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: ITGB4

Gene summary for ITGB4

Gene summary.

Gene information	Species	Human
	Gene symbol	ITGB4
	Gene ID	3691
	Gene name	integrin subunit beta 4
	Gene Alias	CD104
	Cytomap	17q25.1
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A024R8T0

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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
3691	ITGB4	cSCC_p9	Human	Skin	cSCC	5.88e-20	4.22e-01	-0.1991
3691	ITGB4	Pat01-B	Human	Stomach	GC	2.11e-22	3.53e-01	0.5754
3691	ITGB4	Pat02-B	Human	Stomach	GC	1.01e-38	3.64e-01	0.0368
3691	ITGB4	Pat03-B	Human	Stomach	GC	2.22e-19	3.20e-01	0.3693
3691	ITGB4	Pat04-B	Human	Stomach	GC	1.60e-13	1.81e-01	-0.1483
3691	ITGB4	Pat05-B	Human	Stomach	GC	1.86e-07	2.01e-01	-0.0353
3691	ITGB4	Pat06-B	Human	Stomach	GC	8.46e-36	3.63e-01	-0.1961
3691	ITGB4	Pat10-B	Human	Stomach	GC	4.00e-04	4.65e-01	0.084
3691	ITGB4	Pat11-B	Human	Stomach	GC	4.89e-15	3.32e-01	-0.182
3691	ITGB4	Pat12-B	Human	Stomach	GC	2.03e-32	6.11e-01	0.0325
3691	ITGB4	Pat13-B	Human	Stomach	GC	2.41e-04	1.86e-01	0.0555
3691	ITGB4	Pat15-B	Human	Stomach	GC	2.10e-11	2.98e-01	-0.0778
3691	ITGB4	Pat16-B	Human	Stomach	GC	1.84e-02	3.66e-02	0.1918
3691	ITGB4	Pat17-B	Human	Stomach	GC	4.51e-02	1.59e-01	0.3109
3691	ITGB4	Pat18-B	Human	Stomach	GC	1.33e-08	3.11e-01	-0.0432
3691	ITGB4	Pat19-B	Human	Stomach	GC	1.78e-11	3.15e-01	0.0826
3691	ITGB4	Pat22-B	Human	Stomach	GC	2.04e-29	4.03e-01	-0.1042
3691	ITGB4	Pat24-B	Human	Stomach	GC	3.07e-14	4.58e-01	-0.1184
3691	ITGB4	Pat25-A	Human	Stomach	CAG with IM	4.71e-24	6.70e-02	-0.1648
3691	ITGB4	Pat26-A	Human	Stomach	CSG	3.47e-21	1.56e-01	-0.2402

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
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

∗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:00315898	Cervix	CC	cell-substrate adhesion	96/2311	363/18723	1.48e-13	8.85e-11	96
GO:00016679	Cervix	CC	ameboidal-type cell migration	110/2311	475/18723	2.66e-11	6.36e-09	110
GO:00435884	Cervix	CC	skin development	71/2311	263/18723	8.04e-11	1.46e-08	71
GO:01501159	Cervix	CC	cell-substrate junction organization	37/2311	101/18723	3.20e-10	4.46e-08	37
GO:00070448	Cervix	CC	cell-substrate junction assembly	34/2311	95/18723	3.35e-09	3.45e-07	34
GO:00071608	Cervix	CC	cell-matrix adhesion	60/2311	233/18723	1.58e-08	1.23e-06	60
GO:00072295	Cervix	CC	integrin-mediated signaling pathway	34/2311	107/18723	1.01e-07	5.25e-06	34
GO:00343298	Cervix	CC	cell junction assembly	88/2311	420/18723	3.42e-07	1.38e-05	88
GO:00435893	Cervix	CC	skin morphogenesis	8/2311	11/18723	6.22e-06	1.51e-04	8
GO:00073695	Cervix	CC	gastrulation	42/2311	185/18723	5.83e-05	8.46e-04	42
GO:00075654	Cervix	CC	female pregnancy	43/2311	193/18723	7.62e-05	1.04e-03	43
GO:00447064	Cervix	CC	multi-multicellular organism process	45/2311	220/18723	4.14e-04	4.21e-03	45
GO:00336272	Cervix	CC	cell adhesion mediated by integrin	19/2311	72/18723	9.11e-04	7.81e-03	19
GO:00075664	Cervix	CC	embryo implantation	15/2311	53/18723	1.43e-03	1.12e-02	15
GO:0001704	Cervix	CC	formation of primary germ layer	27/2311	121/18723	1.49e-03	1.16e-02	27
GO:00487365	Cervix	CC	appendage development	35/2311	172/18723	1.88e-03	1.39e-02	35
GO:00601735	Cervix	CC	limb development	35/2311	172/18723	1.88e-03	1.39e-02	35
GO:00614502	Cervix	CC	trophoblast cell migration	7/2311	17/18723	2.72e-03	1.85e-02	7
GO:000722913	Cervix	HSIL_HPV	integrin-mediated signaling pathway	19/737	107/18723	3.37e-08	2.76e-06	19
GO:000756512	Cervix	HSIL_HPV	female pregnancy	26/737	193/18723	4.32e-08	3.41e-06	26

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0451010	Cervix	CC	Focal adhesion	59/1267	203/8465	1.53e-07	1.84e-06	1.09e-06	59
hsa0481016	Cervix	CC	Regulation of actin cytoskeleton	64/1267	229/8465	2.24e-07	2.59e-06	1.53e-06	64
hsa051657	Cervix	CC	Human papillomavirus infection	74/1267	331/8465	1.70e-04	1.02e-03	6.03e-04	74
hsa0451014	Cervix	CC	Focal adhesion	59/1267	203/8465	1.53e-07	1.84e-06	1.09e-06	59
hsa0481017	Cervix	CC	Regulation of actin cytoskeleton	64/1267	229/8465	2.24e-07	2.59e-06	1.53e-06	64
hsa0516512	Cervix	CC	Human papillomavirus infection	74/1267	331/8465	1.70e-04	1.02e-03	6.03e-04	74
hsa045124	Cervix	HSIL_HPV	ECM-receptor interaction	12/459	89/8465	2.95e-03	1.88e-02	1.52e-02	12
hsa0451023	Cervix	HSIL_HPV	Focal adhesion	21/459	203/8465	3.24e-03	2.02e-02	1.63e-02	21
hsa054127	Cervix	HSIL_HPV	Arrhythmogenic right ventricular cardiomyopathy	10/459	77/8465	8.34e-03	4.70e-02	3.80e-02	10
hsa0451211	Cervix	HSIL_HPV	ECM-receptor interaction	12/459	89/8465	2.95e-03	1.88e-02	1.52e-02	12
hsa0451033	Cervix	HSIL_HPV	Focal adhesion	21/459	203/8465	3.24e-03	2.02e-02	1.63e-02	21
hsa0541212	Cervix	HSIL_HPV	Arrhythmogenic right ventricular cardiomyopathy	10/459	77/8465	8.34e-03	4.70e-02	3.80e-02	10
hsa04810	Colorectum	AD	Regulation of actin cytoskeleton	75/2092	229/8465	3.36e-03	1.76e-02	1.12e-02	75
hsa04510	Colorectum	AD	Focal adhesion	67/2092	203/8465	4.40e-03	2.17e-02	1.38e-02	67
hsa048101	Colorectum	AD	Regulation of actin cytoskeleton	75/2092	229/8465	3.36e-03	1.76e-02	1.12e-02	75
hsa045101	Colorectum	AD	Focal adhesion	67/2092	203/8465	4.40e-03	2.17e-02	1.38e-02	67
hsa048102	Colorectum	SER	Regulation of actin cytoskeleton	60/1580	229/8465	2.74e-03	2.02e-02	1.47e-02	60
hsa048103	Colorectum	SER	Regulation of actin cytoskeleton	60/1580	229/8465	2.74e-03	2.02e-02	1.47e-02	60
hsa048104	Colorectum	MSS	Regulation of actin cytoskeleton	68/1875	229/8465	4.27e-03	1.86e-02	1.14e-02	68
hsa048105	Colorectum	MSS	Regulation of actin cytoskeleton	68/1875	229/8465	4.27e-03	1.86e-02	1.14e-02	68

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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
LAMA2	ITGA6_ITGB4	LAMA2_ITGA6_ITGB4	LAMININ	Breast	DCIS
LAMA3	ITGA6_ITGB4	LAMA3_ITGA6_ITGB4	LAMININ	Breast	DCIS
LAMA4	ITGA6_ITGB4	LAMA4_ITGA6_ITGB4	LAMININ	Breast	DCIS
LAMB1	ITGA6_ITGB4	LAMB1_ITGA6_ITGB4	LAMININ	Breast	DCIS
LAMB2	ITGA6_ITGB4	LAMB2_ITGA6_ITGB4	LAMININ	Breast	DCIS
LAMC1	ITGA6_ITGB4	LAMC1_ITGA6_ITGB4	LAMININ	Breast	DCIS
IGF1	ITGA6_ITGB4	IGF1_ITGA6_ITGB4	IGF	Breast	DCIS
LAMA2	ITGA6_ITGB4	LAMA2_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMA3	ITGA6_ITGB4	LAMA3_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMA4	ITGA6_ITGB4	LAMA4_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMA5	ITGA6_ITGB4	LAMA5_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMB1	ITGA6_ITGB4	LAMB1_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMB2	ITGA6_ITGB4	LAMB2_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMB3	ITGA6_ITGB4	LAMB3_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMC1	ITGA6_ITGB4	LAMC1_ITGA6_ITGB4	LAMININ	Cervix	ADJ
LAMC2	ITGA6_ITGB4	LAMC2_ITGA6_ITGB4	LAMININ	Cervix	ADJ
IGF1	ITGA6_ITGB4	IGF1_ITGA6_ITGB4	IGF	Cervix	ADJ
LAMA2	ITGA6_ITGB4	LAMA2_ITGA6_ITGB4	LAMININ	Cervix	CC
LAMA3	ITGA6_ITGB4	LAMA3_ITGA6_ITGB4	LAMININ	Cervix	CC
LAMA4	ITGA6_ITGB4	LAMA4_ITGA6_ITGB4	LAMININ	Cervix	CC

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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

ITGB4

SNV

Missense_Mutation

rs756270166

c.5071C>T

p.Arg1691Trp

p.R1691W

P16144

protein_coding

tolerated(0.17)

possibly_damaging(0.697)

TCGA-A2-A3XY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

ITGB4

SNV

Missense_Mutation

novel

c.1447N>C

p.Glu483Gln

p.E483Q

P16144

protein_coding

tolerated(0.15)

possibly_damaging(0.706)

TCGA-A8-A09M-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

paclitaxel

ITGB4

SNV

Missense_Mutation

c.2795T>A

p.Met932Lys

p.M932K

P16144

protein_coding

deleterious(0)

possibly_damaging(0.48)

TCGA-AN-A04D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ITGB4

SNV

Missense_Mutation

c.2795N>G

p.Met932Arg

p.M932R

P16144

protein_coding

deleterious(0)

possibly_damaging(0.68)

TCGA-AN-A0FN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ITGB4

SNV

Missense_Mutation

novel

c.2522N>A

p.Ala841Asp

p.A841D

P16144

protein_coding

tolerated(0.66)

benign(0)

TCGA-AN-A0XN-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

ITGB4

SNV

Missense_Mutation

c.2590N>G

p.Leu864Val

p.L864V

P16144

protein_coding

tolerated(0.66)

benign(0.003)

TCGA-AO-A0JD-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

ITGB4

SNV

Missense_Mutation

rs201487753

c.3230G>A

p.Arg1077His

p.R1077H

P16144

protein_coding

deleterious(0.01)

probably_damaging(0.952)

TCGA-BH-A0AU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ITGB4

SNV

Missense_Mutation

novel

c.1148N>T

p.Thr383Ile

p.T383I

P16144

protein_coding

tolerated(0.14)

possibly_damaging(0.797)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ITGB4

SNV

Missense_Mutation

novel

c.168N>A

p.Phe56Leu

p.F56L

P16144

protein_coding

deleterious(0.01)

probably_damaging(0.978)

TCGA-D8-A1JA-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

ITGB4

SNV

Missense_Mutation

c.4019G>A

p.Gly1340Glu

p.G1340E

P16144

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-E2-A1AZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

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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

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