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: MAP3K1

Gene summary for MAP3K1

Gene summary.

Gene information	Species	Human
	Gene symbol	MAP3K1
	Gene ID	4214
	Gene name	mitogen-activated protein kinase kinase kinase 1
	Gene Alias	MAPKKK1
	Cytomap	5q11.2
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q13233

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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
4214	MAP3K1	AEH-subject1	Human	Endometrium	AEH	4.76e-23	5.03e-01	-0.3059
4214	MAP3K1	AEH-subject2	Human	Endometrium	AEH	4.07e-03	2.96e-01	-0.2525
4214	MAP3K1	AEH-subject3	Human	Endometrium	AEH	3.91e-12	3.60e-01	-0.2576
4214	MAP3K1	AEH-subject5	Human	Endometrium	AEH	1.43e-02	1.79e-01	-0.2953
4214	MAP3K1	EEC-subject1	Human	Endometrium	EEC	6.48e-07	2.92e-01	-0.2682
4214	MAP3K1	EEC-subject2	Human	Endometrium	EEC	1.24e-07	2.15e-01	-0.2607
4214	MAP3K1	GSM6177620_NYU_UCEC1_lib1_lib1	Human	Endometrium	EEC	6.67e-11	2.50e-01	-0.1869
4214	MAP3K1	GSM6177620_NYU_UCEC1_lib2_lib2	Human	Endometrium	EEC	2.18e-10	2.75e-01	-0.1875
4214	MAP3K1	GSM6177620_NYU_UCEC1_lib3_lib3	Human	Endometrium	EEC	6.33e-09	1.65e-01	-0.1883
4214	MAP3K1	GSM6177621_NYU_UCEC2_lib1_lib1	Human	Endometrium	EEC	1.33e-11	2.78e-01	-0.1934
4214	MAP3K1	GSM6177622_NYU_UCEC3_lib1_lib1	Human	Endometrium	EEC	3.22e-13	2.71e-01	-0.1917
4214	MAP3K1	GSM6177622_NYU_UCEC3_lib2_lib2	Human	Endometrium	EEC	4.16e-15	2.67e-01	-0.1916
4214	MAP3K1	GSM6177623_NYU_UCEC3_Vis	Human	Endometrium	EEC	1.25e-07	3.58e-01	-0.1269
4214	MAP3K1	GSM5252132_BPH389PrGF	Human	Prostate	BPH	7.83e-03	3.30e-01	-0.2247
4214	MAP3K1	GSM5252135_BPH511PrPUr_Fcol_3GEX	Human	Prostate	BPH	8.76e-03	1.60e-01	-0.1833
4214	MAP3K1	048752_1579-all-cells	Human	Prostate	BPH	8.69e-20	4.42e-01	0.1008
4214	MAP3K1	052095_1628-all-cells	Human	Prostate	BPH	7.78e-20	4.49e-01	0.1032
4214	MAP3K1	052097_1595-all-cells	Human	Prostate	BPH	6.73e-16	4.27e-01	0.0972
4214	MAP3K1	052099_1652-all-cells	Human	Prostate	BPH	2.80e-11	3.73e-01	0.1038
4214	MAP3K1	Dong_P1	Human	Prostate	Tumor	9.75e-10	7.65e-02	0.035

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Endometrium		AEH: Atypical endometrial hyperplasia
Endometrium		EEC: Endometrioid Cancer
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:002260410	Cervix	CC	regulation of cell morphogenesis	84/2311	309/18723	1.00e-12	4.29e-10	84
GO:003367410	Cervix	CC	positive regulation of kinase activity	101/2311	467/18723	8.66e-09	7.22e-07	101
GO:00458608	Cervix	CC	positive regulation of protein kinase activity	85/2311	386/18723	5.61e-08	3.29e-06	85
GO:00310988	Cervix	CC	stress-activated protein kinase signaling cascade	58/2311	247/18723	8.02e-07	2.89e-05	58
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:00109757	Cervix	CC	regulation of neuron projection development	88/2311	445/18723	4.26e-06	1.09e-04	88
GO:00510904	Cervix	CC	regulation of DNA-binding transcription factor activity	87/2311	440/18723	4.85e-06	1.22e-04	87
GO:00107206	Cervix	CC	positive regulation of cell development	64/2311	298/18723	5.69e-06	1.41e-04	64
GO:00313467	Cervix	CC	positive regulation of cell projection organization	72/2311	353/18723	1.04e-05	2.32e-04	72
GO:00160498	Cervix	CC	cell growth	92/2311	482/18723	1.16e-05	2.49e-04	92
GO:00325359	Cervix	CC	regulation of cellular component size	76/2311	383/18723	1.66e-05	3.21e-04	76
GO:00615647	Cervix	CC	axon development	89/2311	467/18723	1.71e-05	3.27e-04	89
GO:00719025	Cervix	CC	positive regulation of protein serine/threonine kinase activity	46/2311	200/18723	1.87e-05	3.47e-04	46
GO:00434104	Cervix	CC	positive regulation of MAPK cascade	90/2311	480/18723	2.92e-05	4.83e-04	90
GO:00181057	Cervix	CC	peptidyl-serine phosphorylation	63/2311	315/18723	6.65e-05	9.47e-04	63
GO:00182096	Cervix	CC	peptidyl-serine modification	66/2311	338/18723	9.58e-05	1.25e-03	66
GO:00074097	Cervix	CC	axonogenesis	78/2311	418/18723	1.14e-04	1.43e-03	78
GO:00459277	Cervix	CC	positive regulation of growth	53/2311	259/18723	1.33e-04	1.64e-03	53
GO:00015588	Cervix	CC	regulation of cell growth	77/2311	414/18723	1.40e-04	1.70e-03	77

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0453026	Endometrium	AEH	Tight junction	54/1197	169/8465	1.99e-09	3.80e-08	2.78e-08	54
hsa0412016	Endometrium	AEH	Ubiquitin mediated proteolysis	41/1197	142/8465	3.42e-06	4.27e-05	3.13e-05	41
hsa0472216	Endometrium	AEH	Neurotrophin signaling pathway	31/1197	119/8465	4.07e-04	3.07e-03	2.25e-03	31
hsa0516626	Endometrium	AEH	Human T-cell leukemia virus 1 infection	50/1197	222/8465	4.30e-04	3.11e-03	2.27e-03	50
hsa04530112	Endometrium	AEH	Tight junction	54/1197	169/8465	1.99e-09	3.80e-08	2.78e-08	54
hsa0412017	Endometrium	AEH	Ubiquitin mediated proteolysis	41/1197	142/8465	3.42e-06	4.27e-05	3.13e-05	41
hsa0472217	Endometrium	AEH	Neurotrophin signaling pathway	31/1197	119/8465	4.07e-04	3.07e-03	2.25e-03	31
hsa05166111	Endometrium	AEH	Human T-cell leukemia virus 1 infection	50/1197	222/8465	4.30e-04	3.11e-03	2.27e-03	50
hsa0453027	Endometrium	EEC	Tight junction	54/1237	169/8465	6.56e-09	1.27e-07	9.46e-08	54
hsa0412023	Endometrium	EEC	Ubiquitin mediated proteolysis	41/1237	142/8465	7.86e-06	9.58e-05	7.14e-05	41
hsa0516627	Endometrium	EEC	Human T-cell leukemia virus 1 infection	52/1237	222/8465	2.73e-04	2.36e-03	1.76e-03	52
hsa0472222	Endometrium	EEC	Neurotrophin signaling pathway	30/1237	119/8465	1.54e-03	9.55e-03	7.12e-03	30
hsa0453036	Endometrium	EEC	Tight junction	54/1237	169/8465	6.56e-09	1.27e-07	9.46e-08	54
hsa0412033	Endometrium	EEC	Ubiquitin mediated proteolysis	41/1237	142/8465	7.86e-06	9.58e-05	7.14e-05	41
hsa0516636	Endometrium	EEC	Human T-cell leukemia virus 1 infection	52/1237	222/8465	2.73e-04	2.36e-03	1.76e-03	52
hsa0472232	Endometrium	EEC	Neurotrophin signaling pathway	30/1237	119/8465	1.54e-03	9.55e-03	7.12e-03	30
hsa0412018	Prostate	BPH	Ubiquitin mediated proteolysis	61/1718	142/8465	5.50e-10	9.07e-09	5.61e-09	61
hsa0453028	Prostate	BPH	Tight junction	68/1718	169/8465	1.70e-09	2.55e-08	1.58e-08	68
hsa0516628	Prostate	BPH	Human T-cell leukemia virus 1 infection	79/1718	222/8465	6.00e-08	6.83e-07	4.23e-07	79
hsa0401010	Prostate	BPH	MAPK signaling pathway	87/1718	302/8465	2.05e-04	1.13e-03	6.98e-04	87

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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

MAP3K1

SNV

Missense_Mutation

c.4121A>G

p.Asn1374Ser

p.N1374S

Q13233

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-A2-A04N-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

MAP3K1

SNV

Missense_Mutation

c.4310G>T

p.Cys1437Phe

p.C1437F

Q13233

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A04N-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

MAP3K1

SNV

Missense_Mutation

c.3989N>G

p.Ser1330Trp

p.S1330W

Q13233

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A0EU-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MAP3K1

SNV

Missense_Mutation

c.3517N>G

p.His1173Asp

p.H1173D

Q13233

protein_coding

tolerated_low_confidence(0.12)

benign(0.395)

TCGA-A2-A0YK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

MAP3K1

SNV

Missense_Mutation

c.2305C>T

p.Pro769Ser

p.P769S

Q13233

protein_coding

tolerated(0.06)

benign(0.158)

TCGA-A2-A1G1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MAP3K1

SNV

Missense_Mutation

c.4298N>C

p.Trp1433Ser

p.W1433S

Q13233

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A259-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

MAP3K1

SNV

Missense_Mutation

c.3934N>T

p.Ala1312Ser

p.A1312S

Q13233

protein_coding

tolerated(0.06)

possibly_damaging(0.533)

TCGA-A2-A25A-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Cytoxan

MAP3K1

SNV

Missense_Mutation

novel

c.975N>A

p.Asn325Lys

p.N325K

Q13233

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-A2-A3Y0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

MAP3K1

SNV

Missense_Mutation

novel

c.3373N>G

p.Asn1125Asp

p.N1125D

Q13233

protein_coding

deleterious_low_confidence(0.01)

benign(0.03)

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

MAP3K1

SNV

Missense_Mutation

rs755757854

c.1403N>C

p.His468Pro

p.H468P

Q13233

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-A8-A095-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

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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
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		cisplatin	CISPLATIN	21636554
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		gefitinib	GEFITINIB	21636554
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		paclitaxel	PACLITAXEL	21636554
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME	inhibitor	223366167	E-6201
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		docetaxel	DOCETAXEL	21636554
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		erlotinib	ERLOTINIB	21636554
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME	inhibitor	CHEMBL1097999	E-6201
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		carboplatin	CARBOPLATIN	21636554
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		CI-1040	CI-1040
4214	MAP3K1	CLINICALLY ACTIONABLE, ENZYME, KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME		Tumor necrosis factor alpha (TNF-alpha) inhibitors		27670765

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