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: PIK3R3

Gene summary for PIK3R3

Gene summary.

Gene information	Species	Human
	Gene symbol	PIK3R3
	Gene ID	8503
	Gene name	phosphoinositide-3-kinase regulatory subunit 3
	Gene Alias	p55
	Cytomap	1p34.1
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	Q8N381

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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
8503	PIK3R3	AEH-subject1	Human	Endometrium	AEH	2.14e-26	6.20e-01	-0.3059
8503	PIK3R3	AEH-subject2	Human	Endometrium	AEH	1.48e-15	5.34e-01	-0.2525
8503	PIK3R3	AEH-subject3	Human	Endometrium	AEH	5.32e-25	6.09e-01	-0.2576
8503	PIK3R3	AEH-subject4	Human	Endometrium	AEH	1.10e-05	3.50e-01	-0.2657
8503	PIK3R3	AEH-subject5	Human	Endometrium	AEH	5.43e-09	3.50e-01	-0.2953
8503	PIK3R3	EEC-subject1	Human	Endometrium	EEC	2.06e-21	6.77e-01	-0.2682
8503	PIK3R3	EEC-subject2	Human	Endometrium	EEC	4.99e-09	4.27e-01	-0.2607
8503	PIK3R3	EEC-subject4	Human	Endometrium	EEC	2.23e-04	2.80e-01	-0.2571
8503	PIK3R3	EEC-subject5	Human	Endometrium	EEC	6.73e-22	5.84e-01	-0.249
8503	PIK3R3	GSM5276934	Human	Endometrium	EEC	1.96e-03	-1.11e-01	-0.0913
8503	PIK3R3	GSM5276935	Human	Endometrium	EEC	8.26e-13	3.71e-01	-0.123
8503	PIK3R3	GSM6177620_NYU_UCEC1_lib1_lib1	Human	Endometrium	EEC	2.92e-03	1.18e-01	-0.1869
8503	PIK3R3	GSM6177620_NYU_UCEC1_lib2_lib2	Human	Endometrium	EEC	5.20e-04	1.90e-01	-0.1875
8503	PIK3R3	GSM6177620_NYU_UCEC1_lib3_lib3	Human	Endometrium	EEC	3.17e-04	1.50e-01	-0.1883
8503	PIK3R3	GSM6177621_NYU_UCEC2_lib1_lib1	Human	Endometrium	EEC	9.35e-03	6.65e-02	-0.1934
8503	PIK3R3	GSM6177622_NYU_UCEC3_lib1_lib1	Human	Endometrium	EEC	8.55e-07	6.26e-02	-0.1917
8503	PIK3R3	GSM6177622_NYU_UCEC3_lib2_lib2	Human	Endometrium	EEC	3.19e-07	7.60e-02	-0.1916
8503	PIK3R3	LZE5T	Human	Esophagus	ESCC	3.85e-02	6.33e-01	0.0514
8503	PIK3R3	LZE7T	Human	Esophagus	ESCC	8.28e-08	6.32e-01	0.0667
8503	PIK3R3	LZE8T	Human	Esophagus	ESCC	1.18e-02	8.07e-02	0.067

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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

∗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:000166710	Endometrium	AEH	ameboidal-type cell migration	90/2100	475/18723	3.73e-07	1.57e-05	90
GO:009013014	Endometrium	AEH	tissue migration	73/2100	365/18723	5.79e-07	2.20e-05	73
GO:009013214	Endometrium	AEH	epithelium migration	72/2100	360/18723	6.90e-07	2.55e-05	72
GO:001063114	Endometrium	AEH	epithelial cell migration	71/2100	357/18723	1.02e-06	3.52e-05	71
GO:00435428	Endometrium	AEH	endothelial cell migration	55/2100	279/18723	2.11e-05	4.15e-04	55
GO:19016539	Endometrium	AEH	cellular response to peptide	64/2100	359/18723	1.16e-04	1.63e-03	64
GO:004343410	Endometrium	AEH	response to peptide hormone	70/2100	414/18723	2.93e-04	3.35e-03	70
GO:00328699	Endometrium	AEH	cellular response to insulin stimulus	37/2100	203/18723	1.97e-03	1.54e-02	37
GO:00713758	Endometrium	AEH	cellular response to peptide hormone stimulus	49/2100	290/18723	2.24e-03	1.72e-02	49
GO:00434914	Endometrium	AEH	protein kinase B signaling	37/2100	211/18723	3.89e-03	2.64e-02	37
GO:00435342	Endometrium	AEH	blood vessel endothelial cell migration	32/2100	176/18723	3.97e-03	2.66e-02	32
GO:00082866	Endometrium	AEH	insulin receptor signaling pathway	23/2100	116/18723	4.58e-03	2.95e-02	23
GO:00328689	Endometrium	AEH	response to insulin	44/2100	264/18723	4.70e-03	3.00e-02	44
GO:000166716	Endometrium	EEC	ameboidal-type cell migration	91/2168	475/18723	7.87e-07	2.80e-05	91
GO:009013015	Endometrium	EEC	tissue migration	73/2168	365/18723	1.91e-06	5.78e-05	73
GO:009013215	Endometrium	EEC	epithelium migration	72/2168	360/18723	2.24e-06	6.59e-05	72
GO:001063115	Endometrium	EEC	epithelial cell migration	71/2168	357/18723	3.24e-06	8.85e-05	71
GO:190165314	Endometrium	EEC	cellular response to peptide	68/2168	359/18723	2.75e-05	4.83e-04	68
GO:004354213	Endometrium	EEC	endothelial cell migration	55/2168	279/18723	5.12e-05	8.18e-04	55
GO:004343416	Endometrium	EEC	response to peptide hormone	74/2168	414/18723	9.11e-05	1.28e-03	74

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0502020	Endometrium	AEH	Prion disease	110/1197	273/8465	2.39e-27	2.44e-25	1.78e-25	110
hsa0517126	Endometrium	AEH	Coronavirus disease - COVID-19	99/1197	232/8465	5.19e-27	3.37e-25	2.47e-25	99
hsa0541525	Endometrium	AEH	Diabetic cardiomyopathy	86/1197	203/8465	2.62e-23	1.22e-21	8.90e-22	86
hsa0520826	Endometrium	AEH	Chemical carcinogenesis - reactive oxygen species	91/1197	223/8465	3.28e-23	1.33e-21	9.76e-22	91
hsa0501020	Endometrium	AEH	Alzheimer disease	124/1197	384/8465	1.20e-20	3.91e-19	2.86e-19	124
hsa0493220	Endometrium	AEH	Non-alcoholic fatty liver disease	67/1197	155/8465	5.91e-19	1.75e-17	1.28e-17	67
hsa0513126	Endometrium	AEH	Shigellosis	78/1197	247/8465	9.23e-13	2.00e-11	1.46e-11	78
hsa0510026	Endometrium	AEH	Bacterial invasion of epithelial cells	32/1197	77/8465	3.28e-09	5.91e-08	4.33e-08	32
hsa0451015	Endometrium	AEH	Focal adhesion	58/1197	203/8465	4.99e-08	7.37e-07	5.39e-07	58
hsa0541826	Endometrium	AEH	Fluid shear stress and atherosclerosis	43/1197	139/8465	2.47e-07	3.49e-06	2.55e-06	43
hsa0467026	Endometrium	AEH	Leukocyte transendothelial migration	37/1197	114/8465	4.51e-07	6.11e-06	4.47e-06	37
hsa0501718	Endometrium	AEH	Spinocerebellar ataxia	43/1197	143/8465	5.92e-07	7.69e-06	5.63e-06	43
hsa0520518	Endometrium	AEH	Proteoglycans in cancer	53/1197	205/8465	5.43e-06	6.53e-05	4.78e-05	53
hsa051466	Endometrium	AEH	Amoebiasis	29/1197	102/8465	1.22e-04	1.10e-03	8.06e-04	29
hsa0401514	Endometrium	AEH	Rap1 signaling pathway	49/1197	210/8465	2.03e-04	1.78e-03	1.30e-03	49
hsa049337	Endometrium	AEH	AGE-RAGE signaling pathway in diabetic complications	28/1197	100/8465	2.11e-04	1.80e-03	1.32e-03	28
hsa0466614	Endometrium	AEH	Fc gamma R-mediated phagocytosis	27/1197	97/8465	3.02e-04	2.39e-03	1.75e-03	27
hsa0491525	Endometrium	AEH	Estrogen signaling pathway	35/1197	138/8465	3.10e-04	2.40e-03	1.75e-03	35
hsa0472216	Endometrium	AEH	Neurotrophin signaling pathway	31/1197	119/8465	4.07e-04	3.07e-03	2.25e-03	31
hsa0406620	Endometrium	AEH	HIF-1 signaling pathway	29/1197	109/8465	4.23e-04	3.11e-03	2.27e-03	29

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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

PIK3R3

SNV

Missense_Mutation

c.1103C>T

p.Ala368Val

p.A368V

Q92569

protein_coding

deleterious(0.04)

probably_damaging(0.967)

TCGA-AR-A24H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

PIK3R3

SNV

Missense_Mutation

rs779089992

c.280N>G

p.Thr94Ala

p.T94A

Q92569

protein_coding

deleterious(0.02)

benign(0.072)

TCGA-E2-A14S-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

PIK3R3

SNV

Missense_Mutation

c.977N>G

p.Leu326Arg

p.L326R

Q92569

protein_coding

deleterious(0)

benign(0.038)

TCGA-E2-A15K-06

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

PIK3R3

SNV

Missense_Mutation

novel

c.499N>G

p.Gln167Glu

p.Q167E

Q92569

protein_coding

tolerated(0.4)

benign(0.084)

TCGA-S3-AA10-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

PIK3R3

deletion

Frame_Shift_Del

c.883delN

p.Met295Ter

p.M295*

Q92569

protein_coding

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

PIK3R3

SNV

Missense_Mutation

novel

c.1304C>T

p.Thr435Ile

p.T435I

Q92569

protein_coding

deleterious(0.01)

benign(0.083)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PIK3R3

SNV

Missense_Mutation

novel

c.314G>A

p.Arg105Gln

p.R105Q

Q92569

protein_coding

deleterious(0.01)

probably_damaging(0.994)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PIK3R3

SNV

Missense_Mutation

novel

c.1010C>G

p.Ala337Gly

p.A337G

Q92569

protein_coding

tolerated(0.49)

benign(0)

TCGA-C5-A2M1-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

PIK3R3

SNV

Missense_Mutation

rs780117361

c.116N>G

p.Pro39Arg

p.P39R

Q92569

protein_coding

deleterious(0)

benign(0.36)

TCGA-EK-A2RJ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

PIK3R3

SNV

Missense_Mutation

c.1015N>A

p.Glu339Lys

p.E339K

Q92569

protein_coding

tolerated(0.12)

benign(0.06)

TCGA-IR-A3LA-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	GDC-0941	PICTILISIB
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	CHEMBL1079593	VS-5584
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	XL-765	VOXTALISIB
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	CHEMBL1234354	PF-04691502
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	BKM120	BUPARLISIB
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	CHEMBL3360203	PILARALISIB
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	BAY80-6946	COPANLISIB
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	CHEMBL586701	ZSTK-474
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	CHEMBL2017974	BUPARLISIB
8503	PIK3R3	KINASE, ENZYME, PHOSPHATIDYLINOSITOL 3 KINASE, CLINICALLY ACTIONABLE	inhibitor	CHEMBL2165191	AZD-6482

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