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: ERAP1

Gene summary for ERAP1

Gene summary.

Gene information	Species	Human
	Gene symbol	ERAP1
	Gene ID	51752
	Gene name	endoplasmic reticulum aminopeptidase 1
	Gene Alias	A-LAP
	Cytomap	5q15
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	Q9NZ08

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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
51752	ERAP1	P26T-E	Human	Esophagus	ESCC	3.37e-15	2.21e-01	0.1276
51752	ERAP1	P27T-E	Human	Esophagus	ESCC	1.67e-13	1.31e-01	0.1055
51752	ERAP1	P28T-E	Human	Esophagus	ESCC	9.79e-03	-4.52e-02	0.1149
51752	ERAP1	P31T-E	Human	Esophagus	ESCC	1.89e-04	-3.30e-02	0.1251
51752	ERAP1	P32T-E	Human	Esophagus	ESCC	7.50e-10	7.71e-02	0.1666
51752	ERAP1	P36T-E	Human	Esophagus	ESCC	3.70e-08	3.02e-01	0.1187
51752	ERAP1	P37T-E	Human	Esophagus	ESCC	1.30e-12	1.17e-01	0.1371
51752	ERAP1	P39T-E	Human	Esophagus	ESCC	1.35e-09	3.71e-02	0.0894
51752	ERAP1	P42T-E	Human	Esophagus	ESCC	2.28e-10	2.01e-01	0.1175
51752	ERAP1	P47T-E	Human	Esophagus	ESCC	2.97e-05	7.51e-02	0.1067
51752	ERAP1	P48T-E	Human	Esophagus	ESCC	3.30e-05	1.27e-01	0.0959
51752	ERAP1	P52T-E	Human	Esophagus	ESCC	3.94e-16	2.74e-01	0.1555
51752	ERAP1	P54T-E	Human	Esophagus	ESCC	3.93e-09	1.97e-01	0.0975
51752	ERAP1	P56T-E	Human	Esophagus	ESCC	3.17e-07	5.75e-01	0.1613
51752	ERAP1	P57T-E	Human	Esophagus	ESCC	5.94e-05	3.80e-02	0.0926
51752	ERAP1	P61T-E	Human	Esophagus	ESCC	1.16e-10	1.42e-01	0.099
51752	ERAP1	P62T-E	Human	Esophagus	ESCC	9.27e-34	6.55e-01	0.1302
51752	ERAP1	P65T-E	Human	Esophagus	ESCC	1.27e-07	6.89e-02	0.0978
51752	ERAP1	P74T-E	Human	Esophagus	ESCC	4.35e-07	1.99e-01	0.1479
51752	ERAP1	P75T-E	Human	Esophagus	ESCC	3.06e-11	1.31e-01	0.1125

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
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
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:00028318	Esophagus	ESCC	regulation of response to biotic stimulus	191/8552	327/18723	2.12e-06	2.45e-05	191
GO:00454449	Esophagus	ESCC	fat cell differentiation	135/8552	229/18723	3.38e-05	2.78e-04	135
GO:004800220	Esophagus	ESCC	antigen processing and presentation of peptide antigen	44/8552	62/18723	4.81e-05	3.78e-04	44
GO:001988225	Esophagus	ESCC	antigen processing and presentation	67/8552	106/18723	2.03e-04	1.28e-03	67
GO:00450885	Esophagus	ESCC	regulation of innate immune response	125/8552	218/18723	3.34e-04	1.96e-03	125
GO:000247418	Esophagus	ESCC	antigen processing and presentation of peptide antigen via MHC class I	22/8552	28/18723	3.95e-04	2.26e-03	22
GO:00065095	Esophagus	ESCC	membrane protein ectodomain proteolysis	31/8552	43/18723	4.04e-04	2.30e-03	31
GO:00336195	Esophagus	ESCC	membrane protein proteolysis	39/8552	57/18723	4.34e-04	2.44e-03	39
GO:000248325	Esophagus	ESCC	antigen processing and presentation of endogenous peptide antigen	16/8552	19/18723	6.45e-04	3.43e-03	16
GO:001988519	Esophagus	ESCC	antigen processing and presentation of endogenous peptide antigen via MHC class I	14/8552	17/18723	2.22e-03	9.78e-03	14
GO:0019883111	Esophagus	ESCC	antigen processing and presentation of endogenous antigen	18/8552	26/18723	1.32e-02	4.31e-02	18
GO:00336192	Liver	Cirrhotic	membrane protein proteolysis	31/4634	57/18723	1.55e-06	3.02e-05	31
GO:00065092	Liver	Cirrhotic	membrane protein ectodomain proteolysis	24/4634	43/18723	1.30e-05	1.82e-04	24
GO:00198827	Liver	Cirrhotic	antigen processing and presentation	44/4634	106/18723	1.07e-04	1.10e-03	44
GO:00480027	Liver	Cirrhotic	antigen processing and presentation of peptide antigen	29/4634	62/18723	1.34e-04	1.31e-03	29
GO:00024837	Liver	Cirrhotic	antigen processing and presentation of endogenous peptide antigen	12/4634	19/18723	4.35e-04	3.55e-03	12
GO:00024747	Liver	Cirrhotic	antigen processing and presentation of peptide antigen via MHC class I	15/4634	28/18723	9.91e-04	6.98e-03	15
GO:001988512	Liver	Cirrhotic	antigen processing and presentation of endogenous peptide antigen via MHC class I	10/4634	17/18723	2.85e-03	1.64e-02	10
GO:00198837	Liver	Cirrhotic	antigen processing and presentation of endogenous antigen	13/4634	26/18723	4.72e-03	2.48e-02	13
GO:00028311	Liver	Cirrhotic	regulation of response to biotic stimulus	101/4634	327/18723	6.58e-03	3.25e-02	101

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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

ERAP1

SNV

Missense_Mutation

c.2092N>G

p.Gln698Glu

p.Q698E

Q9NZ08

protein_coding

tolerated(0.13)

benign(0.007)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ERAP1

SNV

Missense_Mutation

c.1063N>G

p.Leu355Val

p.L355V

Q9NZ08

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-BH-A1EV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

ERAP1

insertion

In_Frame_Ins

novel

c.1684_1685insCCGTCTCTACTAAAATACAAAAAATGAGCCGGG

p.Leu562delinsProValSerThrLysIleGlnLysMetSerArgVal

p.L562delinsPVSTKIQKMSRV

Q9NZ08

protein_coding

TCGA-A2-A0CP-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ERAP1

insertion

Nonsense_Mutation

novel

c.1544_1545insAAAAATATCCTTATAGCAAAATAGAAAATAAATTCTGACTGA

p.Val515_Asp516insLysIleSerLeuTerGlnAsnArgLysTerIleLeuThrGlu

p.V515_D516insKISL*QNRK*ILTE

Q9NZ08

protein_coding

TCGA-AN-A0FS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ERAP1

deletion

Frame_Shift_Del

novel

c.1199delN

p.Phe400SerfsTer11

p.F400Sfs*11

Q9NZ08

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ERAP1

SNV

Missense_Mutation

novel

c.2347G>T

p.Asp783Tyr

p.D783Y

Q9NZ08

protein_coding

deleterious(0)

possibly_damaging(0.849)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ERAP1

SNV

Missense_Mutation

rs149653730

c.424G>A

p.Gly142Arg

p.G142R

Q9NZ08

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ERAP1

SNV

Missense_Mutation

c.2690N>G

p.Ser897Cys

p.S897C

Q9NZ08

protein_coding

deleterious(0)

probably_damaging(0.969)

TCGA-IR-A3LI-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ERAP1

SNV

Missense_Mutation

c.1225N>A

p.Glu409Lys

p.E409K

Q9NZ08

protein_coding

tolerated(0.62)

benign(0.028)

TCGA-JX-A3Q0-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

ERAP1

SNV

Missense_Mutation

novel

c.379C>A

p.Arg127Ser

p.R127S

Q9NZ08

protein_coding

tolerated(0.5)

benign(0.003)

TCGA-A6-A565-01

Colorectum

colon adenocarcinoma

Female

<65

III/IV

Unspecific

5FU

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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
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME		TCMDC-124377	CHEMBL531269
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME	inhibitor	252166866
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME	inhibitor	CHEMBL2103847	TOSEDOSTAT
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME		UMBELLIFERONE	UMBELLIFERONE
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME		TCMDC-124673	CHEMBL587247
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME	inhibitor	348353641
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME	inhibitor	348353642
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME		SCOPOLETIN	SCOPOLETIN
51752	ERAP1	PROTEASE, ENZYME, DRUGGABLE GENOME		ESCULETIN	ESCULETIN

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