Prognostic and Predictive Molecular Markers in Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA.

Keywords: biliary tract cancer; biomarker; cholangiocarcinoma; predictive; prognosis; targeted therapy.

Figure 1

Anatomical classification of cholangiocarcinoma. CCA is anatomically divided into intrahepatic (iCCA), perihillar (pCCA) and distal (dCCA) cholangiocarcinoma, with pCCA and dCCA being summarized as extrahepatic cholangiocarcinoma (eCCA). Different CCA subtypes possess distinct molecular aberrations and differ in terms of their etiology, while certain risk factors and genetic mutations are not subtype-specific. The most common risk factors and prevailing genetic alterations are presented. HBV: Hepatitis B virus; HCV: Hepatitis C virus; PSC: Primary sclerosing cholangitis; IDH1/2: Isocitrate dehydrogenase 1/2; FGFR2: Fibroblast growth factor receptor 2; BAP1: BRCA1 associated protein 1; KRAS: Kirsten rat sarcoma virus; TP53: Tumor suppressor protein 53; ARID1A: AT-rich interactive domain-containing protein 1A; PRKACA: Protein kinase cAMP-activated catalytic subunit alpha; PRKACB: Protein kinase cAMP-activated catalytic subunit beta; ERBB2: Erb-B2 receptor tyrosine kinase 2; SMAD4: Mothers against decapentaplegic homolog 4.

Figure 2

Signaling pathways in cholangiocarcinoma. Multiple signaling pathways are involved in the development and progression of CCA. Receptor tyrosine kinases activate the RAS-MAPK pathway and the PI3K-AKT pathway. IL-6 induces the JAK/STAT signaling pathway. Consequently, these pathways impact important cellular processes, such as cell proliferation, differentiation, survival, and angiogenesis. IDH 1/2 mutations lead to the accumulation of the oncometabolite intracellular 2-hydroxyglutarate (2-HG). Adapted from [30]. FGFR2: Fibroblast growth factor receptor 2; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; Her2/neu: Human epidermal growth factor receptor 2; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; HGF: Hepatocyte growth factor; MET: C-met-encoded receptor for hepatocyte growth factor; IL-6: Interleukin-6; JAK: Janus kinase; SOCS3: Suppressor of cytokine signaling 3; STAT3: Signal transducer and activator of transcription protein; RAS: Rat sarcoma; RAF: Rat fibrosarcoma; MEK1/2: Mitogen-activated protein kinase kinase; ERK1/2: Extracellular signal-regulated kinase 1/2; PI3K: Phosphatidylinositol 3 kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; α-KG: α-Ketoglutaric acid; 2-HG: 2- hydroxyglutarate; IDH: Isocitrate dehydrogenase; TCA cycle: Citric acid cycle.