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: MAP2K1

Gene summary for MAP2K1

Gene summary.

Gene information	Species	Human
	Gene symbol	MAP2K1
	Gene ID	5604
	Gene name	mitogen-activated protein kinase kinase 1
	Gene Alias	CFC3
	Cytomap	15q22.31
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A4QPA9

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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
5604	MAP2K1	CCI_1	Human	Cervix	CC	3.83e-11	1.23e+00	0.528
5604	MAP2K1	CCI_2	Human	Cervix	CC	2.24e-11	8.89e-01	0.5249
5604	MAP2K1	Tumor	Human	Cervix	CC	6.84e-04	1.73e-01	0.1241
5604	MAP2K1	sample3	Human	Cervix	CC	6.41e-05	1.90e-01	0.1387
5604	MAP2K1	T3	Human	Cervix	CC	1.22e-03	1.99e-01	0.1389
5604	MAP2K1	LZE2T	Human	Esophagus	ESCC	8.97e-05	3.36e-01	0.082
5604	MAP2K1	LZE4T	Human	Esophagus	ESCC	2.35e-03	1.03e-01	0.0811
5604	MAP2K1	LZE7T	Human	Esophagus	ESCC	6.55e-03	3.32e-01	0.0667
5604	MAP2K1	LZE20T	Human	Esophagus	ESCC	2.87e-02	2.40e-02	0.0662
5604	MAP2K1	LZE24T	Human	Esophagus	ESCC	2.79e-14	2.19e-01	0.0596
5604	MAP2K1	P1T-E	Human	Esophagus	ESCC	1.36e-07	7.45e-01	0.0875
5604	MAP2K1	P2T-E	Human	Esophagus	ESCC	1.02e-16	2.51e-01	0.1177
5604	MAP2K1	P4T-E	Human	Esophagus	ESCC	1.06e-34	8.37e-01	0.1323
5604	MAP2K1	P5T-E	Human	Esophagus	ESCC	3.76e-23	4.45e-01	0.1327
5604	MAP2K1	P8T-E	Human	Esophagus	ESCC	3.15e-22	2.51e-01	0.0889
5604	MAP2K1	P9T-E	Human	Esophagus	ESCC	3.91e-13	1.97e-01	0.1131
5604	MAP2K1	P10T-E	Human	Esophagus	ESCC	2.97e-17	3.72e-01	0.116
5604	MAP2K1	P11T-E	Human	Esophagus	ESCC	1.17e-06	4.78e-01	0.1426
5604	MAP2K1	P12T-E	Human	Esophagus	ESCC	6.92e-19	3.89e-01	0.1122
5604	MAP2K1	P15T-E	Human	Esophagus	ESCC	1.54e-28	6.79e-01	0.1149

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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
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
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ

∗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:00085446	Cervix	CC	epidermis development	83/2311	324/18723	3.91e-11	8.54e-09	83
GO:00435884	Cervix	CC	skin development	71/2311	263/18723	8.04e-11	1.46e-08	71
GO:00506737	Cervix	CC	epithelial cell proliferation	98/2311	437/18723	2.01e-09	2.15e-07	98
GO:003367410	Cervix	CC	positive regulation of kinase activity	101/2311	467/18723	8.66e-09	7.22e-07	101
GO:00302164	Cervix	CC	keratinocyte differentiation	42/2311	139/18723	1.74e-08	1.28e-06	42
GO:00099137	Cervix	CC	epidermal cell differentiation	53/2311	202/18723	5.48e-08	3.25e-06	53
GO:00458608	Cervix	CC	positive regulation of protein kinase activity	85/2311	386/18723	5.61e-08	3.29e-06	85
GO:00075689	Cervix	CC	aging	75/2311	339/18723	2.75e-07	1.13e-05	75
GO:00018908	Cervix	CC	placenta development	40/2311	144/18723	4.59e-07	1.77e-05	40
GO:19030349	Cervix	CC	regulation of response to wounding	44/2311	167/18723	6.33e-07	2.31e-05	44
GO:00310988	Cervix	CC	stress-activated protein kinase signaling cascade	58/2311	247/18723	8.02e-07	2.89e-05	58
GO:00614588	Cervix	CC	reproductive system development	87/2311	427/18723	1.37e-06	4.55e-05	87
GO:00486088	Cervix	CC	reproductive structure development	86/2311	424/18723	1.90e-06	5.97e-05	86
GO:00719007	Cervix	CC	regulation of protein serine/threonine kinase activity	75/2311	359/18723	2.76e-06	8.02e-05	75
GO:00514038	Cervix	CC	stress-activated MAPK cascade	55/2311	239/18723	2.96e-06	8.31e-05	55
GO:00323868	Cervix	CC	regulation of intracellular transport	71/2311	337/18723	3.70e-06	9.74e-05	71
GO:00109757	Cervix	CC	regulation of neuron projection development	88/2311	445/18723	4.26e-06	1.09e-04	88
GO:00107206	Cervix	CC	positive regulation of cell development	64/2311	298/18723	5.69e-06	1.41e-04	64
GO:00703027	Cervix	CC	regulation of stress-activated protein kinase signaling cascade	46/2311	195/18723	9.35e-06	2.11e-04	46
GO:00313467	Cervix	CC	positive regulation of cell projection organization	72/2311	353/18723	1.04e-05	2.32e-04	72

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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
hsa0501018	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0502218	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa0513220	Cervix	CC	Salmonella infection	74/1267	249/8465	1.33e-09	2.54e-08	1.50e-08	74
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0520516	Cervix	CC	Proteoglycans in cancer	60/1267	205/8465	9.13e-08	1.18e-06	7.00e-07	60
hsa0421810	Cervix	CC	Cellular senescence	49/1267	156/8465	1.30e-07	1.63e-06	9.61e-07	49
hsa0451010	Cervix	CC	Focal adhesion	59/1267	203/8465	1.53e-07	1.84e-06	1.09e-06	59
hsa0481016	Cervix	CC	Regulation of actin cytoskeleton	64/1267	229/8465	2.24e-07	2.59e-06	1.53e-06	64
hsa0491520	Cervix	CC	Estrogen signaling pathway	44/1267	138/8465	3.55e-07	3.97e-06	2.35e-06	44
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0401512	Cervix	CC	Rap1 signaling pathway	56/1267	210/8465	6.23e-06	5.61e-05	3.32e-05	56
hsa0466612	Cervix	CC	Fc gamma R-mediated phagocytosis	31/1267	97/8465	1.78e-05	1.42e-04	8.40e-05	31
hsa0517016	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
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
hsa0407110	Cervix	CC	Sphingolipid signaling pathway	35/1267	121/8465	5.70e-05	3.93e-04	2.32e-04	35
hsa0521010	Cervix	CC	Colorectal cancer	27/1267	86/8465	8.60e-05	5.57e-04	3.30e-04	27
hsa052197	Cervix	CC	Bladder cancer	16/1267	41/8465	1.45e-04	9.05e-04	5.35e-04	16

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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

MAP2K1

SNV

Missense_Mutation

novel

c.12G>T

p.Lys4Asn

p.K4N

Q02750

protein_coding

deleterious(0.01)

benign(0.135)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MAP2K1

SNV

Missense_Mutation

c.256N>G

p.Ser86Ala

p.S86A

Q02750

protein_coding

tolerated(0.67)

benign(0.027)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

MAP2K1

SNV

Missense_Mutation

c.607N>A

p.Glu203Lys

p.E203K

Q02750

protein_coding

deleterious(0)

possibly_damaging(0.838)

TCGA-E2-A159-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

MAP2K1

SNV

Missense_Mutation

rs754765552

c.1006G>C

p.Asp336His

p.D336H

Q02750

protein_coding

deleterious(0.03)

possibly_damaging(0.897)

TCGA-PE-A5DE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

MAP2K1

insertion

Frame_Shift_Ins

novel

c.845_846insCCCAGGCTGGAGTGCAGTGGTGCGATCT

p.Ala283ProfsTer12

p.A283Pfs*12

Q02750

protein_coding

TCGA-A2-A0EM-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

MAP2K1

SNV

Missense_Mutation

novel

c.770N>T

p.Ala257Val

p.A257V

Q02750

protein_coding

tolerated(0.11)

benign(0.274)

TCGA-EA-A3HS-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MAP2K1

SNV

Missense_Mutation

c.1046N>A

p.Arg349Lys

p.R349K

Q02750

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-EK-A2RA-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

MAP2K1

SNV

Missense_Mutation

c.1099N>C

p.Glu367Gln

p.E367Q

Q02750

protein_coding

tolerated(0.07)

benign(0.062)

TCGA-VS-A94Z-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MAP2K1

SNV

Missense_Mutation

c.308N>A

p.Ile103Asn

p.I103N

Q02750

protein_coding

deleterious(0)

possibly_damaging(0.866)

TCGA-VS-A9UQ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MAP2K1

SNV

Missense_Mutation

c.692N>T

p.Ser231Leu

p.S231L

Q02750

protein_coding

deleterious(0)

possibly_damaging(0.871)

TCGA-A6-5661-01

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
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR		SELUMETINIB	SELUMETINIB
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR		WX-554	WX-554
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR		Pyridic ketone derivative 1
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR		PANITUMUMAB	PANITUMUMAB	31227518
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR	allosteric modulator	363894205	TAK-733
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR	allosteric modulator	249565604	BINIMETINIB
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR		BAY 869766
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR	inhibitor	PIMASERTIB	PIMASERTIB
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR	inhibitor	CHEMBL2146883	COBIMETINIB
5604	MAP2K1	ENZYME, DRUGGABLE GENOME, KINASE, CLINICALLY ACTIONABLE, SERINE THREONINE KINASE, DRUG RESISTANCE, TYROSINE KINASE, NUCLEAR HORMONE RECEPTOR		VEMURAFENIB	VEMURAFENIB	22197931,7651428,18632602,19915144,23569304,25157968

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