Table 1:

Key oncogenic drivers and pathways de-regulated in HCC

Altered pathway	Altered gene	Type of alteration	Prevalence in HCC % (range)
Telomere maintenance	TERT$	Promoter Activating mutation	55 (44–59)
		High-level focal amplification	6 (1–9)
		Viral insertion	3 (1 – 5)
Cell cycle regulation	TP53$	Loss of function mutation	27 (18–31)
		Homozygous deletion	2 (0–2)
	ATM	Loss of function mutation	4 (2–5)
	RB1	Loss of function mutation	4 (3–5)
		Homozygous deletion	5 (4–6)
	CDKN2A	Loss of function mutation	2 (1–3)
		Homozygous deletion	5 (4–6)
	MYC	High-level focal amplification	12 (4–18)
	CCND1$	High-level focal amplification	7 (5–7)
Wnt / β-catenin signaling	CTNNB1$	Activating mutation	29 (23–36)
	AXIN1	Loss of function mutation	7 (4–10)
	APC	Loss of function mutation	2 (0–3)
Chromatin remodeling	ARID1A	Loss of function mutation	8 (4–12)
	ARID2	Loss of function mutation	7 (3–10)
	KMT2A	Loss of function mutation	3 (0–4)
	KMT2C	Loss of function mutation	3 (2–5)
	KMT2B	Loss of function mutation	2 (0–4)
	BAP1	Loss of function mutation	2 (0–5)
	ARID1B	Loss of function mutation	1 (0–3)
Ras/PI3K/mTOR	RPS6KA3	Unclassified	4 (3–6)
	PIK3CA #	Activating mutation	2 (1–4)
	KRAS #	Activating mutation	1 (0–1)
	NRAS	Activating mutation	0 (0–1)
	PDGFRA #	Mutation	1 (0–4)
	EGFR #	Activating mutation	1 (0–2)
	PTEN	Loss of function mutation	1 (0–2)
FGF signaling#	FGF19	High-level focal amplification	6 (5–6)
VEGF pathway#	VEGFA	High-level focal amplification	5 (1–8)
Oxidative stress	NFE2L2&	Activating mutation	4 (2–6)
	KEAP1&	Activating mutation	3 (2–5)
Hepatocyte differentiation	ALB	Mutation	9 (5–13)
	APOB	Mutation	8 (1–10)
JAK–STAT	IL6ST	Mutation	2 (0–3)
	JAK1$	Mutation	1 (0–3)
TGFβ signaling$	ACVR2A	Loss of function mutation	4 (1–10)
IGF signaling$	IGF2R	Mutation	1 (0–2)

Mutation frequencies are reported for a total of 1,339 patients included in multiple whole-exome sequencing studies^{3,41,60,170,171} (modified and updated from⁵); TERT promoter mutations were assessed using Sanger sequencing (n=1,517 patients)¹⁷². Copy number alterations were detected using single-nucleotide polymorphism (SNP) arrays (n=857 patients)^{3,41,45,60,170}. Viral integrations were detected using viral capture and DNA sequencing (n=645 patients). HCC, hepatocellular carcinoma; IGF, insulin growth factor; mTOR, mammalian Target of Rapamycin; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β.

^#: targetable by an FDA-approved drug.

^$: targetable by a drug in testing phases.

^&: targetable using mTOR inhibitors in testing phases.