Integrative analysis of layers of data in hepatocellular carcinoma reveals pathway dependencies

Table 1 List of the final 85 selected publications for each layer of data. For each publication the number of hepatocellular carcinoma samples and controls and the platform used for the analysis are reported

Gene expression
No.	year	PMID	HCC (n)	Controls (n)	GEO dataset
1	2004	17393520	35	13	GSE6764
2	2008	18504433	11	2	GSE6222
3	2008	18923165	80	82	GSE10143
4	2009	19098997	47	58	GSE14323
5	2009	19861515	16	47	GSE17967
6	2011	21320499	34	34	GSE20140 (GSE10141, GSE10140)
7	2011	21712445	40	40	GSE28248
8	2013	23691139	15	15	GSE17548
9	2013	23800896	GSE36376_276; GSE25097_211	GSE36376_247; GSE25097_283	GSE36376, GSE25097
10	2014	24498002	46	46	GSE47595
11	2014	24564407	45	45	GSE45114
12	2014	25093504	39	40	GSE57958
13	2014	25141867	11	11	GSE55092
14	2014	25376302	18	18	GSE60502
15	2014	25536056	72	72	GSE39791
16	2015	25666192	132	132	GSE54236
17	2015	25645722	228	168	GSE63898
18	2016	27499918	60	60	GSE64041
19	2016	25964079	26	20	GSE54238
Proteomics
No.	year	PMID	HCC (n)	Controls (n)
1	2004	14726492	8	8
2	2008	19003864	12	12
3	2005	15759316	10	10
4	2005	16097030	14	14
5	2007	17627933	12	12
6	2014	23621634	3	3
7	2009	19562805	3	3
8	2016	26709725	24	12
9	2013	23589362	20	20
10	2012	22813877	10	10
11	2012	22082227	11	11
12	2011	21631109	69	123
13	2010	20230046	5	5
14	2010	19956837	20	20
15	2009	19715608	18	18
16	2009	19535095	3	3
17	2009	19161326	80	80
18	2004	15221772	20	20
19	2003	14673798	21	21
20	2003	14654528	21	21
21	2002	12481271	11	11
22	2013	23462207	7	7
23	2005	16335951	8	8
24	2006	16342242	10	10
25	2011	22034872	3	3
26	2005	15852300	7	7
27	2011	21913717	3	3
28	2007	17203974	25	28
29	2007	17586277	10	10
Whole exome sequencing
No.	year	PMID	HCC (n)	Controls (n)	GEO dataset
1	2013	23912677	3	3	N/A
2	2014	24055508	4	7	N/A
3	2017	28323123	5	5	N/A
4	2014	24798001	231	231	GSE54504
5	2012	22561517	24	24	N/A
Epigenetic_miRNAs
No.	year	PMID	HCC (n)	Controls (n)	GEO dataset
1	2015	26190160	9	7	N/A
2	2014	24789420	10	9	GSE31383
3	2014	24564407	45	45	GSE10694
4	2011	21298008	73	73	GSE21362
5	2008	18649363	78	10	N/A
6	2012	22135159	20	20	N/A
7	2011	21319996	94	94	N/A
8	2009	19473441	20	20	N/A
9	2009	19173277	35		N/A
10	2007	18171346	10	10	N/A
11	2006	16331254	25	25	N/A
12	2015	26062888	30	30	N/A
13	2015	26046780	327	43	N/A
14	2015	25861255	66	66	GSE54751
15	2015	25500075	6	6	GSE54537
16	2014	24875649	24	24
17	2013	23812667	166	166	GSE31384
18	2013	23390000	9	17	GSE40744
19	2012	23082062	18	18	N/A
20	2014	24586785	29	29	N/A
21	2013	24417970	78	78	N/A
Epigenetic methylation
No.	year	PMID	HCC (n)	Controls (n)	GEO dataset
1	2011	21500188	13	12	N/A
2	2014	24306662	45	45	N/A
3	2014	25376292	22	22	N/A
4	2015	25945129	8	8	GSE59260
5	2011	21747116	12	12	GSE29720
6	2010	20165882	20	20	GSE18081
7	2012	22234943	62	62	GSE37988
8	2013	24012984	20	8	GSE44970
9	2013	23208076	66	66	GSE54503
10	2014	25093504	59	59	GSE57956
11	2014	25294808	27	27	GSE60753

HCC: Hepatocellular carcinoma; GEO: Gene Expression Omnibus; N/A: Not applicable.

Table 2 Prognostic value of the 9 dysregulated genes associated with the 3 common dysregulated pathways (EGFR, epidermal growth factor, β1-integrin and axon guidance) among the 4 types of data in obtained with KMplotter

Gene	Modulation in the 19 HCC papers	Probe-ID	HR	CI	Log-Rank P value	Median survival low (mo)	Median survival high (mo)	Estradiol gene modulation predicted by CTD
COL2A1	Up	1280	1.49	1.05-2.11	0.0229	61.7	54.1	N/A
FGA	Down	2243	0.52	0.35-0.77	0.0009	49.7	70.5	+
FGG	Down	2266	0.56	0.39-0.79	0.0009	38.3	70.5	+
LAMC1	Up	3915	1.43	0.98-2.09	0.06	56.5	38.3	N/A
CDK5	Up	1020	1.85	1.22-2.81	0.0035	81.9	6.2	N/A
EPHB1	Down	2047	0.72	0.048-1.08	0.1135	54.1	70.5	N/A
RPS6KA3	Up	6197	1.2	0.8-1.78	0.3743	54.1	56.5	-
EGFR	Down	1956	0.61	0.43-0.89	0.0085	31	70.5	+
ITGB1	Up	3688	1.37	0.95-1.97	0.0924	82.9	49.7	N/A

CTD based prediction identified Estradiol to efficiently affect the expression of the 4/9 genes based on their hazard ratios values. HR: Hazard ratios; HCC: Hepatocellular carcinoma; CI: Confidence interval; N/A: Not applicable.

Table 3 Modulation of the 9 dysregulated genes associated with the 3 common dysregulated pathways (EGFR, epidermal growth factor, β1-integrin and axon guidance) identified in the 19 hepatocellular carcinoma gene expression papers. Their genetic alteration in hepatocellular carcinoma and their mechanism in cancer are reported

Gene	Modulation in the 19 HCC papers	PMID	Mutation in HCC (PMID)	Role in cancer (PMID)
COL2A1	Up (2/19)	23800896/25666192	(rs3917) polymorphism is associated with higher risk of HCC (21665180)	COL2A1 promotes migration in HCC (29858962)
FGA	Down (9/19)	21320499/23800896/25093504/25536056/25141867/25376302/25666192/25645722/25666192	Deleted in HCC patients (27511114)	FGA is a positive predictor of survival in gastric cancer patients (15756001)
FGG	Down 8/19	21320499/23800896/25093504/25536056/25141867/25376302/25645722/24498002	Allelic loss (16980951)	FGG is involved in amino acid and redox metabolism pathway in HCC (28089356)
LAMC1	Up (4/19)	23800896/25536056/25141867/25645722	Not identified	LAMC1 promotes tumor cell invasion and migration in HCC (28928891)
CDK5	Up (2/19)	25141867/25376302	Not identified	CDK5 promotes proliferation in HCC (29312535)
EPHB1	Down (2/19)	23800896/25141867	Missense mutation (19469653)	EPHB1 inhibits cell migration(22242939)
RPS6KA3	Up 1/19	25141867	Somatic mutation and copy number variations (22561517)	RPS6KA3 increases cell proliferation (15833840)
EGFR	Down (2/19)	19098997/25141867	Missense mutation (26436086)	EGFR promotes cell adhesion (31465839)
ITGB1	Up (1/19)	25141867	Somatic number variations (24512821)	ITGB1 promotes migration (30664185)

HCC: Hepatocellular carcinoma.