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: PIK3CA

Gene summary for PIK3CA

Gene summary.

Gene information	Species	Human
	Gene symbol	PIK3CA
	Gene ID	5290
	Gene name	phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
	Gene Alias	CLAPO
	Cytomap	3q26.32
	Gene Type	protein-coding
	GO ID	GO:0001101
	UniProtAcc	P42336

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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
5290	PIK3CA	CA_HPV_2	Human	Cervix	CC	6.44e-06	3.23e-01	0.0391
5290	PIK3CA	CCI_2	Human	Cervix	CC	3.01e-09	1.19e+00	0.5249
5290	PIK3CA	CCI_3	Human	Cervix	CC	8.00e-05	6.32e-01	0.516
5290	PIK3CA	HCC1_Meng	Human	Liver	HCC	7.90e-28	1.41e-02	0.0246
5290	PIK3CA	HCC2_Meng	Human	Liver	HCC	8.04e-25	1.29e-01	0.0107
5290	PIK3CA	HCC1	Human	Liver	HCC	6.95e-10	3.40e+00	0.5336
5290	PIK3CA	HCC2	Human	Liver	HCC	1.23e-13	3.78e+00	0.5341
5290	PIK3CA	S028	Human	Liver	HCC	9.79e-07	3.87e-01	0.2503
5290	PIK3CA	S029	Human	Liver	HCC	2.66e-04	3.62e-01	0.2581
5290	PIK3CA	male-WTA	Human	Thyroid	PTC	3.74e-13	5.74e-02	0.1037
5290	PIK3CA	PTC01	Human	Thyroid	PTC	2.99e-12	4.20e-02	0.1899
5290	PIK3CA	PTC04	Human	Thyroid	PTC	2.28e-16	2.51e-01	0.1927
5290	PIK3CA	PTC05	Human	Thyroid	PTC	3.40e-11	4.25e-01	0.2065
5290	PIK3CA	PTC06	Human	Thyroid	PTC	9.79e-15	4.11e-01	0.2057
5290	PIK3CA	PTC07	Human	Thyroid	PTC	8.04e-18	2.27e-01	0.2044
5290	PIK3CA	ATC09	Human	Thyroid	ATC	4.79e-05	1.50e-01	0.2871
5290	PIK3CA	ATC11	Human	Thyroid	ATC	1.53e-05	4.32e-01	0.3386
5290	PIK3CA	ATC12	Human	Thyroid	ATC	1.44e-08	8.02e-02	0.34
5290	PIK3CA	ATC13	Human	Thyroid	ATC	1.25e-43	7.28e-01	0.34
5290	PIK3CA	ATC1	Human	Thyroid	ATC	4.24e-06	2.20e-01	0.2878

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
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:004206010	Cervix	CC	wound healing	109/2311	422/18723	1.84e-14	1.57e-11	109
GO:000701510	Cervix	CC	actin filament organization	109/2311	442/18723	4.92e-13	2.45e-10	109
GO:00453339	Cervix	CC	cellular respiration	66/2311	230/18723	2.07e-11	5.39e-09	66
GO:009013210	Cervix	CC	epithelium migration	90/2311	360/18723	2.45e-11	6.11e-09	90
GO:00016679	Cervix	CC	ameboidal-type cell migration	110/2311	475/18723	2.66e-11	6.36e-09	110
GO:001063110	Cervix	CC	epithelial cell migration	89/2311	357/18723	3.72e-11	8.54e-09	89
GO:003297010	Cervix	CC	regulation of actin filament-based process	96/2311	397/18723	4.00e-11	8.54e-09	96
GO:009013010	Cervix	CC	tissue migration	90/2311	365/18723	5.42e-11	1.05e-08	90
GO:190290310	Cervix	CC	regulation of supramolecular fiber organization	92/2311	383/18723	1.49e-10	2.48e-08	92
GO:002240710	Cervix	CC	regulation of cell-cell adhesion	103/2311	448/18723	1.78e-10	2.87e-08	103
GO:004578510	Cervix	CC	positive regulation of cell adhesion	101/2311	437/18723	1.96e-10	3.08e-08	101
GO:003295610	Cervix	CC	regulation of actin cytoskeleton organization	86/2311	358/18723	5.90e-10	7.51e-08	86
GO:00421108	Cervix	CC	T cell activation	107/2311	487/18723	1.24e-09	1.46e-07	107
GO:00508638	Cervix	CC	regulation of T cell activation	80/2311	329/18723	1.28e-09	1.47e-07	80
GO:00060919	Cervix	CC	generation of precursor metabolites and energy	105/2311	490/18723	7.40e-09	6.61e-07	105
GO:00071598	Cervix	CC	leukocyte cell-cell adhesion	85/2311	371/18723	8.27e-09	7.07e-07	85
GO:003367410	Cervix	CC	positive regulation of kinase activity	101/2311	467/18723	8.66e-09	7.22e-07	101
GO:00071738	Cervix	CC	epidermal growth factor receptor signaling pathway	36/2311	108/18723	1.04e-08	8.44e-07	36
GO:00159809	Cervix	CC	energy derivation by oxidation of organic compounds	74/2311	318/18723	3.83e-08	2.53e-06	74
GO:011005310	Cervix	CC	regulation of actin filament organization	67/2311	278/18723	4.01e-08	2.54e-06	67

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0517120	Cervix	CC	Coronavirus disease - COVID-19	111/1267	232/8465	1.82e-33	5.90e-31	3.49e-31	111
hsa0520820	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa0502018	Cervix	CC	Prion disease	98/1267	273/8465	2.64e-18	1.42e-16	8.42e-17	98
hsa0541520	Cervix	CC	Diabetic cardiomyopathy	76/1267	203/8465	1.40e-15	6.46e-14	3.82e-14	76
hsa0501018	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0493218	Cervix	CC	Non-alcoholic fatty liver disease	58/1267	155/8465	3.58e-12	1.05e-10	6.23e-11	58
hsa0541820	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa0513220	Cervix	CC	Salmonella infection	74/1267	249/8465	1.33e-09	2.54e-08	1.50e-08	74
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
hsa0513120	Cervix	CC	Shigellosis	69/1267	247/8465	7.64e-08	1.03e-06	6.10e-07	69
hsa0520516	Cervix	CC	Proteoglycans in cancer	60/1267	205/8465	9.13e-08	1.18e-06	7.00e-07	60
hsa0421810	Cervix	CC	Cellular senescence	49/1267	156/8465	1.30e-07	1.63e-06	9.61e-07	49
hsa0451010	Cervix	CC	Focal adhesion	59/1267	203/8465	1.53e-07	1.84e-06	1.09e-06	59
hsa0481016	Cervix	CC	Regulation of actin cytoskeleton	64/1267	229/8465	2.24e-07	2.59e-06	1.53e-06	64
hsa0491520	Cervix	CC	Estrogen signaling pathway	44/1267	138/8465	3.55e-07	3.97e-06	2.35e-06	44
hsa0516920	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0467020	Cervix	CC	Leukocyte transendothelial migration	36/1267	114/8465	5.22e-06	4.83e-05	2.86e-05	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

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

PIK3CA

SNV

Missense_Mutation

rs121913273

c.1624G>A

p.Glu542Lys

p.E542K

P42336

protein_coding

deleterious(0.04)

probably_damaging(0.912)

TCGA-3C-AALK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

docetaxel

PIK3CA

SNV

Missense_Mutation

c.3012G>T

p.Met1004Ile

p.M1004I

P42336

protein_coding

deleterious(0.01)

benign(0.047)

TCGA-3C-AALK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

docetaxel

PIK3CA

SNV

Missense_Mutation

rs121913279

c.3140A>T

p.His1047Leu

p.H1047L

P42336

protein_coding

tolerated(0.44)

benign(0.007)

TCGA-5L-AAT0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PIK3CA

SNV

Missense_Mutation

rs121913287

c.263G>A

p.Arg88Gln

p.R88Q

P42336

protein_coding

tolerated(0.06)

probably_damaging(0.971)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

PIK3CA

SNV

Missense_Mutation

rs121913273

c.1624G>A

p.Glu542Lys

p.E542K

P42336

protein_coding

deleterious(0.04)

probably_damaging(0.912)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

PIK3CA

SNV

Missense_Mutation

rs867262025

c.2176N>A

p.Glu726Lys

p.E726K

P42336

protein_coding

tolerated(0.36)

benign(0.396)

TCGA-A1-A0SI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PIK3CA

SNV

Missense_Mutation

rs121913279

c.3140N>G

p.His1047Arg

p.H1047R

P42336

protein_coding

tolerated(0.11)

benign(0.085)

TCGA-A1-A0SI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PIK3CA

SNV

Missense_Mutation

rs121913273

c.1624N>A

p.Glu542Lys

p.E542K

P42336

protein_coding

deleterious(0.04)

probably_damaging(0.912)

TCGA-A2-A04N-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

PIK3CA

SNV

Missense_Mutation

rs121913287

c.263N>A

p.Arg88Gln

p.R88Q

P42336

protein_coding

tolerated(0.06)

probably_damaging(0.971)

TCGA-A2-A04P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxol

PIK3CA

SNV

Missense_Mutation

rs121913281

c.3139N>T

p.His1047Tyr

p.H1047Y

P42336

protein_coding

tolerated(1)

benign(0)

TCGA-A2-A04T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

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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
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE	inhibitor	249565638	ALPELISIB
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE	inhibitor	INK-1117	INK-1117
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE	inhibitor	354702297	GSK-1059615
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE		MS417		26058079
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE		Olaparib	OLAPARIB	26909613
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE		NSC-79888	CHEMBL1939433	22212721
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE		CH-5132799	PA-799
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE	inhibitor	381118806	ACALISIB
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE		ALPELISIB	ALPELISIB	31091374,24608574
5290	PIK3CA	PHOSPHATIDYLINOSITOL 3 KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, ENZYME, SERINE THREONINE KINASE, DRUG RESISTANCE		Linsitinib	LINSITINIB	27196766

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