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: AGR2

Gene summary for AGR2

Gene summary.

Gene information	Species	Human
	Gene symbol	AGR2
	Gene ID	10551
	Gene name	anterior gradient 2, protein disulphide isomerase family member
	Gene Alias	AG-2
	Cytomap	7p21.1
	Gene Type	protein-coding
	GO ID	GO:0002065
	UniProtAcc	O95994

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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
10551	AGR2	GSM4909281	Human	Breast	IDC	8.10e-07	-2.72e-01	0.21
10551	AGR2	GSM4909282	Human	Breast	IDC	5.64e-06	-2.44e-01	-0.0288
10551	AGR2	GSM4909285	Human	Breast	IDC	6.94e-03	-2.49e-01	0.21
10551	AGR2	GSM4909286	Human	Breast	IDC	8.32e-08	-2.73e-01	0.1081
10551	AGR2	GSM4909287	Human	Breast	IDC	3.74e-03	-2.61e-01	0.2057
10551	AGR2	GSM4909290	Human	Breast	IDC	3.04e-02	3.04e-01	0.2096
10551	AGR2	GSM4909293	Human	Breast	IDC	2.39e-09	3.36e-01	0.1581
10551	AGR2	GSM4909294	Human	Breast	IDC	5.35e-05	4.10e-01	0.2022
10551	AGR2	GSM4909295	Human	Breast	IDC	9.25e-03	-2.89e-01	0.0898
10551	AGR2	GSM4909297	Human	Breast	IDC	4.45e-13	6.34e-01	0.1517
10551	AGR2	GSM4909298	Human	Breast	IDC	2.50e-02	1.54e-01	0.1551
10551	AGR2	GSM4909302	Human	Breast	IDC	1.39e-03	3.91e-01	0.1545
10551	AGR2	GSM4909303	Human	Breast	IDC	4.24e-02	4.53e-01	0.0438
10551	AGR2	GSM4909304	Human	Breast	IDC	3.52e-44	9.43e-01	0.1636
10551	AGR2	GSM4909305	Human	Breast	IDC	2.74e-03	2.17e-01	0.0436
10551	AGR2	GSM4909306	Human	Breast	IDC	5.21e-11	4.67e-01	0.1564
10551	AGR2	GSM4909307	Human	Breast	IDC	3.51e-34	9.15e-01	0.1569
10551	AGR2	GSM4909308	Human	Breast	IDC	3.59e-99	1.45e+00	0.158
10551	AGR2	GSM4909309	Human	Breast	IDC	5.38e-20	7.67e-01	0.0483
10551	AGR2	GSM4909311	Human	Breast	IDC	2.29e-03	-1.52e-01	0.1534

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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:00069869	Breast	Precancer	response to unfolded protein	28/1080	137/18723	3.81e-09	3.00e-07	28
GO:00359669	Breast	Precancer	response to topologically incorrect protein	29/1080	159/18723	3.00e-08	1.89e-06	29
GO:00349769	Breast	Precancer	response to endoplasmic reticulum stress	38/1080	256/18723	7.89e-08	4.60e-06	38
GO:00346209	Breast	Precancer	cellular response to unfolded protein	21/1080	96/18723	9.80e-08	5.46e-06	21
GO:00457859	Breast	Precancer	positive regulation of cell adhesion	52/1080	437/18723	5.74e-07	2.49e-05	52
GO:00359679	Breast	Precancer	cellular response to topologically incorrect protein	22/1080	116/18723	6.84e-07	2.80e-05	22
GO:19058979	Breast	Precancer	regulation of response to endoplasmic reticulum stress	16/1080	82/18723	1.53e-05	3.75e-04	16
GO:00309687	Breast	Precancer	endoplasmic reticulum unfolded protein response	15/1080	74/18723	1.74e-05	4.17e-04	15
GO:00508789	Breast	Precancer	regulation of body fluid levels	40/1080	379/18723	1.68e-04	2.77e-03	40
GO:19038299	Breast	Precancer	positive regulation of cellular protein localization	30/1080	276/18723	6.48e-04	7.99e-03	30
GO:00604792	Breast	Precancer	lung cell differentiation	6/1080	24/18723	1.99e-03	1.90e-02	6
GO:00364992	Breast	Precancer	PERK-mediated unfolded protein response	5/1080	18/18723	2.88e-03	2.49e-02	5
GO:19054777	Breast	Precancer	positive regulation of protein localization to membrane	14/1080	106/18723	3.07e-03	2.62e-02	14
GO:00069845	Breast	Precancer	ER-nucleus signaling pathway	8/1080	46/18723	4.40e-03	3.43e-02	8
GO:00108119	Breast	Precancer	positive regulation of cell-substrate adhesion	15/1080	123/18723	4.80e-03	3.64e-02	15
GO:19043757	Breast	Precancer	regulation of protein localization to cell periphery	15/1080	125/18723	5.58e-03	4.07e-02	15
GO:19054757	Breast	Precancer	regulation of protein localization to membrane	19/1080	175/18723	5.98e-03	4.22e-02	19
GO:19043778	Breast	Precancer	positive regulation of protein localization to cell periphery	10/1080	69/18723	5.98e-03	4.22e-02	10
GO:19001016	Breast	Precancer	regulation of endoplasmic reticulum unfolded protein response	6/1080	30/18723	6.54e-03	4.51e-02	6
GO:19030767	Breast	Precancer	regulation of protein localization to plasma membrane	13/1080	104/18723	6.79e-03	4.65e-02	13

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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

AGR2

SNV

Missense_Mutation

rs375782337

c.418G>A

p.Asp140Asn

p.D140N

O95994

protein_coding

deleterious(0)

probably_damaging(0.956)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

AGR2

SNV

Missense_Mutation

novel

c.226N>G

p.His76Asp

p.H76D

O95994

protein_coding

deleterious(0.01)

probably_damaging(0.964)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

AGR2

SNV

Missense_Mutation

c.281N>G

p.Asn94Ser

p.N94S

O95994

protein_coding

tolerated(0.87)

benign(0)

TCGA-CA-6718-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

AGR2

SNV

Missense_Mutation

rs755871634

c.443N>A

p.Arg148His

p.R148H

O95994

protein_coding

tolerated(0.14)

benign(0.006)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AGR2

SNV

Missense_Mutation

c.93G>T

p.Lys31Asn

p.K31N

O95994

protein_coding

tolerated(0.05)

benign(0.444)

TCGA-AX-A0J0-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AGR2

SNV

Missense_Mutation

novel

c.31C>A

p.Leu11Ile

p.L11I

O95994

protein_coding

deleterious(0.03)

benign(0.048)

TCGA-AX-A2HC-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

AGR2

SNV

Missense_Mutation

c.457N>A

p.Glu153Lys

p.E153K

O95994

protein_coding

tolerated(0.09)

benign(0.227)

TCGA-AX-A2HD-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

III/IV

Unknown

AGR2

SNV

Missense_Mutation

c.264N>T

p.Lys88Asn

p.K88N

O95994

protein_coding

deleterious(0)

probably_damaging(0.942)

TCGA-AX-A2HD-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

III/IV

Unknown

AGR2

SNV

Missense_Mutation

rs755871634

c.443N>A

p.Arg148His

p.R148H

O95994

protein_coding

tolerated(0.14)

benign(0.006)

TCGA-BG-A0LX-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AGR2

SNV

Missense_Mutation

c.264N>T

p.Lys88Asn

p.K88N

O95994

protein_coding

deleterious(0)

probably_damaging(0.942)

TCGA-D1-A103-01

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

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