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: GSK3B

Gene summary for GSK3B

Gene summary.

Gene information	Species	Human
	Gene symbol	GSK3B
	Gene ID	2932
	Gene name	glycogen synthase kinase 3 beta
	Gene Alias	GSK3B
	Cytomap	3q13.33
	Gene Type	protein-coding
	GO ID	GO:0000226
	UniProtAcc	P49841

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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
2932	GSK3B	CCI_1	Human	Cervix	CC	1.65e-20	1.50e+00	0.528
2932	GSK3B	CCI_2	Human	Cervix	CC	1.69e-18	1.78e+00	0.5249
2932	GSK3B	CCI_3	Human	Cervix	CC	8.36e-47	2.13e+00	0.516
2932	GSK3B	sample1	Human	Cervix	CC	3.58e-02	3.05e-01	0.0959
2932	GSK3B	T1	Human	Cervix	CC	5.51e-07	3.34e-01	0.0918
2932	GSK3B	T3	Human	Cervix	CC	2.89e-03	1.39e-01	0.1389
2932	GSK3B	HTA11_3410_2000001011	Human	Colorectum	AD	8.70e-28	-6.99e-01	0.0155
2932	GSK3B	HTA11_2487_2000001011	Human	Colorectum	SER	1.59e-06	-4.00e-01	-0.1808
2932	GSK3B	HTA11_3361_2000001011	Human	Colorectum	AD	2.42e-05	-6.07e-01	-0.1207
2932	GSK3B	HTA11_83_2000001011	Human	Colorectum	SER	1.11e-04	-3.58e-01	-0.1526
2932	GSK3B	HTA11_696_2000001011	Human	Colorectum	AD	6.33e-07	-3.49e-01	-0.1464
2932	GSK3B	HTA11_5212_2000001011	Human	Colorectum	AD	2.40e-03	-5.57e-01	-0.2061
2932	GSK3B	HTA11_9341_2000001011	Human	Colorectum	SER	6.83e-03	-7.22e-01	-0.00410000000000005
2932	GSK3B	HTA11_866_3004761011	Human	Colorectum	AD	5.43e-15	-6.44e-01	0.096
2932	GSK3B	HTA11_9408_2000001011	Human	Colorectum	AD	1.94e-02	-8.19e-01	0.0451
2932	GSK3B	HTA11_8622_2000001021	Human	Colorectum	SER	1.52e-02	-6.51e-01	0.0528
2932	GSK3B	HTA11_6801_2000001011	Human	Colorectum	SER	1.90e-02	-4.08e-01	0.0171
2932	GSK3B	HTA11_7696_3000711011	Human	Colorectum	AD	3.27e-08	-4.63e-01	0.0674
2932	GSK3B	HTA11_11156_2000001011	Human	Colorectum	AD	7.19e-03	-9.12e-01	0.0397
2932	GSK3B	HTA11_6818_2000001021	Human	Colorectum	AD	2.21e-05	-3.36e-01	0.0588

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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
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
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:001603210	Cervix	CC	viral process	109/2311	415/18723	5.40e-15	6.46e-12	109
GO:004217610	Cervix	CC	regulation of protein catabolic process	104/2311	391/18723	9.39e-15	9.36e-12	104
GO:200123310	Cervix	CC	regulation of apoptotic signaling pathway	96/2311	356/18723	4.08e-14	3.05e-11	96
GO:001081010	Cervix	CC	regulation of cell-substrate adhesion	69/2311	221/18723	8.57e-14	5.69e-11	69
GO:00315898	Cervix	CC	cell-substrate adhesion	96/2311	363/18723	1.48e-13	8.85e-11	96
GO:004586210	Cervix	CC	positive regulation of proteolysis	95/2311	372/18723	1.84e-12	6.86e-10	95
GO:190336210	Cervix	CC	regulation of cellular protein catabolic process	72/2311	255/18723	5.98e-12	2.10e-09	72
GO:00071639	Cervix	CC	establishment or maintenance of cell polarity	63/2311	218/18723	4.25e-11	8.76e-09	63
GO:004573210	Cervix	CC	positive regulation of protein catabolic process	65/2311	231/18723	7.44e-11	1.39e-08	65
GO:001049810	Cervix	CC	proteasomal protein catabolic process	111/2311	490/18723	8.98e-11	1.58e-08	111
GO:004578510	Cervix	CC	positive regulation of cell adhesion	101/2311	437/18723	1.96e-10	3.08e-08	101
GO:190382910	Cervix	CC	positive regulation of cellular protein localization	72/2311	276/18723	3.20e-10	4.46e-08	72
GO:000989610	Cervix	CC	positive regulation of catabolic process	109/2311	492/18723	5.26e-10	6.99e-08	109
GO:190305010	Cervix	CC	regulation of proteolysis involved in cellular protein catabolic process	60/2311	221/18723	1.82e-09	1.98e-07	60
GO:004325410	Cervix	CC	regulation of protein-containing complex assembly	96/2311	428/18723	2.91e-09	3.05e-07	96
GO:00160557	Cervix	CC	Wnt signaling pathway	98/2311	444/18723	4.82e-09	4.65e-07	98
GO:01987387	Cervix	CC	cell-cell signaling by wnt	98/2311	446/18723	6.16e-09	5.58e-07	98
GO:00060919	Cervix	CC	generation of precursor metabolites and energy	105/2311	490/18723	7.40e-09	6.61e-07	105
GO:00019528	Cervix	CC	regulation of cell-matrix adhesion	40/2311	128/18723	1.32e-08	1.04e-06	40
GO:00071608	Cervix	CC	cell-matrix adhesion	60/2311	233/18723	1.58e-08	1.23e-06	60

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0493263	Oral cavity	NEOLP	Non-alcoholic fatty liver disease	51/1112	155/8465	1.26e-10	3.84e-09	2.41e-09	51
hsa0502262	Oral cavity	NEOLP	Pathways of neurodegeneration - multiple diseases	112/1112	476/8465	1.33e-10	3.84e-09	2.41e-09	112
hsa0502062	Oral cavity	NEOLP	Prion disease	73/1112	273/8465	7.94e-10	2.10e-08	1.32e-08	73
hsa0516762	Oral cavity	NEOLP	Kaposi sarcoma-associated herpesvirus infection	56/1112	194/8465	4.05e-09	9.20e-08	5.78e-08	56
hsa0513163	Oral cavity	NEOLP	Shigellosis	62/1112	247/8465	1.93e-07	2.79e-06	1.75e-06	62
hsa0415141	Oral cavity	NEOLP	PI3K-Akt signaling pathway	79/1112	354/8465	8.42e-07	9.92e-06	6.24e-06	79
hsa0516061	Oral cavity	NEOLP	Hepatitis C	43/1112	157/8465	1.26e-06	1.34e-05	8.43e-06	43
hsa0516361	Oral cavity	NEOLP	Human cytomegalovirus infection	55/1112	225/8465	2.32e-06	2.30e-05	1.45e-05	55
hsa0521542	Oral cavity	NEOLP	Prostate cancer	28/1112	97/8465	3.15e-05	2.57e-04	1.62e-04	28
hsa051626	Oral cavity	NEOLP	Measles	35/1112	139/8465	8.30e-05	6.14e-04	3.86e-04	35
hsa0472261	Oral cavity	NEOLP	Neurotrophin signaling pathway	31/1112	119/8465	1.06e-04	7.67e-04	4.82e-04	31
hsa0411061	Oral cavity	NEOLP	Cell cycle	37/1112	157/8465	2.29e-04	1.58e-03	9.95e-04	37
hsa0541763	Oral cavity	NEOLP	Lipid and atherosclerosis	47/1112	215/8465	2.39e-04	1.61e-03	1.01e-03	47
hsa0513561	Oral cavity	NEOLP	Yersinia infection	33/1112	137/8465	3.20e-04	2.00e-03	1.26e-03	33
hsa0466041	Oral cavity	NEOLP	T cell receptor signaling pathway	26/1112	104/8465	7.37e-04	3.72e-03	2.34e-03	26
hsa0439025	Oral cavity	NEOLP	Hippo signaling pathway	35/1112	157/8465	9.91e-04	4.85e-03	3.05e-03	35
hsa0472821	Oral cavity	NEOLP	Dopaminergic synapse	30/1112	132/8465	1.61e-03	7.30e-03	4.59e-03	30
hsa0491942	Oral cavity	NEOLP	Thyroid hormone signaling pathway	28/1112	121/8465	1.70e-03	7.62e-03	4.80e-03	28
hsa0152142	Oral cavity	NEOLP	EGFR tyrosine kinase inhibitor resistance	20/1112	79/8465	2.47e-03	1.03e-02	6.49e-03	20
hsa0436041	Oral cavity	NEOLP	Axon guidance	37/1112	182/8465	4.02e-03	1.64e-02	1.03e-02	37

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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

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

GSK3B

SNV

Missense_Mutation

c.46N>T

p.Pro16Ser

p.P16S

P49841

protein_coding

tolerated_low_confidence(0.36)

benign(0.003)

TCGA-AN-A0FX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

GSK3B

SNV

Missense_Mutation

novel

c.857C>G

p.Pro286Arg

p.P286R

P49841

protein_coding

deleterious(0.03)

benign(0.162)

TCGA-C8-A8HR-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

5-fluorouracil

GSK3B

insertion

Nonsense_Mutation

novel

c.1146_1147insGAAACCGGGAGGCGGAGGTTGCATTGAGCCGAGATTGCGCC

p.Asn383GlufsTer9

p.N383Efs*9

P49841

protein_coding

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

GSK3B

insertion

In_Frame_Ins

novel

c.44_45insATCACAAGGAGAACTCTGTTTTGA

p.Lys15_Pro16insSerGlnGlyGluLeuCysPheGlu

p.K15_P16insSQGELCFE

P49841

protein_coding

TCGA-AN-A0FX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

GSK3B

deletion

Frame_Shift_Del

novel

c.850delN

p.Met284Ter

p.M284*

P49841

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

GSK3B

SNV

Missense_Mutation

novel

c.259G>A

p.Val87Ile

p.V87I

P49841

protein_coding

deleterious(0)

probably_damaging(0.927)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

GSK3B

SNV

Missense_Mutation

novel

c.683N>A

p.Ile228Asn

p.I228N

P49841

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-VS-A8EL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

GSK3B

SNV

Missense_Mutation

rs72548709

c.995N>A

p.Arg332His

p.R332H

P49841

protein_coding

tolerated(0.07)

benign(0.003)

TCGA-AA-3663-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

GSK3B

SNV

Missense_Mutation

c.713N>C

p.Ile238Thr

p.I238T

P49841

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-AA-3715-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

GSK3B

SNV

Missense_Mutation

c.901T>C

p.Trp301Arg

p.W301R

P49841

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

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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
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		PMID26161698-Compound-18
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		Neu-120
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		SOTRASTAURIN	SOTRASTAURIN
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		CYC-116	CYC-116
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		tideglusib	TIDEGLUSIB
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR	inhibitor	404859135
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		ALSTERPAULLONE	ALSTERPAULLONE
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR	inhibitor	CHEMBL1200826	LITHIUM CARBONATE
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		AMO-02
2932	GSK3B	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		BETULINIC ACID	BETULINIC ACID	19716700

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