Molecular heterogeneity in intrahepatic cholangiocarcinoma

Table 1 Frequency of genetic alteration in intrahepatic cholangiocarcinoma

Pathway	Gene	Frequency of alteration
NADPH metabolism	IDH1/2	4-36
Chromatic remodeling	BAP1	9%-25%
	ARID1A	11-36
	PBRM1	11-17
Cell cycle regulation and DNA damage response	CDKN2A	7
	CDK6	7
	TP53	3-38
	BRCA1/2	4
PI3K signaling	PIK3CA	4-6
	PTEN	1-11
Ras/Raf/MEK/ERK	EGFR	2.2
	KRAS	9-24
	NRAS	3.6
	BRAF	3-22
FGF	FGFR2	4-38

DNA: Deoxyribonucleic acid; ERK: Extracellular signal-regulated kinase; MEK: Mitogen-activated protein kinase kinase; NADPH: Nicotinamide adenosine dinucleotide phosphate; PI3K: Phosphoinositide-3-kinase.

Table 2 Integrative clinical-molecular subclassification of intrahepatic cholangiocarcinoma

	Good prognostic subclass	Poor prognostic subclass
GSE26566		Periductal infiltrating type, perineural invasion; KRAS mutation, EGFR and HER2 signatures
GSE32225	Well differentiated tumor; inflammation-related signatures	Poor differentiated tumor; RTK-related pathways (AKT, MET, RAS/RAF/MAPK); overexpression of EGFR; KRAS mutation
GSE32879		EMT-related signatures; TGFβ1, NCAM1, CD133
GSE89749	Fluke-negative; FGFR fusion; BAP1, IDH mutation	Fluke-positive; BRCA1/2, TP53 mutation; ERBB2 gain
GSE107943	Small duct type (cholangiolar type); underlying hepatitis, cirrhosis; metabolism-related signatures; FGFR2 fusion	Large duct type (bile duct type); Elevated CEA, CA 19-9; underlying cholangitis; P53, inflammation-related signatures; KRAS mutation
TCGA1	Mitochondria/metabolic-related signatures; IDH, BAP1 mutation	Inflammation-related pathways

¹In The Cancer Genome Atlas, two subtypes have no statistical different survival.

BRCA1/2: Breast cancer gene 1/2; CA 19-9: Carbohydrate antigen 19-9; CEA: Carcinoembryonic antigen; EGFR: Endothelial growth factor receptor; EMT: Epithelial to mesenchymal transition; FGFR2: Fibroblast growth factor receptor 2; HER2: Human epidermal growth factor receptor 2; IDH: Isocitrate dehydrogenase; MAPK: Mitogen-activated protein kinase; NCAM1: Neural cell adhesion molecule; TCGA: The Cancer Genome Atlas; TGFβ1: Transforming growth factor beta 1.