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: VEGFB

Gene summary for VEGFB

Gene summary.

Gene information	Species	Human
	Gene symbol	VEGFB
	Gene ID	7423
	Gene name	vascular endothelial growth factor B
	Gene Alias	VEGFL
	Cytomap	11q13.1
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	P49765

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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
7423	VEGFB	LZE24T	Human	Esophagus	ESCC	1.17e-06	2.39e-01	0.0596
7423	VEGFB	P1T-E	Human	Esophagus	ESCC	4.22e-02	2.03e-01	0.0875
7423	VEGFB	P2T-E	Human	Esophagus	ESCC	1.32e-03	-1.08e-02	0.1177
7423	VEGFB	P4T-E	Human	Esophagus	ESCC	7.11e-12	3.22e-01	0.1323
7423	VEGFB	P5T-E	Human	Esophagus	ESCC	1.15e-12	1.90e-01	0.1327
7423	VEGFB	P8T-E	Human	Esophagus	ESCC	7.00e-09	9.51e-02	0.0889
7423	VEGFB	P9T-E	Human	Esophagus	ESCC	3.07e-04	1.12e-01	0.1131
7423	VEGFB	P10T-E	Human	Esophagus	ESCC	1.68e-06	3.22e-02	0.116
7423	VEGFB	P12T-E	Human	Esophagus	ESCC	7.39e-07	7.19e-02	0.1122
7423	VEGFB	P15T-E	Human	Esophagus	ESCC	1.24e-02	-3.47e-02	0.1149
7423	VEGFB	P16T-E	Human	Esophagus	ESCC	2.22e-05	8.49e-03	0.1153
7423	VEGFB	P17T-E	Human	Esophagus	ESCC	2.62e-05	2.34e-01	0.1278
7423	VEGFB	P21T-E	Human	Esophagus	ESCC	1.01e-06	2.03e-01	0.1617
7423	VEGFB	P22T-E	Human	Esophagus	ESCC	2.86e-06	3.49e-02	0.1236
7423	VEGFB	P23T-E	Human	Esophagus	ESCC	9.89e-07	1.60e-01	0.108
7423	VEGFB	P24T-E	Human	Esophagus	ESCC	8.22e-03	-1.06e-02	0.1287
7423	VEGFB	P26T-E	Human	Esophagus	ESCC	1.65e-07	3.07e-02	0.1276
7423	VEGFB	P27T-E	Human	Esophagus	ESCC	1.41e-05	1.97e-02	0.1055
7423	VEGFB	P28T-E	Human	Esophagus	ESCC	6.49e-10	2.38e-01	0.1149
7423	VEGFB	P31T-E	Human	Esophagus	ESCC	1.61e-17	8.70e-02	0.1251

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
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:0070482111	Esophagus	ESCC	response to oxygen levels	218/8552	347/18723	6.91e-11	2.17e-09	218
GO:0036293111	Esophagus	ESCC	response to decreased oxygen levels	201/8552	322/18723	8.37e-10	2.04e-08	201
GO:0001666111	Esophagus	ESCC	response to hypoxia	192/8552	307/18723	1.59e-09	3.69e-08	192
GO:00091002	Esophagus	ESCC	glycoprotein metabolic process	226/8552	387/18723	2.64e-07	3.94e-06	226
GO:00700854	Esophagus	ESCC	glycosylation	144/8552	240/18723	5.12e-06	5.38e-05	144
GO:00064865	Esophagus	ESCC	protein glycosylation	135/8552	226/18723	1.36e-05	1.24e-04	135
GO:00434135	Esophagus	ESCC	macromolecule glycosylation	135/8552	226/18723	1.36e-05	1.24e-04	135
GO:00091012	Esophagus	ESCC	glycoprotein biosynthetic process	181/8552	317/18723	2.54e-05	2.15e-04	181
GO:000941020	Esophagus	ESCC	response to xenobiotic stimulus	253/8552	462/18723	4.55e-05	3.58e-04	253
GO:005067318	Esophagus	ESCC	epithelial cell proliferation	238/8552	437/18723	1.19e-04	8.20e-04	238
GO:005067817	Esophagus	ESCC	regulation of epithelial cell proliferation	206/8552	381/18723	5.51e-04	3.02e-03	206
GO:000268515	Esophagus	ESCC	regulation of leukocyte migration	114/8552	210/18723	7.26e-03	2.63e-02	114
GO:00064931	Esophagus	ESCC	protein O-linked glycosylation	51/8552	86/18723	7.54e-03	2.70e-02	51
GO:00513025	Esophagus	ESCC	regulation of cell division	97/8552	177/18723	8.93e-03	3.12e-02	97
GO:007048219	Oral cavity	OSCC	response to oxygen levels	200/7305	347/18723	1.17e-12	5.13e-11	200
GO:000166619	Oral cavity	OSCC	response to hypoxia	177/7305	307/18723	2.21e-11	7.50e-10	177
GO:003629319	Oral cavity	OSCC	response to decreased oxygen levels	182/7305	322/18723	1.14e-10	3.41e-09	182
GO:000268714	Oral cavity	OSCC	positive regulation of leukocyte migration	78/7305	135/18723	7.43e-06	8.08e-05	78
GO:005067310	Oral cavity	OSCC	epithelial cell proliferation	212/7305	437/18723	2.82e-05	2.61e-04	212
GO:000941018	Oral cavity	OSCC	response to xenobiotic stimulus	222/7305	462/18723	4.00e-05	3.48e-04	222

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0493310	Esophagus	ESCC	AGE-RAGE signaling pathway in diabetic complications	72/4205	100/8465	4.15e-06	2.28e-05	1.17e-05	72
hsa0451020	Esophagus	ESCC	Focal adhesion	127/4205	203/8465	1.25e-04	4.99e-04	2.56e-04	127
hsa049268	Esophagus	ESCC	Relaxin signaling pathway	81/4205	129/8465	1.72e-03	5.09e-03	2.61e-03	81
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0493317	Esophagus	ESCC	AGE-RAGE signaling pathway in diabetic complications	72/4205	100/8465	4.15e-06	2.28e-05	1.17e-05	72
hsa04510111	Esophagus	ESCC	Focal adhesion	127/4205	203/8465	1.25e-04	4.99e-04	2.56e-04	127
hsa0492616	Esophagus	ESCC	Relaxin signaling pathway	81/4205	129/8465	1.72e-03	5.09e-03	2.61e-03	81
hsa0415114	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0451019	Oral cavity	OSCC	Focal adhesion	128/3704	203/8465	1.71e-08	1.63e-07	8.31e-08	128
hsa049339	Oral cavity	OSCC	AGE-RAGE signaling pathway in diabetic complications	69/3704	100/8465	2.61e-07	1.65e-06	8.41e-07	69
hsa0401014	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa041516	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa049267	Oral cavity	OSCC	Relaxin signaling pathway	74/3704	129/8465	1.20e-03	3.37e-03	1.72e-03	74
hsa0401518	Oral cavity	OSCC	Rap1 signaling pathway	107/3704	210/8465	2.01e-02	4.34e-02	2.21e-02	107
hsa04510110	Oral cavity	OSCC	Focal adhesion	128/3704	203/8465	1.71e-08	1.63e-07	8.31e-08	128
hsa0493316	Oral cavity	OSCC	AGE-RAGE signaling pathway in diabetic complications	69/3704	100/8465	2.61e-07	1.65e-06	8.41e-07	69
hsa0401015	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa0415113	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa0492615	Oral cavity	OSCC	Relaxin signaling pathway	74/3704	129/8465	1.20e-03	3.37e-03	1.72e-03	74
hsa0401519	Oral cavity	OSCC	Rap1 signaling pathway	107/3704	210/8465	2.01e-02	4.34e-02	2.21e-02	107

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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
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Breast	DCIS
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Breast	Healthy
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Cervix	ADJ
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Cervix	CC
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Cervix	Healthy
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Cervix	Precancer
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	CRC	AD
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	CRC	MSI-H
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Endometrium	ADJ
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Endometrium	AEH
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Endometrium	EEC
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Endometrium	Healthy
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	HNSCC	ADJ
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	HNSCC	Healthy
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	HNSCC	OSCC
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	HNSCC	Precancer
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Lung	AAH
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Lung	ADJ
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Lung	AIS
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Lung	IAC

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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

VEGFB

SNV

Missense_Mutation

novel

c.385N>C

p.Lys129Gln

p.K129Q

P49765

protein_coding

tolerated(0.26)

benign(0.023)

TCGA-OL-A66O-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

VEGFB

SNV

Missense_Mutation

novel

c.406G>A

p.Asp136Asn

p.D136N

P49765

protein_coding

tolerated(0.12)

benign(0.395)

TCGA-Q1-A73P-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

VEGFB

SNV

Missense_Mutation

novel

c.323N>A

p.Ser108Asn

p.S108N

P49765

protein_coding

tolerated(0.17)

possibly_damaging(0.587)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

VEGFB

SNV

Missense_Mutation

novel

c.364N>C

p.Cys122Arg

p.C122R

P49765

protein_coding

deleterious(0)

probably_damaging(0.959)

TCGA-A5-A1OF-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

VEGFB

SNV

Missense_Mutation

rs753557187

c.131N>A

p.Arg44His

p.R44H

P49765

protein_coding

deleterious(0.01)

probably_damaging(0.965)

TCGA-B5-A1MX-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Hormone Therapy

megace

VEGFB

SNV

Missense_Mutation

novel

c.136A>C

p.Thr46Pro

p.T46P

P49765

protein_coding

tolerated(0.2)

possibly_damaging(0.795)

TCGA-BG-A0VZ-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

cisplatin

VEGFB

SNV

Missense_Mutation

rs200892426

c.307N>C

p.Met103Leu

p.M103L

P49765

protein_coding

tolerated(0.07)

benign(0.003)

TCGA-BS-A0UJ-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

VEGFB

SNV

Missense_Mutation

novel

c.257G>T

p.Gly86Val

p.G86V

P49765

protein_coding

deleterious(0.01)

possibly_damaging(0.895)

TCGA-D1-A175-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

paclitaxel

VEGFB

SNV

Missense_Mutation

novel

c.536N>T

p.Ala179Val

p.A179V

P49765

protein_coding

tolerated(0.12)

benign(0.005)

TCGA-D1-A17Q-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

VEGFB

SNV

Missense_Mutation

novel

c.262N>C

p.Glu88Gln

p.E88Q

P49765

protein_coding

tolerated(0.12)

probably_damaging(0.998)

TCGA-EY-A1GS-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

III/IV

Chemotherapy

taxol

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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
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR	inhibitor	CHEMBL2108313	CONBERCEPT
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR		VEGF-2
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR	inhibitor	SORAFENIB TOSYLATE
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR		bevacizumab	BEVACIZUMAB	20124951
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR		BEVACIZUMAB	BEVACIZUMAB
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR	antibody	ZIV-AFLIBERCEPT	AFLIBERCEPT
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR		aflibercept	AFLIBERCEPT	20124951
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR		Aflibercept	AFLIBERCEPT
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR	inhibitor	ENDOSTATIN (84-114)-NH2 (JKC367)
7423	VEGFB	CLINICALLY ACTIONABLE, DRUGGABLE GENOME, GROWTH FACTOR		LENALIDOMIDE	LENALIDOMIDE

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