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: ERAP2

Gene summary for ERAP2

Gene summary.

Gene information	Species	Human
	Gene symbol	ERAP2
	Gene ID	64167
	Gene name	endoplasmic reticulum aminopeptidase 2
	Gene Alias	L-RAP
	Cytomap	5q15
	Gene Type	protein-coding
	GO ID	GO:0002250
	UniProtAcc	B2R769

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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
64167	ERAP2	P56T-E	Human	Esophagus	ESCC	4.86e-08	1.08e+00	0.1613
64167	ERAP2	P57T-E	Human	Esophagus	ESCC	2.60e-12	1.73e-01	0.0926
64167	ERAP2	P61T-E	Human	Esophagus	ESCC	1.43e-09	3.87e-01	0.099
64167	ERAP2	P62T-E	Human	Esophagus	ESCC	6.27e-51	9.37e-01	0.1302
64167	ERAP2	P65T-E	Human	Esophagus	ESCC	1.59e-06	1.20e-01	0.0978
64167	ERAP2	P75T-E	Human	Esophagus	ESCC	9.20e-20	5.06e-01	0.1125
64167	ERAP2	P76T-E	Human	Esophagus	ESCC	1.99e-06	6.05e-02	0.1207
64167	ERAP2	P80T-E	Human	Esophagus	ESCC	7.79e-27	8.90e-01	0.155
64167	ERAP2	P82T-E	Human	Esophagus	ESCC	3.77e-04	5.10e-01	0.1072
64167	ERAP2	P83T-E	Human	Esophagus	ESCC	5.52e-13	4.16e-01	0.1738
64167	ERAP2	P107T-E	Human	Esophagus	ESCC	5.10e-25	6.51e-01	0.171
64167	ERAP2	P127T-E	Human	Esophagus	ESCC	1.50e-14	3.80e-01	0.0826
64167	ERAP2	P130T-E	Human	Esophagus	ESCC	1.53e-04	7.82e-03	0.1676
64167	ERAP2	HCC1_Meng	Human	Liver	HCC	3.40e-29	1.61e-02	0.0246
64167	ERAP2	HCC1	Human	Liver	HCC	3.34e-09	9.01e-01	0.5336
64167	ERAP2	HCC2	Human	Liver	HCC	3.02e-17	1.19e+00	0.5341
64167	ERAP2	HCC5	Human	Liver	HCC	1.11e-29	3.38e+00	0.4932
64167	ERAP2	S027	Human	Liver	HCC	9.78e-03	3.33e-01	0.2446
64167	ERAP2	S028	Human	Liver	HCC	1.12e-08	3.94e-01	0.2503
64167	ERAP2	S029	Human	Liver	HCC	7.02e-08	4.85e-01	0.2581

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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
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: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: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: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:001988212	Liver	HCC	antigen processing and presentation	65/7958	106/18723	7.06e-05	6.37e-04	65
GO:000248312	Liver	HCC	antigen processing and presentation of endogenous peptide antigen	16/7958	19/18723	2.37e-04	1.79e-03	16
GO:004800212	Liver	HCC	antigen processing and presentation of peptide antigen	40/7958	62/18723	3.84e-04	2.62e-03	40
GO:000247411	Liver	HCC	antigen processing and presentation of peptide antigen via MHC class I	21/7958	28/18723	4.94e-04	3.23e-03	21
GO:001988522	Liver	HCC	antigen processing and presentation of endogenous peptide antigen via MHC class I	14/7958	17/18723	9.39e-04	5.47e-03	14
GO:001988312	Liver	HCC	antigen processing and presentation of endogenous antigen	18/7958	26/18723	5.37e-03	2.24e-02	18
GO:001988220	Oral cavity	OSCC	antigen processing and presentation	65/7305	106/18723	2.69e-06	3.32e-05	65
GO:004800219	Oral cavity	OSCC	antigen processing and presentation of peptide antigen	40/7305	62/18723	4.20e-05	3.63e-04	40
GO:000247416	Oral cavity	OSCC	antigen processing and presentation of peptide antigen via MHC class I	21/7305	28/18723	1.19e-04	8.54e-04	21
GO:000248320	Oral cavity	OSCC	antigen processing and presentation of endogenous peptide antigen	15/7305	19/18723	4.64e-04	2.76e-03	15
GO:001988517	Oral cavity	OSCC	antigen processing and presentation of endogenous peptide antigen via MHC class I	13/7305	17/18723	1.92e-03	8.94e-03	13
GO:001988319	Oral cavity	OSCC	antigen processing and presentation of endogenous antigen	17/7305	26/18723	5.83e-03	2.23e-02	17
GO:0019882110	Oral cavity	LP	antigen processing and presentation	48/4623	106/18723	2.96e-06	6.44e-05	48
GO:0048002110	Oral cavity	LP	antigen processing and presentation of peptide antigen	30/4623	62/18723	4.46e-05	6.35e-04	30

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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

ERAP2

SNV

Missense_Mutation

c.1480N>T

p.Asp494Tyr

p.D494Y

Q6P179

protein_coding

deleterious(0)

probably_damaging(0.945)

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

ERAP2

SNV

Missense_Mutation

c.1726N>C

p.Glu576Gln

p.E576Q

Q6P179

protein_coding

tolerated(0.22)

benign(0.017)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ERAP2

SNV

Missense_Mutation

rs113436741

c.1666N>A

p.Gly556Arg

p.G556R

Q6P179

protein_coding

deleterious(0.01)

benign(0.379)

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

ERAP2

SNV

Missense_Mutation

novel

c.2123N>G

p.His708Arg

p.H708R

Q6P179

protein_coding

tolerated(0.62)

benign(0)

TCGA-AR-A2LR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

ERAP2

SNV

Missense_Mutation

c.367N>G

p.Gln123Glu

p.Q123E

Q6P179

protein_coding

tolerated(1)

benign(0.001)

TCGA-E2-A1LG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ERAP2

SNV

Missense_Mutation

novel

c.1690G>C

p.Glu564Gln

p.E564Q

Q6P179

protein_coding

deleterious(0.01)

benign(0.342)

TCGA-GM-A3NW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

fluorouracil

ERAP2

SNV

Missense_Mutation

novel

c.1343A>C

p.Glu448Ala

p.E448A

Q6P179

protein_coding

deleterious(0.01)

benign(0.401)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ERAP2

SNV

Missense_Mutation

rs199653916

c.2550N>G

p.Ile850Met

p.I850M

Q6P179

protein_coding

tolerated(0.08)

possibly_damaging(0.899)

TCGA-IR-A3LF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ERAP2

SNV

Missense_Mutation

novel

c.2871N>A

p.Met957Ile

p.M957I

Q6P179

protein_coding

tolerated(0.12)

benign(0)

TCGA-ZJ-AB0H-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

ERAP2

SNV

Missense_Mutation

c.1115T>C

p.Leu372Pro

p.L372P

Q6P179

protein_coding

deleterious(0)

probably_damaging(0.932)

TCGA-A6-5661-01

Colorectum

colon adenocarcinoma

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
64167	ERAP2	DRUGGABLE GENOME, PROTEASE, ENZYME, NEUTRAL ZINC METALLOPEPTIDASE	inhibitor	348353642
64167	ERAP2	DRUGGABLE GENOME, PROTEASE, ENZYME, NEUTRAL ZINC METALLOPEPTIDASE	inhibitor	252166866
64167	ERAP2	DRUGGABLE GENOME, PROTEASE, ENZYME, NEUTRAL ZINC METALLOPEPTIDASE		ESCULETIN	ESCULETIN
64167	ERAP2	DRUGGABLE GENOME, PROTEASE, ENZYME, NEUTRAL ZINC METALLOPEPTIDASE	inhibitor	348353641
64167	ERAP2	DRUGGABLE GENOME, PROTEASE, ENZYME, NEUTRAL ZINC METALLOPEPTIDASE	inhibitor	CHEMBL2103847	TOSEDOSTAT
64167	ERAP2	DRUGGABLE GENOME, PROTEASE, ENZYME, NEUTRAL ZINC METALLOPEPTIDASE		SCOPOLETIN	SCOPOLETIN

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