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: EPHX2

Gene summary for EPHX2

Gene summary.

Gene information	Species	Human
	Gene symbol	EPHX2
	Gene ID	2053
	Gene name	epoxide hydrolase 2
	Gene Alias	ABHD20
	Cytomap	8p21.2-p21.1
	Gene Type	protein-coding
	GO ID	GO:0006066
	UniProtAcc	P34913

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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
2053	EPHX2	HTA11_2487_2000001011	Human	Colorectum	SER	8.37e-05	4.59e-01	-0.1808
2053	EPHX2	HTA11_78_2000001011	Human	Colorectum	AD	6.33e-04	4.23e-01	-0.1088
2053	EPHX2	HTA11_347_2000001011	Human	Colorectum	AD	1.68e-29	8.81e-01	-0.1954
2053	EPHX2	HTA11_83_2000001011	Human	Colorectum	SER	1.04e-04	5.19e-01	-0.1526
2053	EPHX2	HTA11_696_2000001011	Human	Colorectum	AD	9.63e-03	3.74e-01	-0.1464
2053	EPHX2	HTA11_866_2000001011	Human	Colorectum	AD	8.94e-08	4.16e-01	-0.1001
2053	EPHX2	HTA11_1391_2000001011	Human	Colorectum	AD	2.67e-06	6.05e-01	-0.059
2053	EPHX2	HTA11_2992_2000001011	Human	Colorectum	SER	3.16e-02	6.35e-01	-0.1706
2053	EPHX2	HTA11_866_3004761011	Human	Colorectum	AD	3.54e-05	4.31e-01	0.096
2053	EPHX2	HTA11_7663_2000001011	Human	Colorectum	SER	4.23e-04	7.69e-01	0.0131
2053	EPHX2	HTA11_10711_2000001011	Human	Colorectum	AD	1.47e-02	4.83e-01	0.0338
2053	EPHX2	HTA11_7696_3000711011	Human	Colorectum	AD	2.18e-08	5.33e-01	0.0674
2053	EPHX2	HTA11_6818_2000001011	Human	Colorectum	AD	1.88e-04	4.78e-01	0.0112
2053	EPHX2	HTA11_99999974143_84620	Human	Colorectum	MSS	6.54e-06	4.03e-01	0.3005
2053	EPHX2	A002-C-010	Human	Colorectum	FAP	1.46e-03	-1.66e-01	0.242
2053	EPHX2	A015-C-203	Human	Colorectum	FAP	5.26e-16	-5.99e-02	-0.1294
2053	EPHX2	A002-C-201	Human	Colorectum	FAP	3.35e-05	-1.47e-01	0.0324
2053	EPHX2	A001-C-119	Human	Colorectum	FAP	2.96e-02	-2.23e-01	-0.1557
2053	EPHX2	A001-C-108	Human	Colorectum	FAP	1.99e-09	-2.03e-01	-0.0272
2053	EPHX2	A002-C-205	Human	Colorectum	FAP	4.28e-11	-2.60e-01	-0.1236

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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

∗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:0019439	Colorectum	AD	aromatic compound catabolic process	146/3918	467/18723	7.48e-08	3.84e-06	146
GO:1901361	Colorectum	AD	organic cyclic compound catabolic process	153/3918	495/18723	8.23e-08	4.18e-06	153
GO:0009636	Colorectum	AD	response to toxic substance	88/3918	262/18723	1.12e-06	3.72e-05	88
GO:0016311	Colorectum	AD	dephosphorylation	123/3918	417/18723	1.84e-05	3.82e-04	123
GO:0006066	Colorectum	AD	alcohol metabolic process	106/3918	353/18723	3.02e-05	5.57e-04	106
GO:0030258	Colorectum	AD	lipid modification	67/3918	212/18723	1.66e-04	2.27e-03	67
GO:0018904	Colorectum	AD	ether metabolic process	14/3918	27/18723	3.72e-04	4.29e-03	14
GO:0062012	Colorectum	AD	regulation of small molecule metabolic process	93/3918	334/18723	1.46e-03	1.24e-02	93
GO:0008202	Colorectum	AD	steroid metabolic process	85/3918	319/18723	8.07e-03	4.75e-02	85
GO:00096361	Colorectum	SER	response to toxic substance	71/2897	262/18723	8.63e-07	4.07e-05	71
GO:00060661	Colorectum	SER	alcohol metabolic process	79/2897	353/18723	3.50e-04	5.50e-03	79
GO:19013611	Colorectum	SER	organic cyclic compound catabolic process	104/2897	495/18723	5.46e-04	7.63e-03	104
GO:00194391	Colorectum	SER	aromatic compound catabolic process	98/2897	467/18723	8.09e-04	1.01e-02	98
GO:00163111	Colorectum	SER	dephosphorylation	86/2897	417/18723	2.73e-03	2.46e-02	86
GO:00189041	Colorectum	SER	ether metabolic process	10/2897	27/18723	5.18e-03	3.95e-02	10
GO:00302581	Colorectum	SER	lipid modification	47/2897	212/18723	6.01e-03	4.38e-02	47
GO:19013612	Colorectum	MSS	organic cyclic compound catabolic process	148/3467	495/18723	3.47e-10	3.18e-08	148
GO:00194392	Colorectum	MSS	aromatic compound catabolic process	140/3467	467/18723	8.56e-10	6.85e-08	140
GO:00096362	Colorectum	MSS	response to toxic substance	73/3467	262/18723	1.26e-04	1.94e-03	73
GO:00060662	Colorectum	MSS	alcohol metabolic process	92/3467	353/18723	2.57e-04	3.46e-03	92

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05208	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa052081	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa052082	Colorectum	SER	Chemical carcinogenesis - reactive oxygen species	103/1580	223/8465	1.60e-21	7.57e-20	5.50e-20	103
hsa052083	Colorectum	SER	Chemical carcinogenesis - reactive oxygen species	103/1580	223/8465	1.60e-21	7.57e-20	5.50e-20	103
hsa052084	Colorectum	MSS	Chemical carcinogenesis - reactive oxygen species	118/1875	223/8465	2.71e-24	4.54e-22	2.78e-22	118
hsa052085	Colorectum	MSS	Chemical carcinogenesis - reactive oxygen species	118/1875	223/8465	2.71e-24	4.54e-22	2.78e-22	118
hsa052088	Colorectum	FAP	Chemical carcinogenesis - reactive oxygen species	78/1404	223/8465	1.08e-11	1.80e-09	1.09e-09	78
hsa052089	Colorectum	FAP	Chemical carcinogenesis - reactive oxygen species	78/1404	223/8465	1.08e-11	1.80e-09	1.09e-09	78
hsa05207	Colorectum	CRC	Chemical carcinogenesis - receptor activation	42/1091	212/8465	2.62e-03	1.75e-02	1.19e-02	42
hsa0520810	Colorectum	CRC	Chemical carcinogenesis - reactive oxygen species	43/1091	223/8465	3.96e-03	2.36e-02	1.60e-02	43
hsa052071	Colorectum	CRC	Chemical carcinogenesis - receptor activation	42/1091	212/8465	2.62e-03	1.75e-02	1.19e-02	42
hsa0520811	Colorectum	CRC	Chemical carcinogenesis - reactive oxygen species	43/1091	223/8465	3.96e-03	2.36e-02	1.60e-02	43
hsa05208211	Esophagus	ESCC	Chemical carcinogenesis - reactive oxygen species	168/4205	223/8465	1.83e-15	6.81e-14	3.49e-14	168
hsa041467	Esophagus	ESCC	Peroxisome	55/4205	82/8465	1.04e-03	3.27e-03	1.68e-03	55
hsa05208310	Esophagus	ESCC	Chemical carcinogenesis - reactive oxygen species	168/4205	223/8465	1.83e-15	6.81e-14	3.49e-14	168
hsa0414612	Esophagus	ESCC	Peroxisome	55/4205	82/8465	1.04e-03	3.27e-03	1.68e-03	55
hsa0520814	Liver	NAFLD	Chemical carcinogenesis - reactive oxygen species	44/1043	223/8465	9.22e-04	1.31e-02	1.06e-02	44
hsa04146	Liver	NAFLD	Peroxisome	19/1043	82/8465	4.37e-03	4.10e-02	3.30e-02	19
hsa0520815	Liver	NAFLD	Chemical carcinogenesis - reactive oxygen species	44/1043	223/8465	9.22e-04	1.31e-02	1.06e-02	44
hsa041461	Liver	NAFLD	Peroxisome	19/1043	82/8465	4.37e-03	4.10e-02	3.30e-02	19

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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

EPHX2

SNV

Missense_Mutation

c.559N>T

p.Gly187Trp

p.G187W

P34913

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-A7-A0DB-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

EPHX2

SNV

Missense_Mutation

novel

c.1408N>C

p.Glu470Gln

p.E470Q

P34913

protein_coding

tolerated(0.23)

benign(0.244)

TCGA-AC-A3W6-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

EPHX2

SNV

Missense_Mutation

rs754312469

c.805N>A

p.Glu269Lys

p.E269K

P34913

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

EPHX2

insertion

Nonsense_Mutation

novel

c.401_402insAGTCTAAGACATGAGGTCAAGTTCATCCATAGGCGTTGACT

p.Asp134GlufsTer3

p.D134Efs*3

P34913

protein_coding

TCGA-A2-A0EX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

EPHX2

insertion

Frame_Shift_Ins

novel

c.563_564insACATTCA

p.Asn189HisfsTer3

p.N189Hfs*3

P34913

protein_coding

TCGA-BH-A0B1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

EPHX2

insertion

In_Frame_Ins

novel

c.565_566insTACCCCAATCTATCCATTCTTCTATTG

p.Asn189delinsIleProGlnSerIleHisSerSerIleAsp

p.N189delinsIPQSIHSSID

P34913

protein_coding

TCGA-BH-A0B1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

EPHX2

SNV

Missense_Mutation

rs747000602

c.458N>T

p.Ser153Leu

p.S153L

P34913

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EPHX2

SNV

Missense_Mutation

c.1347N>G

p.Phe449Leu

p.F449L

P34913

protein_coding

deleterious(0.02)

benign(0.419)

TCGA-DS-A0VM-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EPHX2

SNV

Missense_Mutation

c.623N>T

p.Thr208Met

p.T208M

P34913

protein_coding

tolerated(0.19)

benign(0.029)

TCGA-AA-3663-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

EPHX2

SNV

Missense_Mutation

c.1307N>A

p.Pro436His

p.P436H

P34913

protein_coding

deleterious(0.02)

probably_damaging(0.984)

TCGA-AA-A01R-01

Colorectum

colon adenocarcinoma

Male

<65

III/IV

Chemotherapy

5-fluorouracil

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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
2053	EPHX2	DRUGGABLE GENOME, ENZYME	inhibitor	178101928
2053	EPHX2	DRUGGABLE GENOME, ENZYME	inhibitor	178103826	OXAPROZIN
2053	EPHX2	DRUGGABLE GENOME, ENZYME		lithium	LITHIUM	29121268
2053	EPHX2	DRUGGABLE GENOME, ENZYME	inhibitor	363894191
2053	EPHX2	DRUGGABLE GENOME, ENZYME		6BIO	6BIO	24697244
2053	EPHX2	DRUGGABLE GENOME, ENZYME		FULVESTRANT	FULVESTRANT	23684894
2053	EPHX2	DRUGGABLE GENOME, ENZYME	inhibitor	381118834
2053	EPHX2	DRUGGABLE GENOME, ENZYME		AR9281	AR9281
2053	EPHX2	DRUGGABLE GENOME, ENZYME		ALOE-EMODIN	ALOE-EMODIN	26372074
2053	EPHX2	DRUGGABLE GENOME, ENZYME	inhibitor	387065576

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