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: NFE2L2

Gene summary for NFE2L2

Gene summary.

Gene information	Species	Human
	Gene symbol	NFE2L2
	Gene ID	4780
	Gene name	nuclear factor, erythroid 2 like 2
	Gene Alias	HEBP1
	Cytomap	2q31.2
	Gene Type	protein-coding
	GO ID	GO:0000302
	UniProtAcc	Q16236

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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
4780	NFE2L2	CA_HPV_1	Human	Cervix	CC	1.11e-06	-2.28e-01	0.0264
4780	NFE2L2	N_HPV_2	Human	Cervix	N_HPV	3.53e-04	2.52e-01	-0.0131
4780	NFE2L2	CCI_2	Human	Cervix	CC	1.07e-10	1.27e+00	0.5249
4780	NFE2L2	CCI_3	Human	Cervix	CC	6.29e-12	1.00e+00	0.516
4780	NFE2L2	CCII_1	Human	Cervix	CC	3.66e-08	-6.30e-01	0.3249
4780	NFE2L2	sample3	Human	Cervix	CC	2.14e-08	3.07e-01	0.1387
4780	NFE2L2	L1	Human	Cervix	CC	8.06e-06	-4.68e-01	0.0802
4780	NFE2L2	T3	Human	Cervix	CC	2.26e-07	3.14e-01	0.1389
4780	NFE2L2	HTA11_3410_2000001011	Human	Colorectum	AD	6.42e-09	-4.80e-01	0.0155
4780	NFE2L2	HTA11_347_2000001011	Human	Colorectum	AD	1.65e-02	3.69e-01	-0.1954
4780	NFE2L2	HTA11_7696_3000711011	Human	Colorectum	AD	6.65e-03	-3.46e-01	0.0674
4780	NFE2L2	HTA11_99999970781_79442	Human	Colorectum	MSS	5.95e-03	-3.93e-01	0.294
4780	NFE2L2	HTA11_99999973899_84307	Human	Colorectum	MSS	1.47e-04	-6.05e-01	0.2585
4780	NFE2L2	HTA11_99999974143_84620	Human	Colorectum	MSS	4.57e-02	-3.19e-01	0.3005
4780	NFE2L2	A015-C-203	Human	Colorectum	FAP	1.33e-26	-1.97e-01	-0.1294
4780	NFE2L2	A015-C-204	Human	Colorectum	FAP	4.87e-03	-1.76e-01	-0.0228
4780	NFE2L2	A014-C-040	Human	Colorectum	FAP	1.64e-04	-9.44e-02	-0.1184
4780	NFE2L2	A002-C-201	Human	Colorectum	FAP	1.37e-11	1.62e-02	0.0324
4780	NFE2L2	A001-C-119	Human	Colorectum	FAP	1.57e-03	-2.79e-01	-0.1557
4780	NFE2L2	A001-C-108	Human	Colorectum	FAP	1.74e-15	-1.27e-01	-0.0272

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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
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:006113629	Skin	cSCC	regulation of proteasomal protein catabolic process	106/4864	187/18723	4.31e-19	5.87e-17	106
GO:200124229	Skin	cSCC	regulation of intrinsic apoptotic signaling pathway	96/4864	164/18723	9.88e-19	1.32e-16	96
GO:0034976112	Skin	cSCC	response to endoplasmic reticulum stress	128/4864	256/18723	1.16e-16	1.17e-14	128
GO:003243429	Skin	cSCC	regulation of proteasomal ubiquitin-dependent protein catabolic process	80/4864	134/18723	1.54e-16	1.49e-14	80
GO:0035966112	Skin	cSCC	response to topologically incorrect protein	90/4864	159/18723	2.26e-16	2.12e-14	90
GO:200005829	Skin	cSCC	regulation of ubiquitin-dependent protein catabolic process	92/4864	164/18723	2.30e-16	2.12e-14	92
GO:004586229	Skin	cSCC	positive regulation of proteolysis	169/4864	372/18723	2.43e-16	2.21e-14	169
GO:003425026	Skin	cSCC	positive regulation of cellular amide metabolic process	89/4864	162/18723	3.95e-15	3.06e-13	89
GO:000989628	Skin	cSCC	positive regulation of catabolic process	206/4864	492/18723	6.06e-15	4.64e-13	206
GO:0006986112	Skin	cSCC	response to unfolded protein	78/4864	137/18723	1.44e-14	1.03e-12	78
GO:190336429	Skin	cSCC	positive regulation of cellular protein catabolic process	85/4864	155/18723	1.87e-14	1.31e-12	85
GO:003133128	Skin	cSCC	positive regulation of cellular catabolic process	182/4864	427/18723	3.29e-14	2.22e-12	182
GO:004573229	Skin	cSCC	positive regulation of protein catabolic process	112/4864	231/18723	1.37e-13	8.40e-12	112
GO:190180025	Skin	cSCC	positive regulation of proteasomal protein catabolic process	66/4864	114/18723	5.18e-13	3.01e-11	66
GO:000697929	Skin	cSCC	response to oxidative stress	184/4864	446/18723	8.57e-13	4.89e-11	184
GO:190305225	Skin	cSCC	positive regulation of proteolysis involved in cellular protein catabolic process	72/4864	133/18723	4.24e-12	2.27e-10	72
GO:0035967112	Skin	cSCC	cellular response to topologically incorrect protein	65/4864	116/18723	5.93e-12	3.10e-10	65
GO:003243625	Skin	cSCC	positive regulation of proteasomal ubiquitin-dependent protein catabolic process	53/4864	90/18723	4.06e-11	1.96e-09	53
GO:0046700110	Skin	cSCC	heterocycle catabolic process	178/4864	445/18723	4.45e-11	2.13e-09	178
GO:0034620112	Skin	cSCC	cellular response to unfolded protein	55/4864	96/18723	7.74e-11	3.57e-09	55

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0520820	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa0501220	Cervix	CC	Parkinson disease	102/1267	266/8465	1.81e-21	1.47e-19	8.66e-20	102
hsa0541820	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0414120	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa0522510	Cervix	CC	Hepatocellular carcinoma	40/1267	168/8465	1.52e-03	6.39e-03	3.78e-03	40
hsa05208110	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa05012110	Cervix	CC	Parkinson disease	102/1267	266/8465	1.81e-21	1.47e-19	8.66e-20	102
hsa05418110	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa05417110	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa04141110	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa0522513	Cervix	CC	Hepatocellular carcinoma	40/1267	168/8465	1.52e-03	6.39e-03	3.78e-03	40
hsa0501244	Cervix	N_HPV	Parkinson disease	45/349	266/8465	1.93e-16	1.75e-14	1.37e-14	45
hsa0520844	Cervix	N_HPV	Chemical carcinogenesis - reactive oxygen species	32/349	223/8465	4.82e-10	1.87e-08	1.47e-08	32
hsa0541845	Cervix	N_HPV	Fluid shear stress and atherosclerosis	20/349	139/8465	9.29e-07	1.41e-05	1.10e-05	20
hsa0414144	Cervix	N_HPV	Protein processing in endoplasmic reticulum	21/349	174/8465	8.84e-06	1.09e-04	8.55e-05	21
hsa0541745	Cervix	N_HPV	Lipid and atherosclerosis	22/349	215/8465	7.28e-05	7.92e-04	6.19e-04	22
hsa0501254	Cervix	N_HPV	Parkinson disease	45/349	266/8465	1.93e-16	1.75e-14	1.37e-14	45
hsa0520854	Cervix	N_HPV	Chemical carcinogenesis - reactive oxygen species	32/349	223/8465	4.82e-10	1.87e-08	1.47e-08	32
hsa0541855	Cervix	N_HPV	Fluid shear stress and atherosclerosis	20/349	139/8465	9.29e-07	1.41e-05	1.10e-05	20

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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
NFE2L2	MAC	Colorectum	AD	CD44,ZNF710,APBA1, etc.	1.17e-01
NFE2L2	MAC	Colorectum	ADJ	CD44,ZNF710,APBA1, etc.	1.67e-01
NFE2L2	MAC	Colorectum	CRC	CD44,ZNF710,APBA1, etc.	3.45e-01
NFE2L2	MON	Colorectum	CRC	CD44,ZNF710,APBA1, etc.	2.77e-01
NFE2L2	MAC	Colorectum	FAP	CD44,ZNF710,APBA1, etc.	3.50e-01
NFE2L2	MAC	Colorectum	Healthy	CD44,ZNF710,APBA1, etc.	4.51e-01
NFE2L2	MON	Colorectum	MSI-H	CD44,ZNF710,APBA1, etc.	5.01e-01
NFE2L2	MON	Colorectum	MSS	CD44,ZNF710,APBA1, etc.	5.01e-01
NFE2L2	MAC	Colorectum	SER	CD44,ZNF710,APBA1, etc.	1.28e-01
NFE2L2	SPI	Oral cavity	Healthy	KRT5,PERP,AQP3, etc.	3.25e-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

NFE2L2

SNV

Missense_Mutation

c.242N>A

p.Gly81Asp

p.G81D

Q16236

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A7-A26E-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

cytoxan

NFE2L2

SNV

Missense_Mutation

c.959N>G

p.Ser320Cys

p.S320C

Q16236

protein_coding

tolerated(0.19)

benign(0.005)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NFE2L2

SNV

Missense_Mutation

c.371C>G

p.Ala124Gly

p.A124G

Q16236

protein_coding

deleterious(0.03)

benign(0.02)

TCGA-D8-A1X6-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

NFE2L2

insertion

Frame_Shift_Ins

novel

c.1128_1129insTT

p.Glu377LeufsTer6

p.E377Lfs*6

Q16236

protein_coding

TCGA-A8-A09D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NFE2L2

insertion

Frame_Shift_Ins

novel

c.1126_1127insTTGTGGTTATAATTTCCCTGATTTGCCATGAGTTTGAACATCTTCCA

p.Ser376PhefsTer22

p.S376Ffs*22

Q16236

protein_coding

TCGA-A8-A09D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NFE2L2

deletion

Frame_Shift_Del

novel

c.129delN

p.Glu45SerfsTer32

p.E45Sfs*32

Q16236

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

NFE2L2

SNV

Missense_Mutation

novel

c.594G>T

p.Gln198His

p.Q198H

Q16236

protein_coding

tolerated(0.07)

probably_damaging(0.997)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

NFE2L2

SNV

Missense_Mutation

c.1138G>C

p.Glu380Gln

p.E380Q

Q16236

protein_coding

deleterious(0.01)

possibly_damaging(0.522)

TCGA-C5-A1BL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

NFE2L2

SNV

Missense_Mutation

c.85G>C

p.Asp29His

p.D29H

Q16236

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-C5-A1MN-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

NFE2L2

SNV

Missense_Mutation

c.1544N>C

p.Arg515Thr

p.R515T

Q16236

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-DR-A0ZM-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unspecific

Cisplatin

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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
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		ALDICARB	ALDICARB
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		3,3'-DIMETHOXYBENZIDINE	CHEMBL398363
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		LOTEPREDNOL ETABONATE	LOTEPREDNOL ETABONATE
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		BECLOMETHASONE DIPROPIONATE	BECLOMETHASONE DIPROPIONATE
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		PHENOXYCARB	PHENOXYCARB
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		METHIOCARB	METHIOCARB
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		JNJ-1661010	CHEMBL460273
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		NALED	NALED
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		MORNIFLUMATE	MORNIFLUMATE
4780	NFE2L2	CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		RHEIN	RHEIN