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: MAP3K5

Gene summary for MAP3K5

Gene summary.

Gene information	Species	Human
	Gene symbol	MAP3K5
	Gene ID	4217
	Gene name	mitogen-activated protein kinase kinase kinase 5
	Gene Alias	ASK1
	Cytomap	6q23.3
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q99683

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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
4217	MAP3K5	CCI_1	Human	Cervix	CC	2.13e-11	1.20e+00	0.528
4217	MAP3K5	CCI_2	Human	Cervix	CC	2.44e-05	1.23e+00	0.5249
4217	MAP3K5	CCI_3	Human	Cervix	CC	2.65e-07	7.74e-01	0.516
4217	MAP3K5	HTA11_3410_2000001011	Human	Colorectum	AD	1.38e-02	-3.23e-01	0.0155
4217	MAP3K5	HTA11_347_2000001011	Human	Colorectum	AD	4.39e-10	6.12e-01	-0.1954
4217	MAP3K5	HTA11_866_3004761011	Human	Colorectum	AD	4.51e-02	-4.11e-01	0.096
4217	MAP3K5	HTA11_99999974143_84620	Human	Colorectum	MSS	3.97e-19	-5.86e-01	0.3005
4217	MAP3K5	F007	Human	Colorectum	FAP	5.33e-03	-3.60e-01	0.1176
4217	MAP3K5	A015-C-203	Human	Colorectum	FAP	1.63e-22	-5.09e-01	-0.1294
4217	MAP3K5	A015-C-204	Human	Colorectum	FAP	4.03e-04	-3.22e-01	-0.0228
4217	MAP3K5	A014-C-040	Human	Colorectum	FAP	3.06e-02	-4.22e-01	-0.1184
4217	MAP3K5	A002-C-201	Human	Colorectum	FAP	8.18e-08	-2.98e-01	0.0324
4217	MAP3K5	A001-C-119	Human	Colorectum	FAP	3.80e-08	-5.06e-01	-0.1557
4217	MAP3K5	A001-C-108	Human	Colorectum	FAP	9.73e-11	-2.13e-01	-0.0272
4217	MAP3K5	A002-C-205	Human	Colorectum	FAP	4.08e-19	-5.00e-01	-0.1236
4217	MAP3K5	A015-C-005	Human	Colorectum	FAP	3.23e-04	-4.07e-01	-0.0336
4217	MAP3K5	A015-C-006	Human	Colorectum	FAP	1.37e-13	-5.06e-01	-0.0994
4217	MAP3K5	A015-C-106	Human	Colorectum	FAP	2.27e-09	-2.73e-01	-0.0511
4217	MAP3K5	A002-C-114	Human	Colorectum	FAP	1.20e-16	-5.11e-01	-0.1561
4217	MAP3K5	A015-C-104	Human	Colorectum	FAP	8.54e-24	-4.96e-01	-0.1899

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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
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
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
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:00514038	Cervix	CC	stress-activated MAPK cascade	55/2311	239/18723	2.96e-06	8.31e-05	55
GO:003459910	Cervix	CC	cellular response to oxidative stress	63/2311	288/18723	3.58e-06	9.50e-05	63
GO:003166710	Cervix	CC	response to nutrient levels	92/2311	474/18723	5.80e-06	1.42e-04	92
GO:003497610	Cervix	CC	response to endoplasmic reticulum stress	57/2311	256/18723	5.81e-06	1.42e-04	57
GO:20010569	Cervix	CC	positive regulation of cysteine-type endopeptidase activity	38/2311	148/18723	6.94e-06	1.65e-04	38
GO:00703027	Cervix	CC	regulation of stress-activated protein kinase signaling cascade	46/2311	195/18723	9.35e-06	2.11e-04	46
GO:00092678	Cervix	CC	cellular response to starvation	39/2311	156/18723	1.04e-05	2.32e-04	39
GO:00432809	Cervix	CC	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	34/2311	129/18723	1.13e-05	2.45e-04	34
GO:00700599	Cervix	CC	intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	21/2311	63/18723	1.18e-05	2.51e-04	21
GO:00425948	Cervix	CC	response to starvation	46/2311	197/18723	1.24e-05	2.59e-04	46
GO:00316698	Cervix	CC	cellular response to nutrient levels	49/2311	215/18723	1.32e-05	2.68e-04	49
GO:00346129	Cervix	CC	response to tumor necrosis factor	55/2311	253/18723	1.75e-05	3.32e-04	55
GO:00713569	Cervix	CC	cellular response to tumor necrosis factor	51/2311	229/18723	1.75e-05	3.32e-04	51
GO:00719025	Cervix	CC	positive regulation of protein serine/threonine kinase activity	46/2311	200/18723	1.87e-05	3.47e-04	46
GO:00075695	Cervix	CC	cell aging	34/2311	132/18723	1.92e-05	3.53e-04	34
GO:00434104	Cervix	CC	positive regulation of MAPK cascade	90/2311	480/18723	2.92e-05	4.83e-04	90
GO:00328727	Cervix	CC	regulation of stress-activated MAPK cascade	44/2311	192/18723	3.09e-05	5.10e-04	44
GO:007099710	Cervix	CC	neuron death	70/2311	361/18723	7.50e-05	1.03e-03	70
GO:190121610	Cervix	CC	positive regulation of neuron death	26/2311	97/18723	8.64e-05	1.15e-03	26
GO:00903981	Cervix	CC	cellular senescence	25/2311	93/18723	1.11e-04	1.40e-03	25

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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
hsa0501018	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0501618	Cervix	CC	Huntington disease	94/1267	306/8465	8.49e-13	3.06e-11	1.81e-11	94
hsa0502218	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa0493218	Cervix	CC	Non-alcoholic fatty liver disease	58/1267	155/8465	3.58e-12	1.05e-10	6.23e-11	58
hsa0471420	Cervix	CC	Thermogenesis	76/1267	232/8465	4.29e-12	1.16e-10	6.85e-11	76
hsa0501418	Cervix	CC	Amyotrophic lateral sclerosis	103/1267	364/8465	1.79e-11	4.47e-10	2.64e-10	103
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
hsa0453020	Cervix	CC	Tight junction	49/1267	169/8465	1.87e-06	1.78e-05	1.05e-05	49
hsa0407110	Cervix	CC	Sphingolipid signaling pathway	35/1267	121/8465	5.70e-05	3.93e-04	2.32e-04	35
hsa042109	Cervix	CC	Apoptosis	36/1267	136/8465	3.21e-04	1.68e-03	9.91e-04	36
hsa0472214	Cervix	CC	Neurotrophin signaling pathway	32/1267	119/8465	5.01e-04	2.42e-03	1.43e-03	32
hsa0501716	Cervix	CC	Spinocerebellar ataxia	35/1267	143/8465	1.77e-03	7.21e-03	4.26e-03	35
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
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

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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

MAP3K5

SNV

Missense_Mutation

rs771379166

c.3427C>T

p.Arg1143Trp

p.R1143W

Q99683

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MAP3K5

SNV

Missense_Mutation

c.1276N>A

p.Glu426Lys

p.E426K

Q99683

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-AC-A2B8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

chemo

MAP3K5

SNV

Missense_Mutation

c.3040C>T

p.Arg1014Trp

p.R1014W

Q99683

protein_coding

deleterious(0.02)

probably_damaging(0.993)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MAP3K5

SNV

Missense_Mutation

c.702N>C

p.Leu234Phe

p.L234F

Q99683

protein_coding

tolerated(0.08)

possibly_damaging(0.883)

TCGA-AN-A0AR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MAP3K5

SNV

Missense_Mutation

novel

c.1307N>A

p.Ala436Glu

p.A436E

Q99683

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AN-A0FZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

MAP3K5

SNV

Missense_Mutation

novel

c.1531N>T

p.Leu511Phe

p.L511F

Q99683

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-BH-A0B7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

MAP3K5

SNV

Missense_Mutation

novel

c.2311N>A

p.Gly771Ser

p.G771S

Q99683

protein_coding

deleterious(0)

possibly_damaging(0.896)

TCGA-BH-A0BL-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

MAP3K5

SNV

Missense_Mutation

c.1276G>A

p.Glu426Lys

p.E426K

Q99683

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-BH-A0DZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

docetaxel

MAP3K5

SNV

Missense_Mutation

novel

c.3817G>A

p.Ala1273Thr

p.A1273T

Q99683

protein_coding

tolerated(0.79)

benign(0.257)

TCGA-E2-A14R-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

MAP3K5

SNV

Missense_Mutation

novel

c.850C>G

p.Arg284Gly

p.R284G

Q99683

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-GI-A2C9-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

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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
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME		GS-4997	SELONSERTIB
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME	inhibitor	249565756
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME		GS-4977
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME	inhibitor	249565813
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME	inhibitor	385612190
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME	inhibitor	CHEMBL3545429	SELONSERTIB
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME		hydroxyurea	HYDROXYUREA	23556445
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME	inhibitor	315661125	SELONSERTIB
4217	MAP3K5	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE, TRANSCRIPTION FACTOR, ENZYME	inhibitor	404859049

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