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: MAP4K2

Gene summary for MAP4K2

Gene summary.

Gene information	Species	Human
	Gene symbol	MAP4K2
	Gene ID	5871
	Gene name	mitogen-activated protein kinase kinase kinase kinase 2
	Gene Alias	BL44
	Cytomap	11q13.1
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q12851

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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
5871	MAP4K2	LZE4T	Human	Esophagus	ESCC	2.33e-02	7.76e-02	0.0811
5871	MAP4K2	LZE22T	Human	Esophagus	ESCC	7.79e-05	3.78e-01	0.068
5871	MAP4K2	LZE24T	Human	Esophagus	ESCC	6.95e-14	1.80e-01	0.0596
5871	MAP4K2	LZE6T	Human	Esophagus	ESCC	8.81e-04	1.93e-01	0.0845
5871	MAP4K2	P2T-E	Human	Esophagus	ESCC	1.96e-05	9.05e-02	0.1177
5871	MAP4K2	P4T-E	Human	Esophagus	ESCC	1.24e-16	2.74e-01	0.1323
5871	MAP4K2	P5T-E	Human	Esophagus	ESCC	1.66e-02	8.24e-02	0.1327
5871	MAP4K2	P8T-E	Human	Esophagus	ESCC	3.28e-14	2.38e-01	0.0889
5871	MAP4K2	P9T-E	Human	Esophagus	ESCC	1.34e-07	1.17e-01	0.1131
5871	MAP4K2	P10T-E	Human	Esophagus	ESCC	4.44e-08	1.57e-01	0.116
5871	MAP4K2	P11T-E	Human	Esophagus	ESCC	8.25e-03	1.96e-01	0.1426
5871	MAP4K2	P12T-E	Human	Esophagus	ESCC	1.23e-20	3.63e-01	0.1122
5871	MAP4K2	P15T-E	Human	Esophagus	ESCC	1.19e-06	1.41e-01	0.1149
5871	MAP4K2	P16T-E	Human	Esophagus	ESCC	9.44e-07	1.57e-01	0.1153
5871	MAP4K2	P19T-E	Human	Esophagus	ESCC	2.17e-02	3.64e-01	0.1662
5871	MAP4K2	P20T-E	Human	Esophagus	ESCC	3.85e-07	1.42e-01	0.1124
5871	MAP4K2	P21T-E	Human	Esophagus	ESCC	1.77e-22	3.87e-01	0.1617
5871	MAP4K2	P22T-E	Human	Esophagus	ESCC	9.20e-06	1.21e-01	0.1236
5871	MAP4K2	P23T-E	Human	Esophagus	ESCC	8.23e-12	2.66e-01	0.108
5871	MAP4K2	P24T-E	Human	Esophagus	ESCC	9.53e-09	1.64e-01	0.1287

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma

∗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:005165617	Esophagus	ESCC	establishment of organelle localization	273/8552	390/18723	9.13e-23	1.81e-20	273
GO:007190016	Esophagus	ESCC	regulation of protein serine/threonine kinase activity	227/8552	359/18723	1.12e-11	4.10e-10	227
GO:005165016	Esophagus	ESCC	establishment of vesicle localization	114/8552	161/18723	8.20e-11	2.53e-09	114
GO:005164815	Esophagus	ESCC	vesicle localization	119/8552	177/18723	5.16e-09	1.08e-07	119
GO:00069038	Esophagus	ESCC	vesicle targeting	38/8552	45/18723	8.42e-08	1.43e-06	38
GO:003109818	Esophagus	ESCC	stress-activated protein kinase signaling cascade	154/8552	247/18723	8.53e-08	1.44e-06	154
GO:005140318	Esophagus	ESCC	stress-activated MAPK cascade	147/8552	239/18723	5.43e-07	7.18e-06	147
GO:00719029	Esophagus	ESCC	positive regulation of protein serine/threonine kinase activity	124/8552	200/18723	2.27e-06	2.61e-05	124
GO:004586018	Esophagus	ESCC	positive regulation of protein kinase activity	219/8552	386/18723	6.91e-06	6.97e-05	219
GO:003367420	Esophagus	ESCC	positive regulation of kinase activity	260/8552	467/18723	7.26e-06	7.22e-05	260
GO:007030217	Esophagus	ESCC	regulation of stress-activated protein kinase signaling cascade	119/8552	195/18723	1.07e-05	1.01e-04	119
GO:003287217	Esophagus	ESCC	regulation of stress-activated MAPK cascade	116/8552	192/18723	2.63e-05	2.21e-04	116
GO:00072549	Esophagus	ESCC	JNK cascade	102/8552	167/18723	4.22e-05	3.39e-04	102
GO:00463289	Esophagus	ESCC	regulation of JNK cascade	80/8552	133/18723	5.35e-04	2.95e-03	80
GO:00434055	Esophagus	ESCC	regulation of MAP kinase activity	102/8552	177/18723	8.89e-04	4.55e-03	102
GO:00703046	Esophagus	ESCC	positive regulation of stress-activated protein kinase signaling cascade	74/8552	128/18723	3.77e-03	1.53e-02	74
GO:00328745	Esophagus	ESCC	positive regulation of stress-activated MAPK cascade	72/8552	126/18723	6.24e-03	2.29e-02	72
GO:00463302	Esophagus	ESCC	positive regulation of JNK cascade	52/8552	89/18723	1.04e-02	3.56e-02	52
GO:005165610	Oral cavity	OSCC	establishment of organelle localization	239/7305	390/18723	2.46e-19	3.31e-17	239
GO:007190010	Oral cavity	OSCC	regulation of protein serine/threonine kinase activity	201/7305	359/18723	3.90e-11	1.27e-09	201

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0401014	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa0401015	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165

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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

MAP4K2

SNV

Missense_Mutation

c.2263N>T

p.Ser755Cys

p.S755C

Q12851

protein_coding

deleterious(0.04)

probably_damaging(0.996)

TCGA-A2-A04T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

MAP4K2

insertion

Frame_Shift_Ins

novel

c.978_979insTGTAATCT

p.Pro327CysfsTer12

p.P327Cfs*12

Q12851

protein_coding

TCGA-A8-A09E-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

MAP4K2

insertion

Frame_Shift_Ins

novel

c.976_977insAAAAAAAAAAGCCCGGGTGTGGCTCATG

p.Thr326LysfsTer30

p.T326Kfs*30

Q12851

protein_coding

TCGA-A8-A09E-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

MAP4K2

insertion

Frame_Shift_Ins

novel

c.935_936insTGAGGATACGCTGGAGAAGGTG

p.Thr313GlufsTer41

p.T313Efs*41

Q12851

protein_coding

TCGA-BH-A0B1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

MAP4K2

SNV

Missense_Mutation

novel

c.2297N>A

p.Gly766Asp

p.G766D

Q12851

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MAP4K2

SNV

Missense_Mutation

rs373206883

c.1459N>A

p.Ala487Thr

p.A487T

Q12851

protein_coding

deleterious(0.04)

benign(0)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MAP4K2

SNV

Missense_Mutation

c.748N>T

p.Leu250Phe

p.L250F

Q12851

protein_coding

deleterious(0)

possibly_damaging(0.837)

TCGA-FU-A3NI-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MAP4K2

SNV

Missense_Mutation

c.738C>A

p.Phe246Leu

p.F246L

Q12851

protein_coding

deleterious(0.01)

probably_damaging(0.946)

TCGA-MY-A913-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MAP4K2

SNV

Missense_Mutation

c.833N>A

p.Pro278His

p.P278H

Q12851

protein_coding

deleterious(0.01)

benign(0.053)

TCGA-A6-5665-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

MAP4K2

SNV

Missense_Mutation

c.1193N>T

p.Thr398Ile

p.T398I

Q12851

protein_coding

tolerated(0.19)

benign(0.001)

TCGA-AZ-6601-01

Colorectum

colon adenocarcinoma

Male

>=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
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE	inhibitor	249565754
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		DACTOLISIB	DACTOLISIB
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		Quinazoline derivative 9
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		PHA-767491	CHEMBL225519
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		SP-600125	SP-600125
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		ENTRECTINIB	ENTRECTINIB
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		CENISERTIB	CENISERTIB
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE	inhibitor	348353652
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		ILORASERTIB	ILORASERTIB
5871	MAP4K2	ENZYME, DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE		PALBOCICLIB	PALBOCICLIB

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