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: PI3

Gene summary for PI3

Gene summary.

Gene information	Species	Human
	Gene symbol	PI3
	Gene ID	5266
	Gene name	peptidase inhibitor 3
	Gene Alias	ESI
	Cytomap	20q13.12
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P19957

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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
5266	PI3	GSM4909281	Human	Breast	IDC	3.41e-19	-8.01e-01	0.21
5266	PI3	GSM4909282	Human	Breast	IDC	2.05e-11	-3.27e-01	-0.0288
5266	PI3	GSM4909285	Human	Breast	IDC	1.41e-22	-8.15e-01	0.21
5266	PI3	GSM4909286	Human	Breast	IDC	2.52e-23	-8.17e-01	0.1081
5266	PI3	GSM4909287	Human	Breast	IDC	2.65e-15	-7.49e-01	0.2057
5266	PI3	GSM4909289	Human	Breast	IDC	1.59e-04	-8.17e-01	0.1064
5266	PI3	GSM4909290	Human	Breast	IDC	2.60e-18	-8.17e-01	0.2096
5266	PI3	GSM4909291	Human	Breast	IDC	1.76e-12	-8.08e-01	0.1753
5266	PI3	GSM4909293	Human	Breast	IDC	7.78e-22	-8.12e-01	0.1581
5266	PI3	GSM4909294	Human	Breast	IDC	1.41e-22	-8.12e-01	0.2022
5266	PI3	GSM4909295	Human	Breast	IDC	1.37e-03	-6.52e-01	0.0898
5266	PI3	GSM4909296	Human	Breast	IDC	2.79e-18	-7.99e-01	0.1524
5266	PI3	GSM4909297	Human	Breast	IDC	1.25e-19	-8.05e-01	0.1517
5266	PI3	GSM4909298	Human	Breast	IDC	2.52e-23	-8.17e-01	0.1551
5266	PI3	GSM4909299	Human	Breast	IDC	8.97e-16	-7.52e-01	0.035
5266	PI3	GSM4909301	Human	Breast	IDC	5.96e-23	-8.17e-01	0.1577
5266	PI3	GSM4909302	Human	Breast	IDC	5.77e-25	-8.17e-01	0.1545
5266	PI3	GSM4909303	Human	Breast	IDC	3.88e-07	-8.17e-01	0.0438
5266	PI3	GSM4909304	Human	Breast	IDC	1.41e-22	-8.17e-01	0.1636
5266	PI3	GSM4909305	Human	Breast	IDC	3.94e-09	-7.30e-01	0.0436

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
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:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:00458619	Breast	Precancer	negative regulation of proteolysis	50/1080	351/18723	2.99e-09	2.39e-07	50
GO:00513468	Breast	Precancer	negative regulation of hydrolase activity	50/1080	379/18723	3.85e-08	2.34e-06	50
GO:00104668	Breast	Precancer	negative regulation of peptidase activity	38/1080	262/18723	1.46e-07	7.82e-06	38
GO:00109519	Breast	Precancer	negative regulation of endopeptidase activity	37/1080	252/18723	1.55e-07	8.05e-06	37
GO:00197307	Breast	Precancer	antimicrobial humoral response	19/1080	122/18723	7.02e-05	1.40e-03	19
GO:005254714	Breast	IDC	regulation of peptidase activity	96/1434	461/18723	7.58e-20	6.15e-17	96
GO:005254814	Breast	IDC	regulation of endopeptidase activity	88/1434	432/18723	1.20e-17	4.85e-15	88
GO:004586114	Breast	IDC	negative regulation of proteolysis	70/1434	351/18723	8.21e-14	2.22e-11	70
GO:005134613	Breast	IDC	negative regulation of hydrolase activity	71/1434	379/18723	1.33e-12	2.90e-10	71
GO:001046613	Breast	IDC	negative regulation of peptidase activity	56/1434	262/18723	1.39e-12	2.92e-10	56
GO:001095112	Breast	IDC	negative regulation of endopeptidase activity	52/1434	252/18723	3.53e-11	5.57e-09	52
GO:001973011	Breast	IDC	antimicrobial humoral response	23/1434	122/18723	4.67e-05	1.04e-03	23
GO:00069596	Breast	IDC	humoral immune response	40/1434	317/18723	1.25e-03	1.33e-02	40
GO:0018149	Breast	IDC	peptide cross-linking	8/1434	35/18723	4.22e-03	3.31e-02	8
GO:005254723	Breast	DCIS	regulation of peptidase activity	88/1390	461/18723	1.18e-16	4.78e-14	88
GO:005254823	Breast	DCIS	regulation of endopeptidase activity	83/1390	432/18723	6.07e-16	2.15e-13	83
GO:004586123	Breast	DCIS	negative regulation of proteolysis	63/1390	351/18723	4.39e-11	6.06e-09	63
GO:005134623	Breast	DCIS	negative regulation of hydrolase activity	64/1390	379/18723	4.32e-10	4.80e-08	64

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

PI3

SNV

Missense_Mutation

rs780306943

c.250N>A

p.Ala84Thr

p.A84T

P19957

protein_coding

tolerated(0.36)

benign(0.188)

TCGA-BH-A0H7-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

doxorubicin

PI3

insertion

Frame_Shift_Ins

novel

c.237_238insCTTTCTCTTCTTGGGTCTCACTGTATTTCAAAACATGAAGAAT

p.Ile81SerfsTer24

p.I81Sfs*24

P19957

protein_coding

TCGA-B6-A0I8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PI3

SNV

Missense_Mutation

rs142652976

c.245G>A

p.Arg82Gln

p.R82Q

P19957

protein_coding

tolerated(0.42)

benign(0.046)

TCGA-Q1-A73Q-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PI3

SNV

Missense_Mutation

c.180N>C

p.Lys60Asn

p.K60N

P19957

protein_coding

deleterious(0.01)

probably_damaging(0.985)

TCGA-A6-6780-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

PI3

SNV

Missense_Mutation

novel

c.194T>C

p.Val65Ala

p.V65A

P19957

protein_coding

tolerated(0.6)

benign(0.01)

TCGA-AG-A002-01

Colorectum

rectum adenocarcinoma

Male

<65

I/II

Unknown

PI3

SNV

Missense_Mutation

rs780145676

c.328G>A

p.Gly110Arg

p.G110R

P19957

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A5-A0VP-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

PI3

SNV

Missense_Mutation

novel

c.40N>G

p.Ile14Val

p.I14V

P19957

protein_coding

tolerated(0.51)

benign(0.006)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

PI3

SNV

Missense_Mutation

c.306N>T

p.Lys102Asn

p.K102N

P19957

protein_coding

deleterious(0.01)

probably_damaging(0.954)

TCGA-AX-A05Z-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

PI3

SNV

Missense_Mutation

c.187N>A

p.Glu63Lys

p.E63K

P19957

protein_coding

tolerated(0.74)

benign(0.003)

TCGA-AX-A06F-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

carboplatin

PI3

SNV

Missense_Mutation

rs754557593

c.139N>A

p.Val47Ile

p.V47I

P19957

protein_coding

tolerated(0.09)

benign(0.405)

TCGA-AX-A0J1-01

Endometrium

uterine corpus endometrioid 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
5266	PI3	DRUGGABLE GENOME, PROTEASE INHIBITOR		PROGESTERONE	PROGESTERONE	14521952

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