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: EZH2

Gene summary for EZH2

Gene summary.

Gene information	Species	Human
	Gene symbol	EZH2
	Gene ID	2146
	Gene name	enhancer of zeste 2 polycomb repressive complex 2 subunit
	Gene Alias	ENX-1
	Cytomap	7q36.1
	Gene Type	protein-coding
	GO ID	GO:0000082
	UniProtAcc	Q15910

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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
2146	EZH2	CCI_1	Human	Cervix	CC	1.88e-03	5.71e-01	0.528
2146	EZH2	CCI_2	Human	Cervix	CC	9.88e-09	1.06e+00	0.5249
2146	EZH2	T1	Human	Cervix	CC	7.58e-05	3.02e-01	0.0918
2146	EZH2	AEH-subject1	Human	Endometrium	AEH	3.31e-06	2.78e-01	-0.3059
2146	EZH2	AEH-subject4	Human	Endometrium	AEH	3.81e-04	2.74e-01	-0.2657
2146	EZH2	AEH-subject5	Human	Endometrium	AEH	1.42e-03	2.76e-01	-0.2953
2146	EZH2	EEC-subject1	Human	Endometrium	EEC	3.30e-09	4.13e-01	-0.2682
2146	EZH2	EEC-subject5	Human	Endometrium	EEC	3.76e-02	2.36e-01	-0.249
2146	EZH2	GSM6177620_NYU_UCEC1_lib3_lib3	Human	Endometrium	EEC	3.05e-02	1.01e-01	-0.1883
2146	EZH2	GSM6177622_NYU_UCEC3_lib1_lib1	Human	Endometrium	EEC	6.89e-04	6.79e-02	-0.1917
2146	EZH2	GSM6177623_NYU_UCEC3_Vis	Human	Endometrium	EEC	1.50e-03	2.27e-01	-0.1269
2146	EZH2	LZE2T	Human	Esophagus	ESCC	1.07e-02	2.76e-01	0.082
2146	EZH2	LZE4T	Human	Esophagus	ESCC	5.75e-06	1.26e-01	0.0811
2146	EZH2	LZE7T	Human	Esophagus	ESCC	1.23e-04	3.44e-01	0.0667
2146	EZH2	LZE22T	Human	Esophagus	ESCC	1.58e-04	4.04e-01	0.068
2146	EZH2	LZE24T	Human	Esophagus	ESCC	2.82e-09	1.32e-01	0.0596
2146	EZH2	LZE21T	Human	Esophagus	ESCC	2.70e-02	2.57e-01	0.0655
2146	EZH2	P1T-E	Human	Esophagus	ESCC	5.30e-10	2.95e-01	0.0875
2146	EZH2	P2T-E	Human	Esophagus	ESCC	2.09e-19	2.71e-01	0.1177
2146	EZH2	P4T-E	Human	Esophagus	ESCC	5.48e-30	6.09e-01	0.1323

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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
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:00085446	Cervix	CC	epidermis development	83/2311	324/18723	3.91e-11	8.54e-09	83
GO:000697910	Cervix	CC	response to oxidative stress	102/2311	446/18723	2.99e-10	4.36e-08	102
GO:003367410	Cervix	CC	positive regulation of kinase activity	101/2311	467/18723	8.66e-09	7.22e-07	101
GO:00430877	Cervix	CC	regulation of GTPase activity	79/2311	348/18723	4.21e-08	2.60e-06	79
GO:00099137	Cervix	CC	epidermal cell differentiation	53/2311	202/18723	5.48e-08	3.25e-06	53
GO:00458608	Cervix	CC	positive regulation of protein kinase activity	85/2311	386/18723	5.61e-08	3.29e-06	85
GO:000030210	Cervix	CC	response to reactive oxygen species	56/2311	222/18723	1.00e-07	5.25e-06	56
GO:006219710	Cervix	CC	cellular response to chemical stress	76/2311	337/18723	1.01e-07	5.25e-06	76
GO:00447725	Cervix	CC	mitotic cell cycle phase transition	89/2311	424/18723	2.70e-07	1.12e-05	89
GO:00163587	Cervix	CC	dendrite development	58/2311	243/18723	4.52e-07	1.76e-05	58
GO:004254210	Cervix	CC	response to hydrogen peroxide	40/2311	146/18723	6.79e-07	2.46e-05	40
GO:00305229	Cervix	CC	intracellular receptor signaling pathway	60/2311	265/18723	1.89e-06	5.97e-05	60
GO:004887210	Cervix	CC	homeostasis of number of cells	61/2311	272/18723	2.17e-06	6.55e-05	61
GO:00719007	Cervix	CC	regulation of protein serine/threonine kinase activity	75/2311	359/18723	2.76e-06	8.02e-05	75
GO:00485118	Cervix	CC	rhythmic process	65/2311	298/18723	2.79e-06	8.04e-05	65
GO:003459910	Cervix	CC	cellular response to oxidative stress	63/2311	288/18723	3.58e-06	9.50e-05	63
GO:00109757	Cervix	CC	regulation of neuron projection development	88/2311	445/18723	4.26e-06	1.09e-04	88
GO:00510904	Cervix	CC	regulation of DNA-binding transcription factor activity	87/2311	440/18723	4.85e-06	1.22e-04	87
GO:00456822	Cervix	CC	regulation of epidermis development	22/2311	65/18723	5.56e-06	1.38e-04	22
GO:20000453	Cervix	CC	regulation of G1/S transition of mitotic cell cycle	37/2311	142/18723	6.33e-06	1.53e-04	37

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0031010	Esophagus	ESCC	Lysine degradation	41/4205	63/8465	9.63e-03	2.27e-02	1.16e-02	41
hsa0031013	Esophagus	ESCC	Lysine degradation	41/4205	63/8465	9.63e-03	2.27e-02	1.16e-02	41
hsa0031041	Liver	HCC	Lysine degradation	47/4020	63/8465	1.02e-05	7.58e-05	4.22e-05	47
hsa0031051	Liver	HCC	Lysine degradation	47/4020	63/8465	1.02e-05	7.58e-05	4.22e-05	47
hsa003109	Lung	IAC	Lysine degradation	17/1053	63/8465	1.35e-03	8.63e-03	5.73e-03	17
hsa0031012	Lung	IAC	Lysine degradation	17/1053	63/8465	1.35e-03	8.63e-03	5.73e-03	17

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
EZH2	BMEM	Liver	Healthy	NSD2,TYMS,DEK, etc.	6.25e-02
EZH2	BAS	Oral cavity	Healthy	PBK,DDX19B,BAX, etc.	2.36e-01

∗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

EZH2

SNV

Missense_Mutation

c.2168N>T

p.Thr723Ile

p.T723I

Q15910

protein_coding

deleterious(0.02)

probably_damaging(0.997)

TCGA-A2-A0YE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Taxotere

EZH2

SNV

Missense_Mutation

novel

c.1475N>A

p.Thr492Asn

p.T492N

Q15910

protein_coding

tolerated(0.27)

probably_damaging(0.997)

TCGA-E9-A1N5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

EZH2

insertion

In_Frame_Ins

novel

c.940_941insGAACAAGAATATTAACAAAAATAAAACGAACATTAG

p.Lys314delinsArgThrArgIleLeuThrLysIleLysArgThrLeuGlu

p.K314delinsRTRILTKIKRTLE

Q15910

protein_coding

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

EZH2

SNV

Missense_Mutation

novel

c.1903G>T

p.Asp635Tyr

p.D635Y

Q15910

protein_coding

deleterious(0.05)

probably_damaging(0.94)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EZH2

SNV

Missense_Mutation

c.1090N>T

p.Pro364Ser

p.P364S

Q15910

protein_coding

tolerated(0.48)

benign(0.178)

TCGA-C5-A1M9-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EZH2

SNV

Missense_Mutation

c.877N>C

p.Asp293His

p.D293H

Q15910

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-EX-A69L-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

EZH2

SNV

Missense_Mutation

c.2084C>T

p.Ser695Leu

p.S695L

Q15910

protein_coding

deleterious(0.05)

probably_damaging(0.994)

TCGA-IR-A3LA-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EZH2

SNV

Missense_Mutation

c.1760C>T

p.Pro587Leu

p.P587L

Q15910

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A6-2679-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

EZH2

SNV

Missense_Mutation

c.926N>G

p.Asn309Ser

p.N309S

Q15910

protein_coding

tolerated(0.17)

possibly_damaging(0.881)

TCGA-A6-3809-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

EZH2

SNV

Missense_Mutation

c.451N>C

p.Lys151Gln

p.K151Q

Q15910

protein_coding

deleterious(0.01)

possibly_damaging(0.727)

TCGA-A6-6141-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Chemotherapy

5-fu

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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
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		GSK2816126
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		PMID28394193-Compound-55
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR	inhibitor	178103592
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		PMID28394193-Compound-54
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		PMID28394193-Compound-20
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		DZNeP		25605023
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		PMID28394193-Compound-17
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		PMID28394193-Compound-40
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR		PMID28394193-Compound-12
2146	EZH2	CLINICALLY ACTIONABLE, ENZYME, METHYL TRANSFERASE, NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR	inhibitor	178103590	TAZEMETOSTAT

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