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: ETS2

Gene summary for ETS2

Gene summary.

Gene information	Species	Human
	Gene symbol	ETS2
	Gene ID	2114
	Gene name	ETS proto-oncogene 2, transcription factor
	Gene Alias	ETS2IT1
	Cytomap	21q22.2
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	P15036

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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
2114	ETS2	CA_HPV_2	Human	Cervix	CC	1.13e-05	3.26e-01	0.0391
2114	ETS2	CA_HPV_3	Human	Cervix	CC	1.78e-10	2.96e-01	0.0414
2114	ETS2	N_HPV_2	Human	Cervix	N_HPV	3.54e-07	3.13e-01	-0.0131
2114	ETS2	CCI_1	Human	Cervix	CC	3.66e-06	7.43e-01	0.528
2114	ETS2	CCI_2	Human	Cervix	CC	5.77e-12	1.23e+00	0.5249
2114	ETS2	CCI_3	Human	Cervix	CC	5.79e-03	7.13e-01	0.516
2114	ETS2	CCII_1	Human	Cervix	CC	2.68e-05	4.40e-01	0.3249
2114	ETS2	sample1	Human	Cervix	CC	1.19e-24	9.07e-01	0.0959
2114	ETS2	sample3	Human	Cervix	CC	3.05e-11	4.41e-01	0.1387
2114	ETS2	T1	Human	Cervix	CC	1.86e-48	9.71e-01	0.0918
2114	ETS2	T2	Human	Cervix	CC	1.97e-03	5.48e-01	0.0709
2114	ETS2	T3	Human	Cervix	CC	3.45e-14	4.29e-01	0.1389
2114	ETS2	HTA11_3410_2000001011	Human	Colorectum	AD	8.44e-05	2.60e-01	0.0155
2114	ETS2	HTA11_7862_2000001011	Human	Colorectum	AD	1.44e-03	6.68e-01	-0.0179
2114	ETS2	HTA11_866_3004761011	Human	Colorectum	AD	1.02e-31	1.21e+00	0.096
2114	ETS2	HTA11_4255_2000001011	Human	Colorectum	SER	3.41e-03	6.59e-01	0.0446
2114	ETS2	HTA11_7663_2000001011	Human	Colorectum	SER	6.20e-09	1.09e+00	0.0131
2114	ETS2	HTA11_7696_3000711011	Human	Colorectum	AD	1.02e-14	8.94e-01	0.0674
2114	ETS2	HTA11_6818_2000001011	Human	Colorectum	AD	8.61e-06	7.93e-01	0.0112
2114	ETS2	HTA11_6818_2000001021	Human	Colorectum	AD	4.10e-12	8.69e-01	0.0588

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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
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
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
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:00073695	Cervix	CC	gastrulation	42/2311	185/18723	5.83e-05	8.46e-04	42
GO:0001704	Cervix	CC	formation of primary germ layer	27/2311	121/18723	1.49e-03	1.16e-02	27
GO:0007369	Colorectum	AD	gastrulation	53/3918	185/18723	7.60e-03	4.60e-02	53
GO:00073691	Colorectum	SER	gastrulation	43/2897	185/18723	3.44e-03	2.92e-02	43
GO:00073692	Colorectum	FAP	gastrulation	42/2622	185/18723	8.97e-04	9.10e-03	42
GO:0009952	Colorectum	FAP	anterior/posterior pattern specification	41/2622	201/18723	7.82e-03	4.63e-02	41
GO:00073693	Colorectum	CRC	gastrulation	36/2078	185/18723	5.54e-04	7.70e-03	36
GO:00099521	Colorectum	CRC	anterior/posterior pattern specification	36/2078	201/18723	2.56e-03	2.40e-02	36
GO:00073698	Esophagus	ESCC	gastrulation	115/8552	185/18723	4.35e-06	4.64e-05	115
GO:00017044	Esophagus	ESCC	formation of primary germ layer	75/8552	121/18723	2.17e-04	1.36e-03	75
GO:00073697	Oral cavity	OSCC	gastrulation	95/7305	185/18723	4.17e-04	2.54e-03	95
GO:00017043	Oral cavity	OSCC	formation of primary germ layer	65/7305	121/18723	7.08e-04	3.90e-03	65
GO:000736913	Oral cavity	EOLP	gastrulation	39/2218	185/18723	2.29e-04	2.25e-03	39
GO:000170412	Oral cavity	EOLP	formation of primary germ layer	24/2218	121/18723	7.53e-03	3.62e-02	24
GO:00073696	Prostate	BPH	gastrulation	50/3107	185/18723	2.20e-04	1.78e-03	50
GO:00017042	Prostate	BPH	formation of primary germ layer	35/3107	121/18723	4.80e-04	3.42e-03	35
GO:000736912	Prostate	Tumor	gastrulation	52/3246	185/18723	1.76e-04	1.55e-03	52
GO:000170411	Prostate	Tumor	formation of primary germ layer	36/3246	121/18723	5.22e-04	3.82e-03	36
GO:00073699	Skin	AK	gastrulation	41/1910	185/18723	1.32e-06	4.13e-05	41
GO:00017045	Skin	AK	formation of primary germ layer	30/1910	121/18723	3.12e-06	8.17e-05	30

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa040142	Cervix	CC	Ras signaling pathway	51/1267	236/8465	3.55e-03	1.34e-02	7.91e-03	51
hsa05166110	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0401411	Cervix	CC	Ras signaling pathway	51/1267	236/8465	3.55e-03	1.34e-02	7.91e-03	51
hsa0516643	Cervix	N_HPV	Human T-cell leukemia virus 1 infection	22/349	222/8465	1.17e-04	1.18e-03	9.23e-04	22
hsa0516653	Cervix	N_HPV	Human T-cell leukemia virus 1 infection	22/349	222/8465	1.17e-04	1.18e-03	9.23e-04	22
hsa05166	Colorectum	AD	Human T-cell leukemia virus 1 infection	72/2092	222/8465	5.24e-03	2.44e-02	1.55e-02	72
hsa051661	Colorectum	AD	Human T-cell leukemia virus 1 infection	72/2092	222/8465	5.24e-03	2.44e-02	1.55e-02	72
hsa051662	Colorectum	MSS	Human T-cell leukemia virus 1 infection	68/1875	222/8465	1.84e-03	9.61e-03	5.89e-03	68
hsa051663	Colorectum	MSS	Human T-cell leukemia virus 1 infection	68/1875	222/8465	1.84e-03	9.61e-03	5.89e-03	68
hsa04014	Colorectum	CRC	Ras signaling pathway	49/1091	236/8465	4.04e-04	4.50e-03	3.05e-03	49
hsa040141	Colorectum	CRC	Ras signaling pathway	49/1091	236/8465	4.04e-04	4.50e-03	3.05e-03	49
hsa05166211	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa05166310	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa0516614	Liver	Cirrhotic	Human T-cell leukemia virus 1 infection	87/2530	222/8465	1.69e-03	8.01e-03	4.94e-03	87
hsa0516615	Liver	Cirrhotic	Human T-cell leukemia virus 1 infection	87/2530	222/8465	1.69e-03	8.01e-03	4.94e-03	87
hsa0516622	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0516632	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0516630	Oral cavity	OSCC	Human T-cell leukemia virus 1 infection	150/3704	222/8465	3.68e-13	7.26e-12	3.70e-12	150
hsa05166113	Oral cavity	OSCC	Human T-cell leukemia virus 1 infection	150/3704	222/8465	3.68e-13	7.26e-12	3.70e-12	150

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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
ETS2	MYOEPI	Breast	ADJ	PGF,CEBPD,VEGFA, etc.	6.14e-01
ETS2	MYOEPI	Breast	Precancer	PGF,CEBPD,VEGFA, etc.	5.89e-01
ETS2	MES	Cervix	Healthy	TM4SF1,KLF10,TGIF1, etc.	4.30e-01
ETS2	STM	Colorectum	AD	SLC12A2,ASCL2,CD44, etc.	1.49e-01
ETS2	STM	Colorectum	MSS	SLC12A2,ASCL2,CD44, etc.	2.68e-01
ETS2	STM	Colorectum	SER	SLC12A2,ASCL2,CD44, etc.	8.14e-02
ETS2	DIFF	Esophagus	Healthy	PHLDA1,MIR205HG,KLF6, etc.	8.29e-02
ETS2	STM	Esophagus	Healthy	PHLDA1,MIR205HG,KLF6, etc.	4.52e-01
ETS2	INMON	Lung	ADJ	NAMPT,VCAN,S100A8, etc.	1.78e-01
ETS2	INMON	Pancreas	PanIN	NLRP3,HBEGF,CSF2RA, etc.	6.56e-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

ETS2

SNV

Missense_Mutation

c.1236N>C

p.Met412Ile

p.M412I

P15036

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-A2-A0YK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ETS2

SNV

Missense_Mutation

c.557N>G

p.Ser186Cys

p.S186C

P15036

protein_coding

tolerated(0.11)

benign(0.425)

TCGA-A8-A09Q-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

ETS2

SNV

Missense_Mutation

c.443N>C

p.Leu148Pro

p.L148P

P15036

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AO-A0JF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

ETS2

SNV

Missense_Mutation

rs777149491

c.829N>A

p.Asp277Asn

p.D277N

P15036

protein_coding

tolerated(0.11)

possibly_damaging(0.632)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ETS2

SNV

Missense_Mutation

c.554N>T

p.Thr185Ile

p.T185I

P15036

protein_coding

tolerated(0.12)

benign(0.121)

TCGA-E2-A158-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

arimidex

ETS2

insertion

Frame_Shift_Ins

novel

c.712_713insGTCAGAGAGCTTCCTTCCCTCTCCAGAAAATAAATTATTC

p.Met238SerfsTer56

p.M238Sfs*56

P15036

protein_coding

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ETS2

SNV

Missense_Mutation

rs372145357

c.559N>A

p.Val187Ile

p.V187I

P15036

protein_coding

tolerated(0.55)

benign(0.007)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ETS2

SNV

Missense_Mutation

c.127N>G

p.Leu43Val

p.L43V

P15036

protein_coding

tolerated(0.2)

benign(0.251)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ETS2

SNV

Missense_Mutation

c.431N>C

p.Lys144Thr

p.K144T

P15036

protein_coding

deleterious(0)

probably_damaging(0.984)

TCGA-AA-A00N-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

ETS2

SNV

Missense_Mutation

c.825N>A

p.Asp275Glu

p.D275E

P15036

protein_coding

tolerated(0.79)

benign(0)

TCGA-AA-A02O-01

Colorectum

colon adenocarcinoma

Male

>=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
2114	ETS2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		TK216
2114	ETS2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		carboplatin	CARBOPLATIN	31616045
2114	ETS2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		gemcitabine	GEMCITABINE	31616045

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