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: STAT3

Gene summary for STAT3

Gene summary.

Gene information	Species	Human
	Gene symbol	STAT3
	Gene ID	6774
	Gene name	signal transducer and activator of transcription 3
	Gene Alias	ADMIO
	Cytomap	17q21.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P40763

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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
6774	STAT3	CA_HPV_1	Human	Cervix	CC	7.33e-10	-1.83e-01	0.0264
6774	STAT3	N_HPV_1	Human	Cervix	N_HPV	2.41e-02	-9.07e-02	0.0079
6774	STAT3	CCI_2	Human	Cervix	CC	5.81e-10	7.59e-01	0.5249
6774	STAT3	CCII_1	Human	Cervix	CC	4.54e-09	-6.18e-01	0.3249
6774	STAT3	Tumor	Human	Cervix	CC	2.23e-06	-3.55e-01	0.1241
6774	STAT3	sample3	Human	Cervix	CC	1.26e-02	-2.16e-01	0.1387
6774	STAT3	L1	Human	Cervix	CC	3.78e-09	-2.85e-01	0.0802
6774	STAT3	T3	Human	Cervix	CC	3.60e-08	-2.45e-01	0.1389
6774	STAT3	HTA11_1938_2000001011	Human	Colorectum	AD	2.81e-02	4.99e-01	-0.0811
6774	STAT3	HTA11_347_2000001011	Human	Colorectum	AD	2.86e-14	6.84e-01	-0.1954
6774	STAT3	HTA11_696_2000001011	Human	Colorectum	AD	4.43e-06	5.20e-01	-0.1464
6774	STAT3	HTA11_866_2000001011	Human	Colorectum	AD	5.79e-06	5.42e-01	-0.1001
6774	STAT3	HTA11_1391_2000001011	Human	Colorectum	AD	1.50e-12	1.08e+00	-0.059
6774	STAT3	HTA11_866_3004761011	Human	Colorectum	AD	8.85e-10	6.18e-01	0.096
6774	STAT3	HTA11_7696_3000711011	Human	Colorectum	AD	4.40e-02	4.14e-01	0.0674
6774	STAT3	HTA11_99999965104_69814	Human	Colorectum	MSS	3.20e-08	7.39e-01	0.281
6774	STAT3	A015-C-203	Human	Colorectum	FAP	7.21e-24	-3.78e-01	-0.1294
6774	STAT3	A015-C-204	Human	Colorectum	FAP	2.48e-05	-3.51e-01	-0.0228
6774	STAT3	A014-C-040	Human	Colorectum	FAP	4.63e-03	-3.68e-01	-0.1184
6774	STAT3	A002-C-201	Human	Colorectum	FAP	3.09e-08	-7.24e-02	0.0324

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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
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
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:004603410	Cervix	CC	ATP metabolic process	90/2311	277/18723	7.90e-19	2.36e-15	90
GO:005254710	Cervix	CC	regulation of peptidase activity	112/2311	461/18723	6.70e-13	3.08e-10	112
GO:004586210	Cervix	CC	positive regulation of proteolysis	95/2311	372/18723	1.84e-12	6.86e-10	95
GO:005254810	Cervix	CC	regulation of endopeptidase activity	103/2311	432/18723	1.89e-11	5.14e-09	103
GO:00725949	Cervix	CC	establishment of protein localization to organelle	99/2311	422/18723	1.23e-10	2.11e-08	99
GO:00421108	Cervix	CC	T cell activation	107/2311	487/18723	1.24e-09	1.46e-07	107
GO:00506737	Cervix	CC	epithelial cell proliferation	98/2311	437/18723	2.01e-09	2.15e-07	98
GO:00060919	Cervix	CC	generation of precursor metabolites and energy	105/2311	490/18723	7.40e-09	6.61e-07	105
GO:001095210	Cervix	CC	positive regulation of peptidase activity	54/2311	197/18723	8.06e-09	6.99e-07	54
GO:00069139	Cervix	CC	nucleocytoplasmic transport	71/2311	301/18723	4.04e-08	2.54e-06	71
GO:00511699	Cervix	CC	nuclear transport	71/2311	301/18723	4.04e-08	2.54e-06	71
GO:00345048	Cervix	CC	protein localization to nucleus	68/2311	290/18723	9.91e-08	5.25e-06	68
GO:003133010	Cervix	CC	negative regulation of cellular catabolic process	63/2311	262/18723	1.10e-07	5.68e-06	63
GO:001095010	Cervix	CC	positive regulation of endopeptidase activity	48/2311	179/18723	1.12e-07	5.71e-06	48
GO:003009910	Cervix	CC	myeloid cell differentiation	83/2311	381/18723	1.31e-07	6.42e-06	83
GO:00506787	Cervix	CC	regulation of epithelial cell proliferation	83/2311	381/18723	1.31e-07	6.42e-06	83
GO:190370610	Cervix	CC	regulation of hemopoiesis	80/2311	367/18723	2.14e-07	9.55e-06	80
GO:000226210	Cervix	CC	myeloid cell homeostasis	43/2311	157/18723	2.66e-07	1.12e-05	43
GO:00075689	Cervix	CC	aging	75/2311	339/18723	2.75e-07	1.13e-05	75
GO:00091449	Cervix	CC	purine nucleoside triphosphate metabolic process	29/2311	88/18723	3.62e-07	1.45e-05	29

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa054174	Colorectum	MSS	Lipid and atherosclerosis	70/1875	215/8465	2.38e-04	1.81e-03	1.11e-03	70
hsa040664	Colorectum	MSS	HIF-1 signaling pathway	39/1875	109/8465	7.61e-04	5.00e-03	3.06e-03	39
hsa04935	Colorectum	MSS	Growth hormone synthesis, secretion and action	42/1875	120/8465	8.17e-04	5.16e-03	3.16e-03	42
hsa052054	Colorectum	MSS	Proteoglycans in cancer	65/1875	205/8465	8.66e-04	5.38e-03	3.29e-03	65
hsa051602	Colorectum	MSS	Hepatitis C	52/1875	157/8465	9.29e-04	5.58e-03	3.42e-03	52
hsa05169	Colorectum	MSS	Epstein-Barr virus infection	63/1875	202/8465	1.63e-03	8.98e-03	5.50e-03	63
hsa05167	Colorectum	MSS	Kaposi sarcoma-associated herpesvirus infection	60/1875	194/8465	2.59e-03	1.27e-02	7.81e-03	60
hsa04931	Colorectum	MSS	Insulin resistance	36/1875	108/8465	4.74e-03	2.01e-02	1.23e-02	36
hsa052122	Colorectum	MSS	Pancreatic cancer	26/1875	76/8465	1.04e-02	3.69e-02	2.26e-02	26
hsa05161	Colorectum	MSS	Hepatitis B	48/1875	162/8465	1.53e-02	4.93e-02	3.02e-02	48
hsa051715	Colorectum	MSS	Coronavirus disease - COVID-19	108/1875	232/8465	6.50e-17	1.67e-15	1.03e-15	108
hsa051635	Colorectum	MSS	Human cytomegalovirus infection	74/1875	225/8465	1.12e-04	1.01e-03	6.19e-04	74
hsa054175	Colorectum	MSS	Lipid and atherosclerosis	70/1875	215/8465	2.38e-04	1.81e-03	1.11e-03	70
hsa040665	Colorectum	MSS	HIF-1 signaling pathway	39/1875	109/8465	7.61e-04	5.00e-03	3.06e-03	39
hsa049351	Colorectum	MSS	Growth hormone synthesis, secretion and action	42/1875	120/8465	8.17e-04	5.16e-03	3.16e-03	42
hsa052055	Colorectum	MSS	Proteoglycans in cancer	65/1875	205/8465	8.66e-04	5.38e-03	3.29e-03	65
hsa051603	Colorectum	MSS	Hepatitis C	52/1875	157/8465	9.29e-04	5.58e-03	3.42e-03	52
hsa051691	Colorectum	MSS	Epstein-Barr virus infection	63/1875	202/8465	1.63e-03	8.98e-03	5.50e-03	63
hsa051671	Colorectum	MSS	Kaposi sarcoma-associated herpesvirus infection	60/1875	194/8465	2.59e-03	1.27e-02	7.81e-03	60
hsa049311	Colorectum	MSS	Insulin resistance	36/1875	108/8465	4.74e-03	2.01e-02	1.23e-02	36

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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
STAT3	TREG	Endometrium	ADJ	GNA12,STAT5B,TNFRSF9, etc.	6.57e-02
STAT3	TREG	Endometrium	AEH	GNA12,STAT5B,TNFRSF9, etc.	1.64e-01
STAT3	CD8TEREX	Endometrium	AEH	GNA12,STAT5B,TNFRSF9, etc.	1.21e-01
STAT3	TREG	Endometrium	EEC	GNA12,STAT5B,TNFRSF9, etc.	1.34e-01
STAT3	CD8TEREX	Endometrium	EEC	GNA12,STAT5B,TNFRSF9, etc.	2.12e-01
STAT3	STM	Esophagus	ESCC	ALDH9A1,MALAT1,ETV6, etc.	4.44e-01
STAT3	CD8TEXINT	Lung	ADJ	SLC2A3,CRYBG1,RAPGEF6, etc.	1.13e-01
STAT3	CD8TEXP	Lung	ADJ	SLC2A3,CRYBG1,RAPGEF6, etc.	1.21e-01
STAT3	MDSC	Lung	Healthy	TAPBP,RSPH3,WARS, etc.	8.71e-01
STAT3	MAIT	Oral cavity	NEOLP	HBP1,DPY19L1,VPS37B, etc.	1.89e-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

STAT3

SNV

Missense_Mutation

novel

c.28C>G

p.Leu10Val

p.L10V

P40763

protein_coding

deleterious(0)

probably_damaging(0.982)

TCGA-A7-A6VX-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

STAT3

SNV

Missense_Mutation

c.2171N>C

p.Leu724Pro

p.L724P

P40763

protein_coding

tolerated(0.13)

possibly_damaging(0.641)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

novel

c.1692N>T

p.Trp564Cys

p.W564C

P40763

protein_coding

deleterious(0.02)

benign(0.015)

TCGA-AC-A8OS-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

c.1229N>G

p.His410Arg

p.H410R

P40763

protein_coding

deleterious(0)

probably_damaging(0.927)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

STAT3

SNV

Missense_Mutation

rs113994137

c.1268N>A

p.Arg423Gln

p.R423Q

P40763

protein_coding

deleterious(0.01)

probably_damaging(0.979)

TCGA-BH-A0B0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

STAT3

SNV

Missense_Mutation

c.1855G>C

p.Val619Leu

p.V619L

P40763

protein_coding

deleterious(0)

benign(0.029)

TCGA-BH-A1F0-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

c.1151T>A

p.Phe384Tyr

p.F384Y

P40763

protein_coding

deleterious(0.02)

probably_damaging(0.978)

TCGA-D8-A1JK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

STAT3

SNV

Missense_Mutation

c.364N>A

p.Ala122Thr

p.A122T

P40763

protein_coding

tolerated(0.59)

benign(0.006)

TCGA-E9-A1R7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

fareston

STAT3

SNV

Missense_Mutation

c.1907N>T

p.Ser636Phe

p.S636F

P40763

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-GM-A2D9-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

STAT3

SNV

Missense_Mutation

novel

c.934C>A

p.Leu312Met

p.L312M

P40763

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-OL-A6VQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

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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
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		NICLOSAMIDE	NICLOSAMIDE
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Gold-complexed thiosaccharide derivative 3
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Platinum IV complexe 1
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		GNF-PF-1399	CHEMBL578504
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Salicylic acid derivative 3
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Peptide analog 7
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		CELECOXIB	CELECOXIB	21678971
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		TAK-114
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		Salicylic acid derivative 1
6774	STAT3	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TUMOR SUPPRESSOR, KINASE		AZD-1480	AZD-1480	21138246,24978112

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