Novel insights into molecular and immune subtypes of biliary tract cancers

Biliary tract cancers (BTCs), which include cholangiocarcinoma (CCA) and gallbladder cancer (GBC), are heterogenous malignancies characterized by distinct molecular features often associated with specific clinical traits and/or outcomes. Such complex molecular heterogeneity, both within each BTC subtype and between distinct subtypes, poses a great challenge to personalized medicine. Recent technological advances have allowed the integration of multiple -omics derived from large cohorts of patients with distinct solid cancers to ultimately design stratification algorithms for prognostic prediction or more efficient treatment allocation. In this regard, although BTCs lag behind other tumors when it comes to our understanding of their molecular complexity, over the past decade, tremendous efforts have been made to generate supervised or unsupervised molecular classifications. As a result, CCAs and GBCs can be assigned to distinct molecular and/or prognostic classes. Notably, the discovery of biologically relevant subgroups of tumors harboring frequent targetable alterations (i.e., mutations in IDH1, FGFR2 fusion proteins) holds important therapeutic implications for BTCs, particularly iCCA. Furthermore, the recent application of single cell-based technologies or more conservative (and less precise) "virtual microdissection" algorithms to isolate signals derived from the immune and stromal cells has identified the first microenvironment-based classes. In this chapter, we will review the molecular and immune classes of BTCs, with a particular focus on their clinical implications.