Schematic overview of the cellular and molecular mechanisms involved in the cancer progression, including the proposed cellular and molecular mechanisms in cancer cells trajectory. AT1: alveolar type 1 cells; AT2: alveolar type 2 cells; AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; IA: invasive adenocarcinoma; EMT: epithelial-mesenchymal transition

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	Gene summary
	Malignant transformation analysis
	Malignant transformation related pathway analysis
	Cell-cell communication analysis
	Single-cell gene regulatory network inference analysis
	Somatic mutation of malignant transformation related genes
	Related drugs of malignant transformation related genes

Gene: VCP

Gene summary for VCP

Gene summary.

Gene information	Species	Human
	Gene symbol	VCP
	Gene ID	7415
	Gene name	valosin containing protein
	Gene Alias	CDC48
	Cytomap	9p13.3
	Gene Type	protein-coding
	GO ID	GO:0000226
	UniProtAcc	P55072

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Malignant transformation analysis

Identification of the aberrant gene expression in precancerous and cancerous lesions by comparing the gene expression of stem-like cells in diseased tissues with normal stem cells

Malignant transformation involving gene list.

Entrez ID	Symbol	Replicates	Species	Organ	Tissue	Adj P-value	Log2FC	Malignancy
7415	VCP	GSM4909286	Human	Breast	IDC	1.33e-08	-2.85e-01	0.1081
7415	VCP	GSM4909290	Human	Breast	IDC	5.24e-06	4.67e-01	0.2096
7415	VCP	GSM4909292	Human	Breast	IDC	1.81e-02	6.01e-01	0.1236
7415	VCP	GSM4909294	Human	Breast	IDC	5.09e-04	-1.39e-01	0.2022
7415	VCP	GSM4909296	Human	Breast	IDC	7.57e-15	-1.89e-01	0.1524
7415	VCP	GSM4909297	Human	Breast	IDC	2.33e-22	-1.98e-01	0.1517
7415	VCP	GSM4909298	Human	Breast	IDC	1.23e-03	-2.33e-01	0.1551
7415	VCP	GSM4909299	Human	Breast	IDC	1.55e-03	-2.38e-01	0.035
7415	VCP	GSM4909301	Human	Breast	IDC	5.59e-06	-1.78e-01	0.1577
7415	VCP	GSM4909302	Human	Breast	IDC	1.66e-03	-2.00e-01	0.1545
7415	VCP	GSM4909311	Human	Breast	IDC	1.45e-32	-2.76e-01	0.1534
7415	VCP	GSM4909312	Human	Breast	IDC	1.42e-22	-2.45e-01	0.1552
7415	VCP	GSM4909313	Human	Breast	IDC	2.58e-03	-2.13e-01	0.0391
7415	VCP	GSM4909315	Human	Breast	IDC	3.58e-07	-3.05e-01	0.21
7415	VCP	GSM4909316	Human	Breast	IDC	2.86e-02	-3.66e-01	0.21
7415	VCP	GSM4909319	Human	Breast	IDC	5.38e-43	-2.90e-01	0.1563
7415	VCP	GSM4909320	Human	Breast	IDC	8.47e-07	-3.81e-01	0.1575
7415	VCP	GSM4909321	Human	Breast	IDC	9.53e-21	-2.01e-01	0.1559
7415	VCP	brca1	Human	Breast	Precancer	3.88e-09	4.44e-01	-0.0338
7415	VCP	brca2	Human	Breast	Precancer	9.28e-24	5.09e-01	-0.024

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Colorectum (GSE201348)		FAP: Familial adenomatous polyposis
		CRC: Colorectal cancer
Colorectum (HTA11)		AD: Adenomas
		SER: Sessile serrated lesions
		MSI-H: Microsatellite-high colorectal cancer
		MSS: Microsatellite stable colorectal cancer
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
Thyroid		ATC: Anaplastic thyroid cancer
		HT: Hashimoto's thyroiditis
		PTC: Papillary thyroid cancer

∗log2FC in expression of this searched gene in stem-like cells from each diseased tissue sample relative to stem-like cells in normal samples in each tissue plotted against the malignancy continuum. Samples are colored based on if they are from different disease stage.

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Malignant transformation related pathway analysis

Find out the enriched GO biological processes and KEGG pathways involved in transition from healthy to precancer to cancer

Figure of enriched GO biological processes.

Tissue	Disease Stage	Enriched GO biological Processes
Colorectum	AD
Colorectum	SER
Colorectum	MSS
Colorectum	MSI-H
Colorectum	FAP

∗Top 15 enriched GO BP terms are showed in the bar plot of each disease state in each tissue. Each row represents a significant GO biological process which is colored according to the -log10(p.adjust).

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Enriched GO biological processes.

GO ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	Count
GO:00460349	Breast	Precancer	ATP metabolic process	82/1080	277/18723	1.94e-36	5.19e-33	82
GO:00061199	Breast	Precancer	oxidative phosphorylation	53/1080	141/18723	1.15e-29	2.04e-26	53
GO:00090608	Breast	Precancer	aerobic respiration	58/1080	189/18723	5.69e-27	7.62e-24	58
GO:00060918	Breast	Precancer	generation of precursor metabolites and energy	94/1080	490/18723	1.54e-25	1.64e-22	94
GO:00453338	Breast	Precancer	cellular respiration	59/1080	230/18723	5.97e-23	5.32e-20	59
GO:00159808	Breast	Precancer	energy derivation by oxidation of organic compounds	70/1080	318/18723	8.33e-23	6.37e-20	70
GO:00718269	Breast	Precancer	ribonucleoprotein complex subunit organization	48/1080	227/18723	2.68e-15	8.45e-13	48
GO:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:00067547	Breast	Precancer	ATP biosynthetic process	21/1080	57/18723	2.31e-12	4.26e-10	21
GO:20001169	Breast	Precancer	regulation of cysteine-type endopeptidase activity	43/1080	235/18723	1.30e-11	1.83e-09	43
GO:00092067	Breast	Precancer	purine ribonucleoside triphosphate biosynthetic process	22/1080	68/18723	1.41e-11	1.88e-09	22
GO:00432819	Breast	Precancer	regulation of cysteine-type endopeptidase activity involved in apoptotic process	40/1080	209/18723	1.59e-11	2.07e-09	40
GO:00091457	Breast	Precancer	purine nucleoside triphosphate biosynthetic process	22/1080	69/18723	1.95e-11	2.43e-09	22
GO:00092017	Breast	Precancer	ribonucleoside triphosphate biosynthetic process	22/1080	74/18723	9.18e-11	1.00e-08	22
GO:00091448	Breast	Precancer	purine nucleoside triphosphate metabolic process	24/1080	88/18723	9.66e-11	1.03e-08	24
GO:00092057	Breast	Precancer	purine ribonucleoside triphosphate metabolic process	23/1080	82/18723	1.27e-10	1.34e-08	23
GO:00091427	Breast	Precancer	nucleoside triphosphate biosynthetic process	23/1080	85/18723	2.82e-10	2.69e-08	23
GO:00160329	Breast	Precancer	viral process	58/1080	415/18723	3.42e-10	3.16e-08	58
GO:00091997	Breast	Precancer	ribonucleoside triphosphate metabolic process	23/1080	89/18723	7.65e-10	6.66e-08	23

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501416	Breast	Precancer	Amyotrophic lateral sclerosis	98/684	364/8465	2.13e-28	8.41e-27	6.44e-27	98
hsa0502216	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0513414	Breast	Precancer	Legionellosis	19/684	57/8465	4.62e-08	9.12e-07	6.98e-07	19
hsa0414118	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0501417	Breast	Precancer	Amyotrophic lateral sclerosis	98/684	364/8465	2.13e-28	8.41e-27	6.44e-27	98
hsa0502217	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0513415	Breast	Precancer	Legionellosis	19/684	57/8465	4.62e-08	9.12e-07	6.98e-07	19
hsa0414119	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0501423	Breast	IDC	Amyotrophic lateral sclerosis	102/867	364/8465	1.29e-22	5.22e-21	3.91e-21	102
hsa0502223	Breast	IDC	Pathways of neurodegeneration - multiple diseases	116/867	476/8465	3.63e-20	1.18e-18	8.82e-19	116
hsa0513422	Breast	IDC	Legionellosis	19/867	57/8465	1.89e-06	3.07e-05	2.29e-05	19
hsa0414124	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0501433	Breast	IDC	Amyotrophic lateral sclerosis	102/867	364/8465	1.29e-22	5.22e-21	3.91e-21	102
hsa0502233	Breast	IDC	Pathways of neurodegeneration - multiple diseases	116/867	476/8465	3.63e-20	1.18e-18	8.82e-19	116
hsa0513432	Breast	IDC	Legionellosis	19/867	57/8465	1.89e-06	3.07e-05	2.29e-05	19
hsa0414134	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0501443	Breast	DCIS	Amyotrophic lateral sclerosis	101/846	364/8465	7.14e-23	2.88e-21	2.12e-21	101
hsa0502243	Breast	DCIS	Pathways of neurodegeneration - multiple diseases	114/846	476/8465	4.74e-20	1.53e-18	1.13e-18	114
hsa0513441	Breast	DCIS	Legionellosis	19/846	57/8465	1.30e-06	2.10e-05	1.55e-05	19
hsa0414143	Breast	DCIS	Protein processing in endoplasmic reticulum	36/846	174/8465	1.60e-05	1.91e-04	1.41e-04	36

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Cell-cell communication analysis

Identification of potential cell-cell interactions between two cell types and their ligand-receptor pairs for different disease states

Ligand

Receptor

LRpair

Pathway

Tissue

Disease Stage

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Single-cell gene regulatory network inference analysis

Find out the significant the regulons (TFs) and the target genes of each regulon across cell types for different disease states

Cell Type

Tissue

Disease Stage

Target Gene

RSS

Regulon Activity

∗The dot plots of a searched regulon are shown for all cell subpopulations in each disease state of each tissue based on the regulon specific score inferred using pySCENIC and by calculating the average expression.

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Somatic mutation of malignant transformation related genes

Annotation of somatic variants for genes involved in malignant transformation

Hugo Symbol

Variant Class

Variant Classification

dbSNP RS

HGVSc

HGVSp

HGVSp Short

SWISSPROT

BIOTYPE

SIFT

PolyPhen

Tumor Sample Barcode

Tissue

Histology

Sex

Age

Stage

Therapy Types

Drugs

Outcome

VCP

SNV

Missense_Mutation

rs748091463

c.211G>A

p.Val71Ile

p.V71I

P55072

protein_coding

tolerated(0.09)

benign(0.013)

TCGA-A8-A07B-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

VCP

SNV

Missense_Mutation

c.574N>C

p.Glu192Gln

p.E192Q

P55072

protein_coding

deleterious(0.02)

possibly_damaging(0.669)

TCGA-A8-A095-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

VCP

SNV

Missense_Mutation

c.764C>T

p.Ala255Val

p.A255V

P55072

protein_coding

deleterious(0.01)

probably_damaging(0.999)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

VCP

SNV

Missense_Mutation

c.1675G>A

p.Val559Ile

p.V559I

P55072

protein_coding

tolerated(0.34)

possibly_damaging(0.863)

TCGA-AR-A0TT-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

VCP

SNV

Missense_Mutation

c.186G>C

p.Lys62Asn

p.K62N

P55072

protein_coding

deleterious(0.02)

probably_damaging(0.979)

TCGA-E2-A10C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

VCP

insertion

Nonsense_Mutation

novel

c.1128_1129insACCTACTGTTCTTAGGTTTGAGG

p.Arg377ThrfsTer5

p.R377Tfs*5

P55072

protein_coding

TCGA-BH-A0EE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

VCP

deletion

Frame_Shift_Del

novel

c.1226delN

p.Ala409ValfsTer3

p.A409Vfs*3

P55072

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

VCP

SNV

Missense_Mutation

c.1271N>A

p.Arg424His

p.R424H

P55072

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

VCP

SNV

Missense_Mutation

c.85N>C

p.Asp29His

p.D29H

P55072

protein_coding

deleterious(0)

probably_damaging(0.955)

TCGA-DS-A1OC-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

gemcitabine

VCP

SNV

Missense_Mutation

c.585A>T

p.Glu195Asp

p.E195D

P55072

protein_coding

tolerated(0.21)

benign(0.017)

TCGA-EA-A1QS-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

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Related drugs of malignant transformation related genes

Identification of chemicals and drugs interact with genes involved in malignant transfromation

(DGIdb 4.0)

Entrez ID	Symbol	Category	Interaction Types	Drug Claim Name	Drug Name	PMIDs
7415	VCP	TRANSPORTER, ENZYME, DNA REPAIR, DRUGGABLE GENOME		AMENTOFLAVONE	AMENTOFLAVONE
7415	VCP	TRANSPORTER, ENZYME, DNA REPAIR, DRUGGABLE GENOME		CB-5083	CB-5083	26104798
7415	VCP	TRANSPORTER, ENZYME, DNA REPAIR, DRUGGABLE GENOME		HEXACHLOROPHENE	HEXACHLOROPHENE

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