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: TBX3

Gene summary for TBX3

Gene summary.

Gene information	Species	Human
	Gene symbol	TBX3
	Gene ID	6926
	Gene name	T-box transcription factor 3
	Gene Alias	TBX3-ISO
	Cytomap	12q24.21
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A024RBQ4

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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
6926	TBX3	HTA11_1391_2000001011	Human	Colorectum	AD	3.20e-04	4.17e-01	-0.059
6926	TBX3	HTA11_866_3004761011	Human	Colorectum	AD	8.09e-08	3.59e-01	0.096
6926	TBX3	HTA11_7696_3000711011	Human	Colorectum	AD	1.06e-09	3.39e-01	0.0674
6926	TBX3	HTA11_99999970781_79442	Human	Colorectum	MSS	2.04e-29	6.06e-01	0.294
6926	TBX3	HTA11_99999971662_82457	Human	Colorectum	MSS	2.00e-05	2.27e-01	0.3859
6926	TBX3	A002-C-010	Human	Colorectum	FAP	3.54e-06	4.34e-01	0.242
6926	TBX3	A001-C-207	Human	Colorectum	FAP	9.07e-08	5.93e-01	0.1278
6926	TBX3	A015-C-203	Human	Colorectum	FAP	3.08e-15	6.13e-01	-0.1294
6926	TBX3	A002-C-201	Human	Colorectum	FAP	9.26e-06	4.85e-01	0.0324
6926	TBX3	A002-C-203	Human	Colorectum	FAP	1.43e-09	4.66e-01	0.2786
6926	TBX3	A001-C-108	Human	Colorectum	FAP	8.11e-08	4.46e-01	-0.0272
6926	TBX3	A002-C-021	Human	Colorectum	FAP	2.61e-25	6.14e-01	0.1171
6926	TBX3	A001-C-104	Human	Colorectum	FAP	9.17e-17	5.19e-01	0.0184
6926	TBX3	A015-C-106	Human	Colorectum	FAP	1.81e-11	5.69e-01	-0.0511
6926	TBX3	A015-C-104	Human	Colorectum	FAP	7.09e-10	4.87e-01	-0.1899
6926	TBX3	A001-C-014	Human	Colorectum	FAP	2.29e-08	4.95e-01	0.0135
6926	TBX3	A014-C-008	Human	Colorectum	FAP	1.16e-04	5.31e-01	-0.191
6926	TBX3	A018-E-020	Human	Colorectum	FAP	4.02e-02	3.79e-01	-0.2034
6926	TBX3	F072B	Human	Colorectum	FAP	1.06e-02	3.11e-01	0.257
6926	TBX3	AEH-subject1	Human	Endometrium	AEH	1.22e-10	-4.04e-01	-0.3059

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Prostate		BPH: Benign Prostatic Hyperplasia
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:0048732	Colorectum	AD	gland development	149/3918	436/18723	6.07e-11	6.33e-09	149
GO:0030879	Colorectum	AD	mammary gland development	53/3918	137/18723	1.46e-06	4.58e-05	53
GO:0001701	Colorectum	AD	in utero embryonic development	110/3918	367/18723	2.36e-05	4.62e-04	110
GO:0061180	Colorectum	AD	mammary gland epithelium development	28/3918	67/18723	8.74e-05	1.35e-03	28
GO:0022612	Colorectum	AD	gland morphogenesis	42/3918	118/18723	1.62e-04	2.23e-03	42
GO:0007568	Colorectum	AD	aging	98/3918	339/18723	2.77e-04	3.39e-03	98
GO:0060562	Colorectum	AD	epithelial tube morphogenesis	93/3918	325/18723	5.65e-04	6.00e-03	93
GO:0061458	Colorectum	AD	reproductive system development	116/3918	427/18723	1.11e-03	1.01e-02	116
GO:0060443	Colorectum	AD	mammary gland morphogenesis	18/3918	43/18723	1.51e-03	1.27e-02	18
GO:0048608	Colorectum	AD	reproductive structure development	114/3918	424/18723	1.78e-03	1.47e-02	114
GO:0048736	Colorectum	AD	appendage development	51/3918	172/18723	4.20e-03	2.89e-02	51
GO:0060173	Colorectum	AD	limb development	51/3918	172/18723	4.20e-03	2.89e-02	51
GO:0048568	Colorectum	AD	embryonic organ development	112/3918	427/18723	4.60e-03	3.14e-02	112
GO:0045787	Colorectum	AD	positive regulation of cell cycle	85/3918	313/18723	4.76e-03	3.22e-02	85
GO:0001763	Colorectum	AD	morphogenesis of a branching structure	56/3918	196/18723	6.60e-03	4.09e-02	56
GO:00487322	Colorectum	MSS	gland development	143/3467	436/18723	3.85e-13	8.01e-11	143
GO:00308792	Colorectum	MSS	mammary gland development	51/3467	137/18723	1.88e-07	8.26e-06	51
GO:00611802	Colorectum	MSS	mammary gland epithelium development	28/3467	67/18723	8.47e-06	2.11e-04	28
GO:00614582	Colorectum	MSS	reproductive system development	115/3467	427/18723	9.86e-06	2.39e-04	115
GO:00486082	Colorectum	MSS	reproductive structure development	113/3467	424/18723	1.94e-05	4.18e-04	113

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
TBX3	TRANS	Cervix	Healthy	DSG1,PRRX1,PITX1, etc.	2.21e-01
TBX3	ECM	Cervix	ADJ	PDGFRA,SSPN,RND3, etc.	2.79e-01
TBX3	INCAF	Cervix	ADJ	PDGFRA,SSPN,RND3, etc.	1.18e-01
TBX3	INCAF	Cervix	Healthy	PDGFRA,SSPN,RND3, etc.	2.09e-01
TBX3	STM	Colorectum	FAP	CEMIP,SELENBP1,NKD1, etc.	1.77e-01
TBX3	GLIA	Colorectum	ADJ	LINC01091,UGCG,LRRC59, etc.	1.01e-01
TBX3	CFIB	Colorectum	CRC	LINC01091,UGCG,LRRC59, etc.	9.77e-02
TBX3	GLIA	Colorectum	FAP	LINC01091,UGCG,LRRC59, etc.	7.88e-02
TBX3	GLIA	Colorectum	Healthy	LINC01091,UGCG,LRRC59, etc.	4.10e-01
TBX3	SURF	Endometrium	EEC	VIM,PHLDA1,AKAP12, etc.	3.60e-01

∗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

TBX3

SNV

Missense_Mutation

c.400C>T

p.Pro134Ser

p.P134S

O15119

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A25A-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Cytoxan

TBX3

SNV

Missense_Mutation

rs756408358

c.632A>C

p.Asn211Thr

p.N211T

O15119

protein_coding

deleterious(0)

probably_damaging(0.987)

TCGA-A8-A08C-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

5-fluorouracil

TBX3

SNV

Missense_Mutation

novel

c.2158N>A

p.Glu720Lys

p.E720K

O15119

protein_coding

deleterious(0)

probably_damaging(0.972)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TBX3

SNV

Missense_Mutation

c.1949C>T

p.Pro650Leu

p.P650L

O15119

protein_coding

deleterious(0)

benign(0)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

TBX3

SNV

Missense_Mutation

novel

c.477N>G

p.Asp159Glu

p.D159E

O15119

protein_coding

deleterious(0)

probably_damaging(0.981)

TCGA-AQ-A7U7-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Targeted Molecular therapy

rituximab

TBX3

SNV

Missense_Mutation

rs767500073

c.1693N>A

p.Ala565Thr

p.A565T

O15119

protein_coding

tolerated(0.21)

benign(0.003)

TCGA-AR-A2LR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

TBX3

SNV

Missense_Mutation

novel

c.559C>T

p.His187Tyr

p.H187Y

O15119

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-BH-A0HQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

TBX3

SNV

Missense_Mutation

novel

c.559N>T

p.His187Tyr

p.H187Y

O15119

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-D8-A1X6-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

TBX3

SNV

Missense_Mutation

c.1088C>G

p.Ser363Trp

p.S363W

O15119

protein_coding

deleterious(0)

probably_damaging(0.975)

TCGA-E2-A15M-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

TBX3

SNV

Missense_Mutation

c.337N>C

p.Trp113Arg

p.W113R

O15119

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-E2-A1IF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

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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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