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	CA_HPV_1	Human	Cervix	CC	1.09e-12	-3.88e-01	0.0264
3691	ITGB4	CA_HPV_3	Human	Cervix	CC	3.22e-03	3.06e-02	0.0414
3691	ITGB4	HSIL_HPV_1	Human	Cervix	HSIL_HPV	5.84e-04	-2.94e-01	0.0116
3691	ITGB4	N_HPV_1	Human	Cervix	N_HPV	3.30e-02	-2.72e-01	0.0079
3691	ITGB4	CCII_1	Human	Cervix	CC	8.34e-31	1.25e+00	0.3249
3691	ITGB4	Tumor	Human	Cervix	CC	1.51e-12	4.34e-01	0.1241
3691	ITGB4	sample3	Human	Cervix	CC	1.45e-27	6.04e-01	0.1387
3691	ITGB4	T1	Human	Cervix	CC	4.65e-05	3.86e-01	0.0918
3691	ITGB4	T3	Human	Cervix	CC	5.10e-24	5.79e-01	0.1389
3691	ITGB4	HTA11_3410_2000001011	Human	Colorectum	AD	1.55e-08	3.65e-01	0.0155
3691	ITGB4	HTA11_2487_2000001011	Human	Colorectum	SER	2.26e-23	1.17e+00	-0.1808
3691	ITGB4	HTA11_2951_2000001011	Human	Colorectum	AD	5.97e-05	8.07e-01	0.0216
3691	ITGB4	HTA11_1938_2000001011	Human	Colorectum	AD	1.12e-23	1.14e+00	-0.0811
3691	ITGB4	HTA11_78_2000001011	Human	Colorectum	AD	8.23e-10	7.13e-01	-0.1088
3691	ITGB4	HTA11_347_2000001011	Human	Colorectum	AD	3.50e-28	7.81e-01	-0.1954
3691	ITGB4	HTA11_411_2000001011	Human	Colorectum	SER	2.33e-12	1.77e+00	-0.2602
3691	ITGB4	HTA11_2112_2000001011	Human	Colorectum	SER	2.59e-08	1.18e+00	-0.2196
3691	ITGB4	HTA11_3361_2000001011	Human	Colorectum	AD	9.64e-12	6.63e-01	-0.1207
3691	ITGB4	HTA11_83_2000001011	Human	Colorectum	SER	1.66e-07	5.78e-01	-0.1526
3691	ITGB4	HTA11_696_2000001011	Human	Colorectum	AD	5.74e-30	9.24e-01	-0.1464

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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:00420631	Liver	HCC	gliogenesis	148/7958	301/18723	1.10e-02	4.07e-02	148
GO:000166721	Liver	HCC	ameboidal-type cell migration	226/7958	475/18723	1.35e-02	4.81e-02	226
GO:00070447	Lung	IAC	cell-substrate junction assembly	36/2061	95/18723	6.81e-12	4.27e-09	36
GO:00071607	Lung	IAC	cell-matrix adhesion	63/2061	233/18723	7.08e-12	4.27e-09	63
GO:00315897	Lung	IAC	cell-substrate adhesion	85/2061	363/18723	8.57e-12	4.27e-09	85
GO:01501157	Lung	IAC	cell-substrate junction organization	36/2061	101/18723	5.37e-11	1.52e-08	36
GO:00343297	Lung	IAC	cell junction assembly	86/2061	420/18723	7.98e-09	1.10e-06	86
GO:00072294	Lung	IAC	integrin-mediated signaling pathway	28/2061	107/18723	9.18e-06	3.06e-04	28
GO:00016677	Lung	IAC	ameboidal-type cell migration	80/2061	475/18723	6.90e-05	1.47e-03	80
GO:00435882	Lung	IAC	skin development	49/2061	263/18723	1.56e-04	2.82e-03	49
GO:0043589	Lung	IAC	skin morphogenesis	6/2061	11/18723	4.99e-04	7.25e-03	6
GO:0033627	Lung	IAC	cell adhesion mediated by integrin	18/2061	72/18723	6.34e-04	8.68e-03	18
GO:0010927	Lung	IAC	cellular component assembly involved in morphogenesis	21/2061	107/18723	5.98e-03	4.33e-02	21
GO:0046847	Lung	IAC	filopodium assembly	14/2061	62/18723	6.56e-03	4.60e-02	14
GO:000716012	Lung	AIS	cell-matrix adhesion	60/1849	233/18723	2.19e-12	2.55e-09	60
GO:003158913	Lung	AIS	cell-substrate adhesion	80/1849	363/18723	3.80e-12	3.16e-09	80
GO:000704413	Lung	AIS	cell-substrate junction assembly	34/1849	95/18723	8.17e-12	5.29e-09	34
GO:015011513	Lung	AIS	cell-substrate junction organization	34/1849	101/18723	5.74e-11	2.09e-08	34
GO:003432912	Lung	AIS	cell junction assembly	84/1849	420/18723	2.16e-10	5.71e-08	84
GO:000722912	Lung	AIS	integrin-mediated signaling pathway	28/1849	107/18723	1.11e-06	7.51e-05	28

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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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