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: MAP2K4

Gene summary for MAP2K4

Gene summary.

Gene information	Species	Human
	Gene symbol	MAP2K4
	Gene ID	6416
	Gene name	mitogen-activated protein kinase kinase 4
	Gene Alias	JNKK
	Cytomap	17p12
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P45985

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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
6416	MAP2K4	CCI_1	Human	Cervix	CC	6.33e-04	6.48e-01	0.528
6416	MAP2K4	CCI_2	Human	Cervix	CC	4.56e-14	1.19e+00	0.5249
6416	MAP2K4	HTA11_3410_2000001011	Human	Colorectum	AD	8.85e-15	-5.32e-01	0.0155
6416	MAP2K4	HTA11_78_2000001011	Human	Colorectum	AD	2.05e-02	-2.15e-01	-0.1088
6416	MAP2K4	HTA11_696_2000001011	Human	Colorectum	AD	5.28e-04	-2.97e-01	-0.1464
6416	MAP2K4	HTA11_866_2000001011	Human	Colorectum	AD	8.31e-03	-3.15e-01	-0.1001
6416	MAP2K4	HTA11_866_3004761011	Human	Colorectum	AD	3.39e-06	-4.30e-01	0.096
6416	MAP2K4	HTA11_7696_3000711011	Human	Colorectum	AD	5.79e-10	-3.71e-01	0.0674
6416	MAP2K4	HTA11_99999970781_79442	Human	Colorectum	MSS	4.81e-08	-3.76e-01	0.294
6416	MAP2K4	HTA11_99999965104_69814	Human	Colorectum	MSS	5.65e-07	-6.09e-01	0.281
6416	MAP2K4	HTA11_99999971662_82457	Human	Colorectum	MSS	1.22e-09	-4.43e-01	0.3859
6416	MAP2K4	HTA11_99999974143_84620	Human	Colorectum	MSS	9.28e-13	-4.47e-01	0.3005
6416	MAP2K4	A001-C-207	Human	Colorectum	FAP	1.14e-02	-2.36e-01	0.1278
6416	MAP2K4	A015-C-203	Human	Colorectum	FAP	5.25e-33	-4.39e-01	-0.1294
6416	MAP2K4	A015-C-204	Human	Colorectum	FAP	6.37e-07	-3.77e-01	-0.0228
6416	MAP2K4	A014-C-040	Human	Colorectum	FAP	2.50e-04	-4.42e-01	-0.1184
6416	MAP2K4	A002-C-201	Human	Colorectum	FAP	1.67e-15	-4.06e-01	0.0324
6416	MAP2K4	A002-C-203	Human	Colorectum	FAP	1.74e-04	-1.57e-01	0.2786
6416	MAP2K4	A001-C-119	Human	Colorectum	FAP	1.05e-10	-5.45e-01	-0.1557
6416	MAP2K4	A001-C-108	Human	Colorectum	FAP	1.33e-18	-3.73e-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
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
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:007149610	Cervix	CC	cellular response to external stimulus	78/2311	320/18723	1.82e-09	1.98e-07	78
GO:00027644	Cervix	CC	immune response-regulating signaling pathway	97/2311	468/18723	1.49e-07	7.07e-06	97
GO:00075689	Cervix	CC	aging	75/2311	339/18723	2.75e-07	1.13e-05	75
GO:00310988	Cervix	CC	stress-activated protein kinase signaling cascade	58/2311	247/18723	8.02e-07	2.89e-05	58
GO:00514038	Cervix	CC	stress-activated MAPK cascade	55/2311	239/18723	2.96e-06	8.31e-05	55
GO:00380933	Cervix	CC	Fc receptor signaling pathway	19/2311	50/18723	3.42e-06	9.17e-05	19
GO:00712148	Cervix	CC	cellular response to abiotic stimulus	69/2311	331/18723	7.36e-06	1.73e-04	69
GO:01040048	Cervix	CC	cellular response to environmental stimulus	69/2311	331/18723	7.36e-06	1.73e-04	69
GO:00160498	Cervix	CC	cell growth	92/2311	482/18723	1.16e-05	2.49e-04	92
GO:00075695	Cervix	CC	cell aging	34/2311	132/18723	1.92e-05	3.53e-04	34
GO:00096127	Cervix	CC	response to mechanical stimulus	48/2311	216/18723	3.23e-05	5.29e-04	48
GO:0038095	Cervix	CC	Fc-epsilon receptor signaling pathway	11/2311	24/18723	5.28e-05	7.88e-04	11
GO:000974310	Cervix	CC	response to carbohydrate	53/2311	253/18723	7.02e-05	9.85e-04	53
GO:007099710	Cervix	CC	neuron death	70/2311	361/18723	7.50e-05	1.03e-03	70
GO:00712602	Cervix	CC	cellular response to mechanical stimulus	23/2311	81/18723	8.34e-05	1.12e-03	23
GO:190121610	Cervix	CC	positive regulation of neuron death	26/2311	97/18723	8.64e-05	1.15e-03	26
GO:00605375	Cervix	CC	muscle tissue development	76/2311	403/18723	9.76e-05	1.27e-03	76
GO:00903981	Cervix	CC	cellular senescence	25/2311	93/18723	1.11e-04	1.40e-03	25
GO:00147064	Cervix	CC	striated muscle tissue development	72/2311	384/18723	1.76e-04	2.07e-03	72
GO:190121410	Cervix	CC	regulation of neuron death	61/2311	319/18723	3.11e-04	3.31e-03	61

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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
hsa0541820	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa0513220	Cervix	CC	Salmonella infection	74/1267	249/8465	1.33e-09	2.54e-08	1.50e-08	74
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516920	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0401210	Cervix	CC	ErbB signaling pathway	28/1267	85/8465	2.40e-05	1.82e-04	1.08e-04	28
hsa0513516	Cervix	CC	Yersinia infection	39/1267	137/8465	3.27e-05	2.41e-04	1.42e-04	39
hsa051207	Cervix	CC	Epithelial cell signaling in Helicobacter pylori infection	24/1267	70/8465	4.35e-05	3.09e-04	1.83e-04	24
hsa04664	Cervix	CC	Fc epsilon RI signaling pathway	22/1267	68/8465	2.35e-04	1.31e-03	7.77e-04	22
hsa0491212	Cervix	CC	GnRH signaling pathway	26/1267	93/8465	8.72e-04	3.87e-03	2.29e-03	26
hsa046686	Cervix	CC	TNF signaling pathway	28/1267	114/8465	4.60e-03	1.62e-02	9.59e-03	28
hsa040109	Cervix	CC	MAPK signaling pathway	62/1267	302/8465	4.89e-03	1.67e-02	9.86e-03	62
hsa049265	Cervix	CC	Relaxin signaling pathway	30/1267	129/8465	7.92e-03	2.56e-02	1.51e-02	30
hsa05208110	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa05418110	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa05132110	Cervix	CC	Salmonella infection	74/1267	249/8465	1.33e-09	2.54e-08	1.50e-08	74
hsa05417110	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa05167110	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60

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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

Cell Type

Tissue

Disease Stage

Target Gene

RSS

Regulon Activity

∗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

MAP2K4

SNV

Missense_Mutation

c.785G>T

p.Ser262Ile

p.S262I

P45985

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A2-A1G4-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

adriamycin

MAP2K4

SNV

Missense_Mutation

c.1187N>C

p.Leu396Pro

p.L396P

P45985

protein_coding

deleterious(0)

probably_damaging(0.992)

TCGA-A7-A26H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

MAP2K4

SNV

Missense_Mutation

c.850G>A

p.Glu284Lys

p.E284K

P45985

protein_coding

deleterious(0)

probably_damaging(0.989)

TCGA-A8-A093-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

MAP2K4

SNV

Missense_Mutation

c.1186C>G

p.Leu396Val

p.L396V

P45985

protein_coding

deleterious(0)

benign(0.306)

TCGA-AO-A0JF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

MAP2K4

SNV

Missense_Mutation

c.803C>T

p.Ser268Phe

p.S268F

P45985

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-AR-A1AS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

MAP2K4

SNV

Missense_Mutation

c.584N>T

p.Ser195Leu

p.S195L

P45985

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-B6-A0WZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MAP2K4

SNV

Missense_Mutation

c.433C>T

p.Arg145Trp

p.R145W

P45985

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-B6-A0X4-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MAP2K4

SNV

Missense_Mutation

c.584N>T

p.Ser195Leu

p.S195L

P45985

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0DP-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

MAP2K4

SNV

Missense_Mutation

c.590N>G

p.Asp197Gly

p.D197G

P45985

protein_coding

deleterious(0.01)

possibly_damaging(0.838)

TCGA-BH-A0EI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MAP2K4

SNV

Missense_Mutation

c.901N>T

p.Val301Phe

p.V301F

P45985

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-BH-A0GY-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cyotxan

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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
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	TRAMETINIB	TRAMETINIB
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	135652717	STAUROSPORINE
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	PD 0325901
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME		ethanol	ALCOHOL
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	GDC-0973	COBIMETINIB
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	BAY869766
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	AZD6244	SELUMETINIB
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	178102628
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	SELUMETINIB	SELUMETINIB
6416	MAP2K4	KINASE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TYROSINE KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	MEK162	BINIMETINIB

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