Genomic alterations in intrahepatic cholangiocarcinoma (iCCA)

FGFR2 fusions: 10–16%^2-5

• Found almost exclusively in iCCA^1,4
• Drive iCCA tumour growth through ligand-independent receptor activity, which leads to overactive signalling and contributes to a variety of tumourigenic processes^7-9
• Detectable early in disease progression, elevating the importance of identifying these alterations in patients at diagnosis¹⁰

IDH mutations: 18–36%^2,6

• Somatic mutations in metabolic enzymes that ultimately affect epigenetic regulation as well as cell differentiation and metabolism^8,11

Other:

KRAS mutations: ~9–24%¹²

• Activating mutations of the proto-oncogene encoding for a protein belonging to the GTPase family^8,13

BRAF mutations: ~3–7%¹²

• Activating mutations in the signal transduction cascade that affect cell proliferation, secretion and differentiation^8,13

MSI-H status: <1–10%^1,12

• Although not a single genomic alteration, MSI-H status reflects a propensity for mutation due to abnormalities of the DNA sequence. It may be identified by expression of genes such as MLH1, PMS2, MSH2 and MSH6^14,15

NTRK fusion: <1%¹⁶

• Chimeric NTRK fusion proteins promote tumourigenesis through constitutive ligand-free activation of intracellular biological pathways and signal transduction cascades that control cell-cycle progression, proliferation, apoptosis and survival¹⁷

EGFR mutations: ~1.5–2%¹²

• EGFR activation leads to downstream activation of mitogen-activated protein kinase, a well-known oncogenic signalling pathway¹⁸