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: PPP3CA

Gene summary for PPP3CA

Gene summary.

Gene information	Species	Human
	Gene symbol	PPP3CA
	Gene ID	5530
	Gene name	protein phosphatase 3 catalytic subunit alpha
	Gene Alias	ACCIID
	Cytomap	4q24
	Gene Type	protein-coding
	GO ID	GO:0000082
	UniProtAcc	A0A0S2Z4C6

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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
5530	PPP3CA	CA_HPV_1	Human	Cervix	CC	3.60e-03	1.50e-02	0.0264
5530	PPP3CA	CCI_1	Human	Cervix	CC	4.48e-10	1.54e+00	0.528
5530	PPP3CA	CCI_2	Human	Cervix	CC	7.67e-05	1.14e+00	0.5249
5530	PPP3CA	CCI_3	Human	Cervix	CC	9.48e-11	1.07e+00	0.516
5530	PPP3CA	HTA11_3410_2000001011	Human	Colorectum	AD	2.30e-24	-7.13e-01	0.0155
5530	PPP3CA	HTA11_2487_2000001011	Human	Colorectum	SER	3.90e-03	-4.53e-01	-0.1808
5530	PPP3CA	HTA11_2951_2000001011	Human	Colorectum	AD	1.00e-05	-9.70e-01	0.0216
5530	PPP3CA	HTA11_3361_2000001011	Human	Colorectum	AD	4.27e-12	-7.73e-01	-0.1207
5530	PPP3CA	HTA11_696_2000001011	Human	Colorectum	AD	3.09e-04	-3.90e-01	-0.1464
5530	PPP3CA	HTA11_546_2000001011	Human	Colorectum	AD	1.09e-02	-3.85e-01	-0.0842
5530	PPP3CA	HTA11_9341_2000001011	Human	Colorectum	SER	2.98e-03	-8.77e-01	-0.00410000000000005
5530	PPP3CA	HTA11_7862_2000001011	Human	Colorectum	AD	3.70e-02	-4.13e-01	-0.0179
5530	PPP3CA	HTA11_866_3004761011	Human	Colorectum	AD	4.72e-09	-5.69e-01	0.096
5530	PPP3CA	HTA11_8622_2000001021	Human	Colorectum	SER	3.27e-05	-7.11e-01	0.0528
5530	PPP3CA	HTA11_10623_2000001011	Human	Colorectum	AD	2.73e-03	-4.83e-01	-0.0177
5530	PPP3CA	HTA11_10711_2000001011	Human	Colorectum	AD	4.28e-12	-7.04e-01	0.0338
5530	PPP3CA	HTA11_7696_3000711011	Human	Colorectum	AD	2.96e-13	-6.29e-01	0.0674
5530	PPP3CA	HTA11_99999970781_79442	Human	Colorectum	MSS	2.04e-04	-3.58e-01	0.294
5530	PPP3CA	HTA11_99999973899_84307	Human	Colorectum	MSS	3.22e-08	-7.34e-01	0.2585
5530	PPP3CA	HTA11_99999974143_84620	Human	Colorectum	MSS	1.67e-34	-8.66e-01	0.3005

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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
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:001703822	Thyroid	ATC	protein import	110/6293	206/18723	3.49e-09	8.09e-08	110
GO:0045807111	Thyroid	ATC	positive regulation of endocytosis	61/6293	100/18723	1.80e-08	3.59e-07	61
GO:005117018	Thyroid	ATC	import into nucleus	86/6293	159/18723	8.02e-08	1.40e-06	86
GO:000660617	Thyroid	ATC	protein import into nucleus	83/6293	155/18723	2.38e-07	3.70e-06	83
GO:005110027	Thyroid	ATC	negative regulation of binding	86/6293	162/18723	2.41e-07	3.73e-06	86
GO:004484316	Thyroid	ATC	cell cycle G1/S phase transition	119/6293	241/18723	2.68e-07	4.10e-06	119
GO:005076723	Thyroid	ATC	regulation of neurogenesis	168/6293	364/18723	3.73e-07	5.48e-06	168
GO:0016358110	Thyroid	ATC	dendrite development	119/6293	243/18723	4.65e-07	6.75e-06	119
GO:000008216	Thyroid	ATC	G1/S transition of mitotic cell cycle	107/6293	214/18723	4.83e-07	6.99e-06	107
GO:006053724	Thyroid	ATC	muscle tissue development	181/6293	403/18723	1.27e-06	1.62e-05	181
GO:0045785210	Thyroid	ATC	positive regulation of cell adhesion	194/6293	437/18723	1.40e-06	1.75e-05	194
GO:005196014	Thyroid	ATC	regulation of nervous system development	195/6293	443/18723	2.62e-06	3.06e-05	195
GO:0010038210	Thyroid	ATC	response to metal ion	165/6293	373/18723	1.07e-05	1.05e-04	165
GO:0006470111	Thyroid	ATC	protein dephosphorylation	129/6293	281/18723	1.11e-05	1.09e-04	129
GO:005109022	Thyroid	ATC	regulation of DNA-binding transcription factor activity	190/6293	440/18723	1.49e-05	1.39e-04	190
GO:001470622	Thyroid	ATC	striated muscle tissue development	168/6293	384/18723	1.91e-05	1.73e-04	168
GO:001631117	Thyroid	ATC	dephosphorylation	179/6293	417/18723	3.88e-05	3.15e-04	179
GO:004269216	Thyroid	ATC	muscle cell differentiation	165/6293	384/18723	7.17e-05	5.46e-04	165
GO:000974333	Thyroid	ATC	response to carbohydrate	114/6293	253/18723	9.26e-05	6.81e-04	114
GO:006014717	Thyroid	ATC	regulation of posttranscriptional gene silencing	31/6293	52/18723	1.06e-04	7.61e-04	31

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0502018	Cervix	CC	Prion disease	98/1267	273/8465	2.64e-18	1.42e-16	8.42e-17	98
hsa0501018	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0502218	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa0501418	Cervix	CC	Amyotrophic lateral sclerosis	103/1267	364/8465	1.79e-11	4.47e-10	2.64e-10	103
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0421810	Cervix	CC	Cellular senescence	49/1267	156/8465	1.30e-07	1.63e-06	9.61e-07	49
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0517016	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa043609	Cervix	CC	Axon guidance	47/1267	182/8465	8.13e-05	5.38e-04	3.18e-04	47
hsa043109	Cervix	CC	Wnt signaling pathway	43/1267	171/8465	3.03e-04	1.64e-03	9.68e-04	43
hsa05152	Cervix	CC	Tuberculosis	42/1267	180/8465	1.78e-03	7.21e-03	4.26e-03	42
hsa046596	Cervix	CC	Th17 cell differentiation	28/1267	108/8465	1.99e-03	7.98e-03	4.72e-03	28
hsa04658	Cervix	CC	Th1 and Th2 cell differentiation	24/1267	92/8465	3.71e-03	1.34e-02	7.91e-03	24
hsa040109	Cervix	CC	MAPK signaling pathway	62/1267	302/8465	4.89e-03	1.67e-02	9.86e-03	62
hsa046254	Cervix	CC	C-type lectin receptor signaling pathway	25/1267	104/8465	9.52e-03	2.94e-02	1.74e-02	25
hsa046604	Cervix	CC	T cell receptor signaling pathway	25/1267	104/8465	9.52e-03	2.94e-02	1.74e-02	25
hsa049218	Cervix	CC	Oxytocin signaling pathway	34/1267	154/8465	1.12e-02	3.42e-02	2.02e-02	34
hsa0502019	Cervix	CC	Prion disease	98/1267	273/8465	2.64e-18	1.42e-16	8.42e-17	98

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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

PPP3CA

SNV

Missense_Mutation

c.1087G>C

p.Glu363Gln

p.E363Q

Q08209

protein_coding

deleterious(0.02)

benign(0.383)

TCGA-A2-A0EQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

PPP3CA

SNV

Missense_Mutation

rs745416220

c.1265N>T

p.Thr422Met

p.T422M

Q08209

protein_coding

tolerated(0.26)

benign(0.075)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

PPP3CA

SNV

Missense_Mutation

c.1349N>G

p.Glu450Gly

p.E450G

Q08209

protein_coding

deleterious(0.02)

benign(0.284)

TCGA-BH-A0BO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PPP3CA

SNV

Missense_Mutation

rs755119794

c.101N>C

p.Val34Ala

p.V34A

Q08209

protein_coding

deleterious(0.03)

possibly_damaging(0.497)

TCGA-BH-A1EU-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PPP3CA

SNV

Missense_Mutation

c.846N>C

p.Glu282Asp

p.E282D

Q08209

protein_coding

deleterious(0.01)

probably_damaging(0.958)

TCGA-EW-A1IZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxotere

PPP3CA

insertion

Nonsense_Mutation

novel

c.837_838insAAAAGAGAGGACTCACAGTGTTTTTAAAATTATAAAT

p.Ala280LysfsTer9

p.A280Kfs*9

Q08209

protein_coding

TCGA-A8-A06X-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PPP3CA

SNV

Missense_Mutation

novel

c.273T>G

p.Ile91Met

p.I91M

Q08209

protein_coding

deleterious(0)

probably_damaging(0.988)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PPP3CA

SNV

Missense_Mutation

novel

c.176N>A

p.Ser59Asn

p.S59N

Q08209

protein_coding

deleterious(0.04)

benign(0.003)

TCGA-4J-AA1J-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

PPP3CA

SNV

Missense_Mutation

c.844N>A

p.Glu282Lys

p.E282K

Q08209

protein_coding

deleterious(0.02)

probably_damaging(0.981)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PPP3CA

SNV

Missense_Mutation

novel

c.442C>T

p.Arg148Cys

p.R148C

Q08209

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AA-3510-01

Colorectum

colon adenocarcinoma

Male

>=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
5530	PPP3CA	DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		Cyclosporine	CYCLOSPORINE
5530	PPP3CA	DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		Voclosporin	VOCLOSPORIN
5530	PPP3CA	DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		Tacrolimus	TACROLIMUS
5530	PPP3CA	DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		VOCLOSPORIN	VOCLOSPORIN
5530	PPP3CA	DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		Pimecrolimus	PIMECROLIMUS

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