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: NR4A1

Gene summary for NR4A1

Gene summary.

Gene information	Species	Human
	Gene symbol	NR4A1
	Gene ID	3164
	Gene name	nuclear receptor subfamily 4 group A member 1
	Gene Alias	GFRP1
	Cytomap	12q13.13
	Gene Type	protein-coding
	GO ID	GO:0001505
	UniProtAcc	P22736

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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
3164	NR4A1	GSM4909282	Human	Breast	IDC	1.14e-10	4.49e-01	-0.0288
3164	NR4A1	GSM4909285	Human	Breast	IDC	8.83e-05	1.10e-01	0.21
3164	NR4A1	GSM4909286	Human	Breast	IDC	3.73e-34	5.84e-01	0.1081
3164	NR4A1	GSM4909291	Human	Breast	IDC	3.64e-10	6.26e-01	0.1753
3164	NR4A1	GSM4909294	Human	Breast	IDC	1.34e-04	-3.17e-01	0.2022
3164	NR4A1	GSM4909299	Human	Breast	IDC	2.23e-12	5.66e-01	0.035
3164	NR4A1	GSM4909300	Human	Breast	IDC	8.01e-10	6.97e-01	0.0334
3164	NR4A1	GSM4909301	Human	Breast	IDC	8.60e-26	7.73e-01	0.1577
3164	NR4A1	GSM4909305	Human	Breast	IDC	1.80e-06	4.34e-01	0.0436
3164	NR4A1	GSM4909306	Human	Breast	IDC	2.42e-04	1.67e-01	0.1564
3164	NR4A1	GSM4909308	Human	Breast	IDC	2.95e-13	4.04e-01	0.158
3164	NR4A1	GSM4909311	Human	Breast	IDC	9.31e-10	-1.91e-01	0.1534
3164	NR4A1	GSM4909313	Human	Breast	IDC	2.70e-09	5.72e-01	0.0391
3164	NR4A1	GSM4909319	Human	Breast	IDC	1.84e-23	2.89e-01	0.1563
3164	NR4A1	brca1	Human	Breast	Precancer	5.32e-08	-3.71e-01	-0.0338
3164	NR4A1	brca2	Human	Breast	Precancer	8.49e-12	-4.32e-01	-0.024
3164	NR4A1	brca3	Human	Breast	Precancer	8.83e-09	-4.30e-01	-0.0263
3164	NR4A1	brca10	Human	Breast	Precancer	4.18e-04	-3.03e-01	-0.0029
3164	NR4A1	M2	Human	Breast	IDC	1.14e-02	-4.55e-01	0.21
3164	NR4A1	NCCBC11	Human	Breast	DCIS	7.34e-03	-4.55e-01	0.1232

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:20001169	Breast	Precancer	regulation of cysteine-type endopeptidase activity	43/1080	235/18723	1.30e-11	1.83e-09	43
GO:00432819	Breast	Precancer	regulation of cysteine-type endopeptidase activity involved in apoptotic process	40/1080	209/18723	1.59e-11	2.07e-09	40
GO:00458619	Breast	Precancer	negative regulation of proteolysis	50/1080	351/18723	2.99e-09	2.39e-07	50
GO:00513468	Breast	Precancer	negative regulation of hydrolase activity	50/1080	379/18723	3.85e-08	2.34e-06	50
GO:00104668	Breast	Precancer	negative regulation of peptidase activity	38/1080	262/18723	1.46e-07	7.82e-06	38
GO:00109519	Breast	Precancer	negative regulation of endopeptidase activity	37/1080	252/18723	1.55e-07	8.05e-06	37
GO:20001179	Breast	Precancer	negative regulation of cysteine-type endopeptidase activity	19/1080	86/18723	3.36e-07	1.58e-05	19
GO:00603266	Breast	Precancer	cell chemotaxis	41/1080	310/18723	5.99e-07	2.55e-05	41
GO:00431548	Breast	Precancer	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process	17/1080	78/18723	1.69e-06	6.08e-05	17
GO:00022378	Breast	Precancer	response to molecule of bacterial origin	43/1080	363/18723	6.05e-06	1.72e-04	43
GO:00324968	Breast	Precancer	response to lipopolysaccharide	41/1080	343/18723	7.94e-06	2.17e-04	41
GO:00106319	Breast	Precancer	epithelial cell migration	40/1080	357/18723	4.57e-05	9.71e-04	40
GO:00901329	Breast	Precancer	epithelium migration	40/1080	360/18723	5.51e-05	1.14e-03	40
GO:00506736	Breast	Precancer	epithelial cell proliferation	46/1080	437/18723	6.02e-05	1.23e-03	46
GO:00435426	Breast	Precancer	endothelial cell migration	33/1080	279/18723	7.28e-05	1.44e-03	33
GO:00901309	Breast	Precancer	tissue migration	40/1080	365/18723	7.48e-05	1.47e-03	40
GO:00506786	Breast	Precancer	regulation of epithelial cell proliferation	40/1080	381/18723	1.88e-04	3.03e-03	40
GO:00016678	Breast	Precancer	ameboidal-type cell migration	47/1080	475/18723	2.19e-04	3.35e-03	47

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa040109	Cervix	CC	MAPK signaling pathway	62/1267	302/8465	4.89e-03	1.67e-02	9.86e-03	62
hsa0401012	Cervix	CC	MAPK signaling pathway	62/1267	302/8465	4.89e-03	1.67e-02	9.86e-03	62
hsa04010	Colorectum	FAP	MAPK signaling pathway	68/1404	302/8465	4.00e-03	1.67e-02	1.02e-02	68
hsa04151	Colorectum	FAP	PI3K-Akt signaling pathway	75/1404	354/8465	1.23e-02	4.19e-02	2.55e-02	75
hsa04925	Colorectum	FAP	Aldosterone synthesis and secretion	25/1404	98/8465	1.55e-02	4.99e-02	3.04e-02	25
hsa040101	Colorectum	FAP	MAPK signaling pathway	68/1404	302/8465	4.00e-03	1.67e-02	1.02e-02	68
hsa041511	Colorectum	FAP	PI3K-Akt signaling pathway	75/1404	354/8465	1.23e-02	4.19e-02	2.55e-02	75
hsa049251	Colorectum	FAP	Aldosterone synthesis and secretion	25/1404	98/8465	1.55e-02	4.99e-02	3.04e-02	25
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0415114	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0401014	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa041516	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa0401015	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa0415113	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa0401023	Oral cavity	EOLP	MAPK signaling pathway	68/1218	302/8465	7.48e-05	3.40e-04	2.01e-04	68
hsa0415123	Oral cavity	EOLP	PI3K-Akt signaling pathway	73/1218	354/8465	7.03e-04	2.69e-03	1.59e-03	73
hsa0401033	Oral cavity	EOLP	MAPK signaling pathway	68/1218	302/8465	7.48e-05	3.40e-04	2.01e-04	68
hsa0415133	Oral cavity	EOLP	PI3K-Akt signaling pathway	73/1218	354/8465	7.03e-04	2.69e-03	1.59e-03	73
hsa0415141	Oral cavity	NEOLP	PI3K-Akt signaling pathway	79/1112	354/8465	8.42e-07	9.92e-06	6.24e-06	79
hsa0401041	Oral cavity	NEOLP	MAPK signaling pathway	59/1112	302/8465	9.40e-04	4.67e-03	2.94e-03	59

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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
NR4A1	AT2	Lung	IAC	RCAN1,GLS,RNF145, etc.	1.86e-01
NR4A1	AT2	Lung	MIAC	RCAN1,GLS,RNF145, etc.	2.75e-01
NR4A1	CLUB	Lung	MIAC	RCAN1,GLS,RNF145, etc.	8.46e-02
NR4A1	STM	Lung	MIAC	RCAN1,GLS,RNF145, etc.	1.73e-02
NR4A1	MAST	Lung	AAH	HSPA1B,HSPA1A,DNAJB1, etc.	1.72e-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

NR4A1

SNV

Missense_Mutation

c.1586G>A

p.Cys529Tyr

p.C529Y

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-A2-A0YH-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

NR4A1

SNV

Missense_Mutation

novel

c.572N>G

p.Ser191Trp

p.S191W

protein_coding

deleterious(0)

probably_damaging(0.989)

TCGA-AC-A6IW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NR4A1

SNV

Missense_Mutation

c.1109N>A

p.Arg370Gln

p.R370Q

protein_coding

deleterious(0.01)

probably_damaging(0.995)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NR4A1

SNV

Missense_Mutation

rs771251157

c.1846C>A

p.Leu616Met

p.L616M

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-C8-A274-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

NR4A1

SNV

Missense_Mutation

rs771251157

c.1846N>A

p.Leu616Met

p.L616M

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-D8-A4Z1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

NR4A1

deletion

Frame_Shift_Del

novel

c.1329delN

p.Glu443AspfsTer147

p.E443Dfs*147

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

NR4A1

SNV

Missense_Mutation

c.1204C>T

p.Arg402Trp

p.R402W

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A6-3809-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

NR4A1

SNV

Missense_Mutation

c.1503C>A

p.Phe501Leu

p.F501L

protein_coding

deleterious(0.01)

possibly_damaging(0.797)

TCGA-AD-A5EK-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

NR4A1

SNV

Missense_Mutation

rs763639989

c.1198C>T

p.Arg400Trp

p.R400W

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

NR4A1

SNV

Missense_Mutation

novel

c.11C>T

p.Ala4Val

p.A4V

protein_coding

deleterious_low_confidence(0)

unknown(0)

TCGA-A5-A1OF-01

Endometrium

uterine corpus endometrioid carcinoma

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
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		L-DOPA	LEVODOPA	16930409,15896973
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		NICOTINE	NICOTINE	12111438,11979430
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		IL-1		7688736,15063754
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		PD-98059	CHEMBL35482	15385570
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		RETINOIC ACID		11602619
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		HALOPERIDOL	HALOPERIDOL	16893530
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		IONOMYCIN	IONOMYCIN	16051191,9705872
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		MORPHINE	MORPHINE	10719211
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		NAC	ACETYLCYSTEINE	8647183
3164	NR4A1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, KINASE, TRANSCRIPTION FACTOR COMPLEX		CYTOSPORONE B	CYTOSPORONE B	18690216

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