Genomic alterations in intrahepatic cholangiocarcinoma (iCCA)

Genomic alterations with potential
therapeutic implications have been
identified in ~40% of iCCA patients,
enabling a more individualised picture
of each patient’s disease biology¹

Two of the most common genomic alterations associated with iCCA include isocitrate dehydrogenase 1 (IDH1) mutations and fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements¹

Potentially actionable genomic alterations are abundant in iCCA^1*

^*Based on a retrospective analysis of 6,130 patients diagnosed with iCCA from the FoundationCORE database who received diagnostic panel sequencing on the FoundationOne platform. Short variants, fusions/rearrangements and copy number alterations in >300 tumour-associated genes were evaluated, and the TMB and MSI status were available for the majority of the cohort.¹

amp, amplification; BRAF, B-Raf proto-oncogene; BRCA1/2, breast cancer gene 1/2; ERBB2, erb-b2 receptor tyrosine kinase 2; FGFR2, fibroblast growth factor receptor 2; iCCA, intrahepatic cholangiocarcinoma; IDH1/2, isocitrate dehydrogenase 1/2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MDM2, mouse double minute 2 homolog 2; MET, mesenchymal epithelial transition proto-oncogene; MSI, microsatellite instability; MSI-H, microsatellite instability-high; mut, mutation; TMB, tumour mutational burden.

Figure adapted from Kendre G, et al. J Hepatol. 2023;78:614–26.¹

IDH1/2 mutations

Oncogenic conversion of IDH1/2 is caused by single amino acid substitutions at R132 in IDH1, and either R140 or R172 in IDH2¹
These mutations decrease enzymatic activity for oxidative decarboxylation of isocitrate to α-ketoglutarate while also inducing the neomorphic nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of α-ketoglutarate to the D-2-hydroxyglutarate oncometabolite¹

FGFR2 fusions/rearrangements and mutations

Oncogenic conversion of FGFR2 entails ligand-independent catalytic activation through high-level gene amplification, short variants/indels or generation of fusion proteins¹
In iCCA, the most prevalent mechanism of FGFR2 activation is caused by chromosomal rearrangements that, by juxtaposing exons 1–17 of FGFR2 to sequences contributed by a 3’ partner gene, generate hybrid transcripts encoding constitutively dimerised/active fusion proteins¹

ERBB2 amplifications and mutations

ERBB2 (or human epidermal growth factor receptor 2 [HER2]) is an oncogenic driver and therapeutic target in several solid tumours¹
While copy number alterations dominate the spectrum of oncogenic ERBB2 alterations, biliary tract cancers harbour a significant proportion of ERBB2 short variants¹

BRAF mutations (non-V600E and V600E)

BRAF belongs to the rapidly accelerated fibrosarcoma (RAF) family of mammalian serine/threonine kinases, which transduce signals downstream of RAS via the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway¹

BRCA1/2 alterations

BRCA1/2 are key components of the DNA damage repair pathway¹

KRAS^G12C mutations

Mutationally activated RAS family genes act as key oncogenic drivers in solid malignancies¹

MET alterations

Oncogenic activation of the MET tyrosine kinase receptor can be caused by protein overexpression and genomic alterations, such as gene amplification, exon 14 skipping mutations and fusions¹

MDM2 amplifications

Tumour protein P53 (TP53) is targeted for proteasomal degradation by the E3 ligase MDM2¹
In several cancer entities, MDM2 is upregulated based on gene amplification, increased transcription and/or enhanced translation¹

TMB^high

TMB was developed as a surrogate marker for neoantigen load and predictive biomarker of response to immunotherapy with checkpoint inhibitors¹

MSI-H

MSI is a consequence of genomic instability and is causally linked to deficiencies in the DNA mismatch repair machinery¹

FGFR genetic alterations have emerged as tumourigenic drivers in cancers such as iCCA, urothelial carcinoma, myeloid/lymphoid neoplasms and other malignancies^2–4
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 tumourigenesis^2,6,7

FGFR, fibroblast growth factor receptor; FGFR2, fibroblast growth factor receptor 2.

Figure based on Lowery MA, et al. 2018,⁸ Jain A, et al. 2018,⁵ and Shibata T, et al. 2018.⁹”

FGFR2, fibroblast growth factor receptor 2.

Figure adapted from Babina IS, Turner NC. 2017,² Moeini A, et al. 2015,⁶ and Touat M, et al. 2015.⁷

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