Table 4.

Genetic alterations and abnormal protein expression found in BTC.

Gene	Percentage of patients	Function/Alterations	Reference
Proliferation
KRAS	24.6% of BTC	Mutation at codon 12 or 13, constitutively active protein	[73]
	54% of BTC		[74]
	45% of BTC		[75]
	33% of BTC		[76]
	7.4% ICC		[77]
	5% of ICC and 23% of ECC		[78]
BRAF	22% of BTC	Mutations at various codons	[75]
	7.4 of ICC	V600E substitution, constitutively	[77]
	3% of ICC	active protein	[78]
EGFR	13.6% of BTC	Mutations at various codons	[79]
	13–15% of BTC		[80]
	26.5% of BTC		[81]
RASSF1A	69% of BTC	Promoter hypermethylation, decreased transcriptional activity	[82]
	68.75% of ECC		[83]
	27% of BTC		[84]
PIK3CA	8.2% of BTC	Gain of function mutation	[81]
	9% of ICC and 0% of ECC		[85]
Cell-cycle regulation
SMAD4	45.2% of ICC	Loss of protein expression	[86]
CDKN2A (p16)	35.7% of ICC	Loss of protein expression	[86]
	16.1%, 57.1%, 20% of BTC	Hypermethylation, mutation, LOH	[87]
TP53	5% of ICC and 14% of ECC	G245S and R175H substitution, loss of protein function	[78]
	37% of ICC	Loss of protein function	[88]
Chronic inflammation
SOCS3	27% of ICC	Promoter hypermethylation	[89]
Metabolism
IDH1/2	23% of ICC and 0% of ECC	Mutation decrease protein function	[78]
	10% of ICC		[90]
	28% of ICC and 7% of ECC		[91]

BTC - biliary tract cancer, CDKN2A - cyclin-dependent kinase inhibitor 2A, ECC - extrahepaticcholangiocarcinoma, EGFR - epidermal growth factor receptor, ICC - intrahepatic cholangiocarcinoma, IDH1/2 - isocitrate dehydrogenase, LOH - loss of heterozygosity, PIK3CA – phosphatidylinositol−4,5-bisphosphate 3-kinase, RASSF1A - Ras association domain family 1 isoform A, SMAD4- mothers against decapentaplegic homolog 4, SOCS3 - suppressor of cytokine signaling 3,TP53- tumor suppressor protein p53