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: ATF2

Gene summary for ATF2

Gene summary.

Gene information	Species	Human
	Gene symbol	ATF2
	Gene ID	1386
	Gene name	activating transcription factor 2
	Gene Alias	CRE-BP1
	Cytomap	2q31.1
	Gene Type	protein-coding
	GO ID	GO:0000075
	UniProtAcc	P15336

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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
1386	ATF2	LZE4T	Human	Esophagus	ESCC	8.37e-18	4.11e-01	0.0811
1386	ATF2	LZE5T	Human	Esophagus	ESCC	9.01e-07	2.20e-01	0.0514
1386	ATF2	LZE7T	Human	Esophagus	ESCC	1.43e-04	2.24e-01	0.0667
1386	ATF2	LZE8T	Human	Esophagus	ESCC	9.88e-05	1.33e-01	0.067
1386	ATF2	LZE20T	Human	Esophagus	ESCC	3.31e-04	6.52e-02	0.0662
1386	ATF2	LZE24T	Human	Esophagus	ESCC	2.08e-15	3.24e-01	0.0596
1386	ATF2	P2T-E	Human	Esophagus	ESCC	3.71e-20	3.14e-01	0.1177
1386	ATF2	P4T-E	Human	Esophagus	ESCC	2.21e-22	5.30e-01	0.1323
1386	ATF2	P5T-E	Human	Esophagus	ESCC	1.63e-16	2.25e-01	0.1327
1386	ATF2	P8T-E	Human	Esophagus	ESCC	5.61e-18	4.42e-01	0.0889
1386	ATF2	P9T-E	Human	Esophagus	ESCC	2.06e-25	5.27e-01	0.1131
1386	ATF2	P10T-E	Human	Esophagus	ESCC	4.73e-21	2.79e-01	0.116
1386	ATF2	P11T-E	Human	Esophagus	ESCC	8.81e-10	5.20e-01	0.1426
1386	ATF2	P12T-E	Human	Esophagus	ESCC	1.98e-31	6.36e-01	0.1122
1386	ATF2	P15T-E	Human	Esophagus	ESCC	6.17e-33	7.16e-01	0.1149
1386	ATF2	P16T-E	Human	Esophagus	ESCC	9.89e-23	4.17e-01	0.1153
1386	ATF2	P17T-E	Human	Esophagus	ESCC	1.73e-02	2.44e-01	0.1278
1386	ATF2	P19T-E	Human	Esophagus	ESCC	2.13e-02	1.71e-01	0.1662
1386	ATF2	P20T-E	Human	Esophagus	ESCC	1.28e-13	4.23e-01	0.1124
1386	ATF2	P21T-E	Human	Esophagus	ESCC	2.07e-21	2.89e-01	0.1617

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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

∗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:001657015	Esophagus	ESCC	histone modification	323/8552	463/18723	2.61e-26	7.88e-24	323
GO:0006979111	Esophagus	ESCC	response to oxidative stress	303/8552	446/18723	7.15e-22	1.30e-19	303
GO:001820514	Esophagus	ESCC	peptidyl-lysine modification	259/8552	376/18723	3.90e-20	5.26e-18	259
GO:0006839110	Esophagus	ESCC	mitochondrial transport	187/8552	254/18723	8.35e-20	9.81e-18	187
GO:0062197111	Esophagus	ESCC	cellular response to chemical stress	234/8552	337/18723	5.37e-19	5.97e-17	234
GO:000734615	Esophagus	ESCC	regulation of mitotic cell cycle	293/8552	457/18723	8.00e-16	5.64e-14	293
GO:000170119	Esophagus	ESCC	in utero embryonic development	243/8552	367/18723	1.00e-15	6.86e-14	243
GO:0034599111	Esophagus	ESCC	cellular response to oxidative stress	197/8552	288/18723	3.76e-15	2.15e-13	197
GO:000700619	Esophagus	ESCC	mitochondrial membrane organization	93/8552	116/18723	2.16e-14	1.11e-12	93
GO:000961518	Esophagus	ESCC	response to virus	238/8552	367/18723	6.65e-14	3.32e-12	238
GO:001839413	Esophagus	ESCC	peptidyl-lysine acetylation	123/8552	169/18723	6.58e-13	2.94e-11	123
GO:004354313	Esophagus	ESCC	protein acylation	165/8552	243/18723	1.69e-12	7.14e-11	165
GO:000647313	Esophagus	ESCC	protein acetylation	140/8552	201/18723	4.37e-12	1.69e-10	140
GO:0048732111	Esophagus	ESCC	gland development	269/8552	436/18723	7.81e-12	2.95e-10	269
GO:000703314	Esophagus	ESCC	vacuole organization	127/8552	180/18723	1.04e-11	3.85e-10	127
GO:001839313	Esophagus	ESCC	internal peptidyl-lysine acetylation	114/8552	158/18723	1.16e-11	4.24e-10	114
GO:000647513	Esophagus	ESCC	internal protein amino acid acetylation	115/8552	160/18723	1.43e-11	5.08e-10	115
GO:0008637110	Esophagus	ESCC	apoptotic mitochondrial changes	83/8552	107/18723	1.43e-11	5.08e-10	83
GO:00165735	Esophagus	ESCC	histone acetylation	110/8552	152/18723	1.95e-11	6.81e-10	110
GO:190198713	Esophagus	ESCC	regulation of cell cycle phase transition	242/8552	390/18723	3.86e-11	1.26e-09	242

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05166211	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa05020210	Esophagus	ESCC	Prion disease	193/4205	273/8465	6.42e-13	1.34e-11	6.89e-12	193
hsa04714211	Esophagus	ESCC	Thermogenesis	163/4205	232/8465	9.22e-11	1.14e-09	5.86e-10	163
hsa0466810	Esophagus	ESCC	TNF signaling pathway	89/4205	114/8465	3.36e-10	4.01e-09	2.06e-09	89
hsa0520325	Esophagus	ESCC	Viral carcinogenesis	137/4205	204/8465	2.47e-07	1.88e-06	9.62e-07	137
hsa05163210	Esophagus	ESCC	Human cytomegalovirus infection	148/4205	225/8465	5.73e-07	4.00e-06	2.05e-06	148
hsa051619	Esophagus	ESCC	Hepatitis B	108/4205	162/8465	7.68e-06	4.15e-05	2.12e-05	108
hsa049268	Esophagus	ESCC	Relaxin signaling pathway	81/4205	129/8465	1.72e-03	5.09e-03	2.61e-03	81
hsa0421114	Esophagus	ESCC	Longevity regulating pathway	58/4205	89/8465	2.19e-03	6.16e-03	3.16e-03	58
hsa0492816	Esophagus	ESCC	Parathyroid hormone synthesis, secretion and action	66/4205	106/8465	5.86e-03	1.47e-02	7.51e-03	66
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0492214	Esophagus	ESCC	Glucagon signaling pathway	64/4205	107/8465	2.18e-02	4.80e-02	2.46e-02	64
hsa05166310	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa0502038	Esophagus	ESCC	Prion disease	193/4205	273/8465	6.42e-13	1.34e-11	6.89e-12	193
hsa04714310	Esophagus	ESCC	Thermogenesis	163/4205	232/8465	9.22e-11	1.14e-09	5.86e-10	163
hsa0466817	Esophagus	ESCC	TNF signaling pathway	89/4205	114/8465	3.36e-10	4.01e-09	2.06e-09	89
hsa0520335	Esophagus	ESCC	Viral carcinogenesis	137/4205	204/8465	2.47e-07	1.88e-06	9.62e-07	137
hsa0516338	Esophagus	ESCC	Human cytomegalovirus infection	148/4205	225/8465	5.73e-07	4.00e-06	2.05e-06	148
hsa0516114	Esophagus	ESCC	Hepatitis B	108/4205	162/8465	7.68e-06	4.15e-05	2.12e-05	108
hsa0492616	Esophagus	ESCC	Relaxin signaling pathway	81/4205	129/8465	1.72e-03	5.09e-03	2.61e-03	81

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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
ATF2	GOB	Colorectum	CRC	AC090630.1,FGF13,PHTF1, etc.	4.49e-02
ATF2	GOB	Colorectum	FAP	AC090630.1,FGF13,PHTF1, etc.	1.14e-01
ATF2	EE	Colorectum	FAP	AC090630.1,FGF13,PHTF1, etc.	8.37e-03
ATF2	CD8TCM	Colorectum	SER	OGG1,STAMBPL1,CFAP97, etc.	4.11e-02
ATF2	KER	Esophagus	ADJ	CHKA,VIT,BLOC1S5, etc.	2.30e-01
ATF2	INMON	Esophagus	ESCC	ZFHX4,TMOD2,PCGF6, etc.	7.46e-02
ATF2	GRA	Oral cavity	LP	ZNF625,MB21D2,SMG8, etc.	2.26e-01
ATF2	NKT	Pancreas	ADJ	AC109322.2,GEN1,OSBPL5, etc.	4.05e-01
ATF2	NKT	Pancreas	PanIN	AC109322.2,GEN1,OSBPL5, etc.	8.99e-02

∗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

ATF2

SNV

Missense_Mutation

novel

c.1499C>T

p.Ser500Leu

p.S500L

P15336

protein_coding

deleterious(0.01)

benign(0.003)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

ATF2

SNV

Missense_Mutation

c.1306N>A

p.Asp436Asn

p.D436N

P15336

protein_coding

tolerated(0.11)

benign(0.077)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATF2

SNV

Missense_Mutation

c.474N>C

p.Gln158His

p.Q158H

P15336

protein_coding

tolerated(0.16)

possibly_damaging(0.525)

TCGA-AC-A2FG-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ATF2

SNV

Missense_Mutation

novel

c.225N>A

p.Phe75Leu

p.F75L

P15336

protein_coding

deleterious(0)

possibly_damaging(0.871)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATF2

SNV

Missense_Mutation

c.1034N>C

p.Arg345Thr

p.R345T

P15336

protein_coding

deleterious(0)

benign(0.037)

TCGA-AO-A0JC-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

fluorouracil

ATF2

SNV

Missense_Mutation

c.1501N>A

p.Gln501Lys

p.Q501K

P15336

protein_coding

tolerated_low_confidence(0.36)

possibly_damaging(0.678)

TCGA-B6-A0I8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATF2

SNV

Missense_Mutation

rs751165068

c.76N>G

p.Leu26Val

p.L26V

P15336

protein_coding

tolerated(1)

benign(0)

TCGA-B6-A0RS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATF2

SNV

Missense_Mutation

novel

c.403G>A

p.Asp135Asn

p.D135N

P15336

protein_coding

tolerated(0.15)

benign(0.003)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ATF2

SNV

Missense_Mutation

c.1082N>A

p.Arg361Gln

p.R361Q

P15336

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-MY-A5BD-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ATF2

SNV

Missense_Mutation

rs767222965

c.935N>T

p.Pro312Leu

p.P312L

P15336

protein_coding

tolerated(0.17)

benign(0.026)

TCGA-AA-3496-01

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
1386	ATF2	TRANSCRIPTION FACTOR		2-METHOXYESTRADIOL	2-METHOXYESTRADIOL	15691880
1386	ATF2	TRANSCRIPTION FACTOR		GLUCOCORTICOID		17525285
1386	ATF2	TRANSCRIPTION FACTOR		TGFBETA1		16125722
1386	ATF2	TRANSCRIPTION FACTOR		STZ	STREPTOZOCIN	12805110
1386	ATF2	TRANSCRIPTION FACTOR		fentanyl	FENTANYL	30106255
1386	ATF2	TRANSCRIPTION FACTOR		H2O2		9773928
1386	ATF2	TRANSCRIPTION FACTOR		ALPHA-DIFLUOROMETHYLORNITHINE		17804813

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