Intended for European healthcare professionals only
Genomic alterations in intrahepatic cholangiocarcinoma (iCCA)
Genomic alterations with potential
therapeutic implications have been
identified in ~50% of intrahepatic
cholangiocarcinoma (iCCA) patients,
enabling a more individualised picture
of each patient’s disease biology1
Two of the most common genomic alterations associated with iCCA include isocitratedehydrogenase (IDH) mutations and fibroblast
growth factor receptor 2 (FGFR2) fusions1,2
Potentially targetable genomic alterations are abundant in iCCA*
*Percentages reported for individual alterations are from different primary analyses and are
not all drawn from a single population of patients with iCCA. Although FGFR2 fusions and IDH
mutations tend to be mutually exclusive in iCCA, mutations in the “other alterations” category
can be found in tumours that also carry other potentially targetable mutations or genetic
REFERENCES:1. Lowery MA, et al. Clin Cancer Res. 2018;24:4154–61.
2. Ross JS, et al. Oncologist. 2014;19:235–42.
3. Farshidfar F, et al. Cell Rep. 2017:18:2780–94.
4. Graham RP, et al. Hum Pathol. 2014;45:1630–8.
5. Jain A, et al. JCO Precis Oncol. 2018;2:1–12.
6. Churi CR, et al. PLoS ONE. 2014;9:e115383.
7. Babina IS, Turner NC. Nat Rev Cancer. 2017;17:318–32.
8. Moeini A, et al. Clin Cancer Res. 2015;22:291–300.
9. Touat M, et al. Clin Cancer Res. 2015;21:2684–94.
10. Rizvi S, et al. J Gastrointest Oncol. 2016;7:789–96.
11. Mondesir J, et al. J Blood Med. 2016;7:171–80.
12. Valle JW, et al. Cancer Discov. 2017;7:943–62.
13. Pellino A, et al. Transl Gastroenterol Hepatol. 2018;3:40.
14. Momoi H, et al. J Hepatol. 2001;35:235–44.
15. Winkelmann R, et al. Int J Mol Sci. 2018;19:1421.
16. Solomon JP, et al. Mod Pathol. 2020;33:38–46.
17. Kheder ES, et al. Clin Cancer Res. 2018;24:5807–14.
18. Rizvi S, et al. Semin Liver Dis. 2014;34:456–64.
19. Pandith AA, et al. Urol Oncol. 2013;31:398–406.
20. Gallo LH, et al. Cytokine Growth Factor Rev. 2015;26:425–49.
21. Shibata T, et al. Cancer Sci. 2018;109:1282–91.
FGFR2 fusions: 10–16%2-5
Found almost exclusively in iCCA1,4
Drive iCCA tumour growth through ligand-independent receptor activity, which leads to overactive signalling and contributes to a variety of tumourigenic processes7-9
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 metabolism8,11
KRAS mutations: ~9–24%12
Activating mutations of the proto-oncogene encoding for a protein belonging to the GTPase family8,13
BRAF mutations: ~3–7%12
Activating mutations in the signal transduction cascade that affect cell proliferation, secretion and differentiation8,13
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 MSH614,15
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
FGFR genetic alterations
FGFR genetic alterations have emerged as tumourigenic drivers in cancers such as iCCA, urothelial carcinoma, myeloid/lymphoid neoplasms and other malignancies7,19,20
Genetic alterations have been observed in all FGFR subtypes (FGFR1, FGFR2, FGFR3 and FGFR4)5
Alterations include point mutations, gene amplifications and chromosomal rearrangements that may result in fusion proteins, including FGFR2 fusions5
FGFR2 fusions result in ligand-independent activation of downstream processes, leading to tumourigenesis7-9
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