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:00305165	Lung	IAC	regulation of axon extension	19/2061	95/18723	7.04e-03	4.83e-02	19
GO:002260413	Lung	AIS	regulation of cell morphogenesis	65/1849	309/18723	2.97e-09	5.09e-07	65
GO:006056012	Lung	AIS	developmental growth involved in morphogenesis	51/1849	234/18723	4.43e-08	5.24e-06	51
GO:003109813	Lung	AIS	stress-activated protein kinase signaling cascade	51/1849	247/18723	2.69e-07	2.37e-05	51
GO:001604912	Lung	AIS	cell growth	83/1849	482/18723	3.26e-07	2.79e-05	83
GO:001810512	Lung	AIS	peptidyl-serine phosphorylation	60/1849	315/18723	4.75e-07	3.64e-05	60
GO:000725413	Lung	AIS	JNK cascade	38/1849	167/18723	7.27e-07	5.36e-05	38
GO:005140313	Lung	AIS	stress-activated MAPK cascade	48/1849	239/18723	1.38e-06	8.75e-05	48
GO:199013812	Lung	AIS	neuron projection extension	38/1849	172/18723	1.57e-06	9.85e-05	38
GO:004858812	Lung	AIS	developmental cell growth	47/1849	234/18723	1.77e-06	1.05e-04	47
GO:001820912	Lung	AIS	peptidyl-serine modification	61/1849	338/18723	2.49e-06	1.41e-04	61
GO:003367412	Lung	AIS	positive regulation of kinase activity	77/1849	467/18723	4.67e-06	2.31e-04	77
GO:004867512	Lung	AIS	axon extension	28/1849	120/18723	1.22e-05	4.71e-04	28
GO:004586012	Lung	AIS	positive regulation of protein kinase activity	65/1849	386/18723	1.27e-05	4.78e-04	65
GO:007190012	Lung	AIS	regulation of protein serine/threonine kinase activity	61/1849	359/18723	1.76e-05	6.17e-04	61
GO:007190211	Lung	AIS	positive regulation of protein serine/threonine kinase activity	38/1849	200/18723	6.00e-05	1.65e-03	38
GO:004863811	Lung	AIS	regulation of developmental growth	55/1849	330/18723	7.63e-05	1.95e-03	55
GO:004863911	Lung	AIS	positive regulation of developmental growth	34/1849	174/18723	8.08e-05	2.02e-03	34
GO:001097512	Lung	AIS	regulation of neuron projection development	69/1849	445/18723	1.05e-04	2.53e-03	69
GO:004577312	Lung	AIS	positive regulation of axon extension	13/1849	42/18723	1.34e-04	2.97e-03	13

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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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