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: ITGA4

Gene summary for ITGA4

Gene summary.

Gene information	Species	Human
	Gene symbol	ITGA4
	Gene ID	3676
	Gene name	integrin subunit alpha 4
	Gene Alias	CD49D
	Cytomap	2q31.3
	Gene Type	protein-coding
	GO ID	GO:0000902
	UniProtAcc	P13612

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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
3676	ITGA4	047563_1562-all-cells	Human	Prostate	BPH	1.07e-04	2.54e-01	0.0791
3676	ITGA4	GSM5353216_PA_PB1A_Pool_1_3_S50_L002	Human	Prostate	Tumor	3.69e-02	5.60e-01	0.159
3676	ITGA4	GSM5353218_PA_PB1B_Pool_1_2_S74_L003	Human	Prostate	Tumor	8.09e-05	6.74e-01	0.1479
3676	ITGA4	GSM5353220_PA_PB1B_Pool_3_S51_L002	Human	Prostate	Tumor	1.07e-05	7.64e-01	0.1531

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Prostate		BPH: Benign Prostatic Hyperplasia

∗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:005109818	Prostate	BPH	regulation of binding	121/3107	363/18723	2.74e-15	4.14e-13	121
GO:001604910	Prostate	BPH	cell growth	139/3107	482/18723	7.53e-12	5.90e-10	139
GO:007149618	Prostate	BPH	cellular response to external stimulus	102/3107	320/18723	8.99e-12	6.79e-10	102
GO:003158910	Prostate	BPH	cell-substrate adhesion	110/3107	363/18723	4.64e-11	2.96e-09	110
GO:003166817	Prostate	BPH	cellular response to extracellular stimulus	79/3107	246/18723	1.32e-09	5.69e-08	79
GO:190165310	Prostate	BPH	cellular response to peptide	104/3107	359/18723	2.51e-09	1.00e-07	104
GO:004578518	Prostate	BPH	positive regulation of cell adhesion	120/3107	437/18723	5.22e-09	1.90e-07	120
GO:000166717	Prostate	BPH	ameboidal-type cell migration	128/3107	475/18723	5.69e-09	2.05e-07	128
GO:003444616	Prostate	BPH	substrate adhesion-dependent cell spreading	43/3107	108/18723	7.20e-09	2.50e-07	43
GO:00516569	Prostate	BPH	establishment of organelle localization	107/3107	390/18723	3.67e-08	1.03e-06	107
GO:000716010	Prostate	BPH	cell-matrix adhesion	72/3107	233/18723	4.17e-08	1.16e-06	72
GO:00506739	Prostate	BPH	epithelial cell proliferation	116/3107	437/18723	7.12e-08	1.85e-06	116
GO:00506789	Prostate	BPH	regulation of epithelial cell proliferation	104/3107	381/18723	7.52e-08	1.92e-06	104
GO:004339316	Prostate	BPH	regulation of protein binding	60/3107	196/18723	7.72e-07	1.45e-05	60
GO:005110017	Prostate	BPH	negative regulation of binding	52/3107	162/18723	8.41e-07	1.56e-05	52
GO:00072297	Prostate	BPH	integrin-mediated signaling pathway	37/3107	107/18723	4.53e-06	6.76e-05	37
GO:00516508	Prostate	BPH	establishment of vesicle localization	49/3107	161/18723	9.12e-06	1.28e-04	49
GO:002240716	Prostate	BPH	regulation of cell-cell adhesion	109/3107	448/18723	1.43e-05	1.85e-04	109
GO:00074924	Prostate	BPH	endoderm development	28/3107	77/18723	2.21e-05	2.67e-04	28
GO:00068989	Prostate	BPH	receptor-mediated endocytosis	66/3107	244/18723	2.34e-05	2.80e-04	66

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0451017	Prostate	BPH	Focal adhesion	85/1718	203/8465	1.17e-12	2.28e-11	1.41e-11	85
hsa051658	Prostate	BPH	Human papillomavirus infection	111/1718	331/8465	6.15e-09	7.81e-08	4.83e-08	111
hsa0481020	Prostate	BPH	Regulation of actin cytoskeleton	80/1718	229/8465	1.23e-07	1.31e-06	8.10e-07	80
hsa0513518	Prostate	BPH	Yersinia infection	49/1718	137/8465	1.65e-05	1.27e-04	7.86e-05	49
hsa041515	Prostate	BPH	PI3K-Akt signaling pathway	104/1718	354/8465	2.07e-05	1.55e-04	9.61e-05	104
hsa0467028	Prostate	BPH	Leukocyte transendothelial migration	41/1718	114/8465	6.86e-05	4.35e-04	2.69e-04	41
hsa045125	Prostate	BPH	ECM-receptor interaction	28/1718	89/8465	8.33e-03	2.64e-02	1.64e-02	28
hsa0514016	Prostate	BPH	Leishmaniasis	24/1718	77/8465	1.57e-02	4.42e-02	2.73e-02	24
hsa0451018	Prostate	BPH	Focal adhesion	85/1718	203/8465	1.17e-12	2.28e-11	1.41e-11	85
hsa0516513	Prostate	BPH	Human papillomavirus infection	111/1718	331/8465	6.15e-09	7.81e-08	4.83e-08	111
hsa04810110	Prostate	BPH	Regulation of actin cytoskeleton	80/1718	229/8465	1.23e-07	1.31e-06	8.10e-07	80
hsa0513519	Prostate	BPH	Yersinia infection	49/1718	137/8465	1.65e-05	1.27e-04	7.86e-05	49
hsa0415112	Prostate	BPH	PI3K-Akt signaling pathway	104/1718	354/8465	2.07e-05	1.55e-04	9.61e-05	104
hsa04670112	Prostate	BPH	Leukocyte transendothelial migration	41/1718	114/8465	6.86e-05	4.35e-04	2.69e-04	41
hsa0451212	Prostate	BPH	ECM-receptor interaction	28/1718	89/8465	8.33e-03	2.64e-02	1.64e-02	28
hsa0514017	Prostate	BPH	Leishmaniasis	24/1718	77/8465	1.57e-02	4.42e-02	2.73e-02	24
hsa0451025	Prostate	Tumor	Focal adhesion	84/1791	203/8465	3.44e-11	6.69e-10	4.15e-10	84
hsa0481025	Prostate	Tumor	Regulation of actin cytoskeleton	84/1791	229/8465	3.40e-08	4.17e-07	2.58e-07	84
hsa0516522	Prostate	Tumor	Human papillomavirus infection	110/1791	331/8465	1.31e-07	1.51e-06	9.36e-07	110
hsa0415122	Prostate	Tumor	PI3K-Akt signaling pathway	105/1791	354/8465	7.42e-05	5.30e-04	3.28e-04	105

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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
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Breast	ADJ
FN1	ITGA4_ITGB1	FN1_ITGA4_ITGB1	FN1	Breast	ADJ
SPP1	ITGA4_ITGB1	SPP1_ITGA4_ITGB1	SPP1	Breast	DCIS
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Breast	DCIS
FN1	ITGA4_ITGB1	FN1_ITGA4_ITGB1	FN1	Breast	DCIS
FN1	ITGA4_ITGB7	FN1_ITGA4_ITGB7	FN1	Breast	DCIS
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Breast	Healthy
FN1	ITGA4_ITGB1	FN1_ITGA4_ITGB1	FN1	Breast	Healthy
FN1	ITGA4_ITGB7	FN1_ITGA4_ITGB7	FN1	Breast	Healthy
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Cervix	ADJ
FN1	ITGA4_ITGB1	FN1_ITGA4_ITGB1	FN1	Cervix	ADJ
FN1	ITGA4_ITGB7	FN1_ITGA4_ITGB7	FN1	Cervix	ADJ
FN1	ITGA4_ITGB1	FN1_ITGA4_ITGB1	FN1	Cervix	CC
SPP1	ITGA4_ITGB1	SPP1_ITGA4_ITGB1	SPP1	Cervix	CC
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Cervix	CC
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Cervix	Healthy
FN1	ITGA4_ITGB1	FN1_ITGA4_ITGB1	FN1	Cervix	Healthy
SPP1	ITGA4_ITGB1	SPP1_ITGA4_ITGB1	SPP1	Cervix	Healthy
SPP1	ITGA4_ITGB1	SPP1_ITGA4_ITGB1	SPP1	Cervix	Precancer
MDK	ITGA4_ITGB1	MDK_ITGA4_ITGB1	MK	Cervix	Precancer

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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

ITGA4

SNV

Missense_Mutation

c.421A>G

p.Ile141Val

p.I141V

P13612

protein_coding

tolerated(0.62)

benign(0.018)

TCGA-A2-A1G4-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

adriamycin

ITGA4

SNV

Missense_Mutation

rs760310901

c.1934N>G

p.Asn645Ser

p.N645S

P13612

protein_coding

tolerated(0.48)

benign(0.077)

TCGA-A8-A081-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ITGA4

SNV

Missense_Mutation

novel

c.1641N>A

p.Ser547Arg

p.S547R

P13612

protein_coding

tolerated(0.55)

benign(0.034)

TCGA-AC-A3QQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ITGA4

SNV

Missense_Mutation

c.2881N>T

p.His961Tyr

p.H961Y

P13612

protein_coding

tolerated(1)

benign(0)

TCGA-AN-A0FZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

ITGA4

SNV

Missense_Mutation

novel

c.1660N>A

p.Glu554Lys

p.E554K

P13612

protein_coding

tolerated(0.9)

benign(0)

TCGA-E2-A1B1-01

Breast

breast invasive carcinoma

Female

<65

I/II

Other, specify in notesbiphosphonate

zoledronic

ITGA4

insertion

Frame_Shift_Ins

novel

c.1639_1640insATAATATCTG

p.Ser547AsnfsTer13

p.S547Nfs*13

P13612

protein_coding

TCGA-AC-A3QQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ITGA4

insertion

Frame_Shift_Ins

novel

c.183_184insG

p.Ala63GlyfsTer46

p.A63Gfs*46

P13612

protein_coding

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ITGA4

deletion

Frame_Shift_Del

novel

c.1907delA

p.Lys636ArgfsTer5

p.K636Rfs*5

P13612

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ITGA4

SNV

Missense_Mutation

novel

c.1364C>A

p.Ser455Tyr

p.S455Y

P13612

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-C5-A1MN-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

ITGA4

SNV

Missense_Mutation

c.1370N>T

p.Ser457Phe

p.S457F

P13612

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-C5-A2LX-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		Vedolizmab
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		PTG-100
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		VEDOLIZUMAB	VEDOLIZUMAB
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME	inhibitor	CHEMBL1743087	VEDOLIZUMAB
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		NATALIZUMAB	NATALIZUMAB
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME	antibody	178103204	NATALIZUMAB
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		FIRATEGRAST	FIRATEGRAST
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		ATL1102
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		NATALIZUMAB	NATALIZUMAB
3676	ITGA4	EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME	antagonist	CHEMBL2104967	FIRATEGRAST

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