent epigenetic mutations or epigenetic alterations in cancer, for example, ARID1A, EZH2, and PBRM1 in CCA. any transmissible alteration to the normal epigenomic profile of a given cell type (e.g., in DNA methylation or histone profile patterns). model of biliary transformation in which hepatic progenitor cells undergo epigenetic alterations leading to clonal expansion of atypical progenitor pools that subsequently acquire a gatekeeper mutation, resulting in carcinoma in situ. Successive genetic and epigenetic alterations later lead to an invasive tumor. model of biliary transformation in which committed hepatocytes act as the cells of origin for epimutation- and mutation-mediated tumorigenesis proceeding through either dedifferentiation followed by cholangiocyte-like differentiation or transdifferentiation. integrative analysis of multiple omics-based data sets matched from a single biological sample.