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: MAPK3

Gene summary for MAPK3

Gene summary.

Gene information	Species	Human
	Gene symbol	MAPK3
	Gene ID	5595
	Gene name	mitogen-activated protein kinase 3
	Gene Alias	ERK-1
	Cytomap	16p11.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P27361

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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
5595	MAPK3	HTA11_3410_2000001011	Human	Colorectum	AD	4.51e-16	4.25e-01	0.0155
5595	MAPK3	HTA11_2487_2000001011	Human	Colorectum	SER	8.18e-36	1.56e+00	-0.1808
5595	MAPK3	HTA11_1938_2000001011	Human	Colorectum	AD	1.13e-19	9.37e-01	-0.0811
5595	MAPK3	HTA11_78_2000001011	Human	Colorectum	AD	5.72e-12	6.56e-01	-0.1088
5595	MAPK3	HTA11_347_2000001011	Human	Colorectum	AD	1.20e-51	1.19e+00	-0.1954
5595	MAPK3	HTA11_411_2000001011	Human	Colorectum	SER	9.09e-22	2.33e+00	-0.2602
5595	MAPK3	HTA11_2112_2000001011	Human	Colorectum	SER	2.15e-20	1.79e+00	-0.2196
5595	MAPK3	HTA11_3361_2000001011	Human	Colorectum	AD	8.94e-24	1.05e+00	-0.1207
5595	MAPK3	HTA11_83_2000001011	Human	Colorectum	SER	1.45e-23	1.14e+00	-0.1526
5595	MAPK3	HTA11_696_2000001011	Human	Colorectum	AD	1.76e-59	1.29e+00	-0.1464
5595	MAPK3	HTA11_866_2000001011	Human	Colorectum	AD	6.76e-29	8.47e-01	-0.1001
5595	MAPK3	HTA11_1391_2000001011	Human	Colorectum	AD	7.93e-35	1.06e+00	-0.059
5595	MAPK3	HTA11_2992_2000001011	Human	Colorectum	SER	3.15e-22	1.48e+00	-0.1706
5595	MAPK3	HTA11_5212_2000001011	Human	Colorectum	AD	1.47e-22	1.57e+00	-0.2061
5595	MAPK3	HTA11_5216_2000001011	Human	Colorectum	SER	9.33e-10	1.09e+00	-0.1462
5595	MAPK3	HTA11_546_2000001011	Human	Colorectum	AD	6.25e-21	9.85e-01	-0.0842
5595	MAPK3	HTA11_7862_2000001011	Human	Colorectum	AD	6.97e-05	4.93e-01	-0.0179
5595	MAPK3	HTA11_866_3004761011	Human	Colorectum	AD	6.69e-07	3.62e-01	0.096
5595	MAPK3	HTA11_4255_2000001011	Human	Colorectum	SER	1.13e-06	7.40e-01	0.0446
5595	MAPK3	HTA11_9408_2000001011	Human	Colorectum	AD	1.10e-02	5.86e-01	0.0451

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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
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:00706618	Oral cavity	OSCC	leukocyte proliferation	145/7305	318/18723	9.31e-03	3.33e-02	145
GO:00703716	Oral cavity	OSCC	ERK1 and ERK2 cascade	150/7305	330/18723	9.47e-03	3.38e-02	150
GO:007162110	Oral cavity	OSCC	granulocyte chemotaxis	62/7305	125/18723	1.02e-02	3.52e-02	62
GO:007124816	Oral cavity	OSCC	cellular response to metal ion	93/7305	197/18723	1.14e-02	3.85e-02	93
GO:0061307	Oral cavity	OSCC	cardiac neural crest cell differentiation involved in heart development	9/7305	12/18723	1.27e-02	4.24e-02	9
GO:0061308	Oral cavity	OSCC	cardiac neural crest cell development involved in heart development	9/7305	12/18723	1.27e-02	4.24e-02	9
GO:0072584	Oral cavity	OSCC	caveolin-mediated endocytosis	9/7305	12/18723	1.27e-02	4.24e-02	9
GO:00313495	Oral cavity	OSCC	positive regulation of defense response	127/7305	278/18723	1.32e-02	4.39e-02	127
GO:00703724	Oral cavity	OSCC	regulation of ERK1 and ERK2 cascade	140/7305	309/18723	1.34e-02	4.46e-02	140
GO:19055175	Oral cavity	OSCC	macrophage migration	30/7305	55/18723	1.39e-02	4.59e-02	30
GO:00487627	Oral cavity	OSCC	mesenchymal cell differentiation	109/7305	236/18723	1.43e-02	4.69e-02	109
GO:00706657	Oral cavity	OSCC	positive regulation of leukocyte proliferation	72/7305	150/18723	1.53e-02	4.95e-02	72
GO:00488637	Oral cavity	OSCC	stem cell differentiation	96/7305	206/18723	1.55e-02	4.99e-02	96
GO:001623615	Oral cavity	LP	macroautophagy	135/4623	291/18723	4.71e-16	6.70e-14	135
GO:0006979110	Oral cavity	LP	response to oxidative stress	181/4623	446/18723	5.74e-14	6.10e-12	181
GO:003238616	Oral cavity	LP	regulation of intracellular transport	145/4623	337/18723	8.58e-14	8.27e-12	145
GO:001050615	Oral cavity	LP	regulation of autophagy	132/4623	317/18723	1.82e-11	1.28e-09	132
GO:0009896110	Oral cavity	LP	positive regulation of catabolic process	187/4623	492/18723	2.30e-11	1.58e-09	187
GO:0045727110	Oral cavity	LP	positive regulation of translation	68/4623	136/18723	1.53e-10	8.51e-09	68
GO:0031331110	Oral cavity	LP	positive regulation of cellular catabolic process	163/4623	427/18723	3.03e-10	1.59e-08	163

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05208	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa05010	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa05020	Colorectum	AD	Prion disease	133/2092	273/8465	2.47e-18	8.29e-17	5.29e-17	133
hsa05022	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa05171	Colorectum	AD	Coronavirus disease - COVID-19	113/2092	232/8465	9.90e-16	2.55e-14	1.63e-14	113
hsa05131	Colorectum	AD	Shigellosis	109/2092	247/8465	1.09e-11	2.44e-10	1.55e-10	109
hsa04520	Colorectum	AD	Adherens junction	50/2092	93/8465	1.52e-09	2.83e-08	1.81e-08	50
hsa05132	Colorectum	AD	Salmonella infection	102/2092	249/8465	7.65e-09	1.28e-07	8.17e-08	102
hsa04666	Colorectum	AD	Fc gamma R-mediated phagocytosis	46/2092	97/8465	9.10e-07	1.22e-05	7.77e-06	46
hsa05130	Colorectum	AD	Pathogenic Escherichia coli infection	79/2092	197/8465	1.05e-06	1.36e-05	8.65e-06	79
hsa05135	Colorectum	AD	Yersinia infection	58/2092	137/8465	3.90e-06	4.35e-05	2.78e-05	58
hsa04066	Colorectum	AD	HIF-1 signaling pathway	48/2092	109/8465	7.25e-06	7.84e-05	5.00e-05	48
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa04722	Colorectum	AD	Neurotrophin signaling pathway	50/2092	119/8465	2.28e-05	2.24e-04	1.43e-04	50
hsa05213	Colorectum	AD	Endometrial cancer	29/2092	58/8465	2.69e-05	2.57e-04	1.64e-04	29
hsa04723	Colorectum	AD	Retrograde endocannabinoid signaling	59/2092	148/8465	2.94e-05	2.73e-04	1.74e-04	59
hsa05216	Colorectum	AD	Thyroid cancer	21/2092	37/8465	3.05e-05	2.76e-04	1.76e-04	21
hsa05230	Colorectum	AD	Central carbon metabolism in cancer	33/2092	70/8465	3.61e-05	3.19e-04	2.03e-04	33
hsa05210	Colorectum	AD	Colorectal cancer	35/2092	86/8465	7.54e-04	5.49e-03	3.50e-03	35
hsa05417	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73

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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

MAPK3

SNV

Missense_Mutation

c.454C>T

p.Arg152Trp

p.R152W

P27361

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0E1-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

MAPK3

insertion

Frame_Shift_Ins

novel

c.908_909insACTTTGGGAGGCCGAGGTGGGTG

p.Asp305TrpfsTer15

p.D305Wfs*15

P27361

protein_coding

TCGA-A8-A07W-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

exemestane

MAPK3

insertion

Frame_Shift_Ins

novel

c.1074_1075insGCTGTGGTGGGAGGACTGCTTGAACCTGGGAGAG

p.Arg359AlafsTer85

p.R359Afs*85

P27361

protein_coding

TCGA-AN-A04A-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

MAPK3

insertion

Frame_Shift_Ins

novel

c.504_505insGAGGGGCTGCCCACTCCTGAAAGGAACGGAC

p.Pro169GlufsTer23

p.P169Efs*23

P27361

protein_coding

TCGA-BH-A0HQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

MAPK3

SNV

Missense_Mutation

rs774690695

c.311G>A

p.Arg104Gln

p.R104Q

P27361

protein_coding

tolerated(0.33)

benign(0.014)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MAPK3

SNV

Missense_Mutation

novel

c.819N>G

p.Ile273Met

p.I273M

P27361

protein_coding

tolerated(0.11)

possibly_damaging(0.815)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MAPK3

SNV

Missense_Mutation

c.869N>C

p.Val290Ala

p.V290A

P27361

protein_coding

tolerated(0.24)

benign(0.075)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

MAPK3

SNV

Missense_Mutation

c.173N>T

p.Ser58Leu

p.S58L

P27361

protein_coding

deleterious(0.01)

possibly_damaging(0.78)

TCGA-AA-A01R-01

Colorectum

colon adenocarcinoma

Male

<65

III/IV

Chemotherapy

5-fluorouracil

MAPK3

SNV

Missense_Mutation

c.251G>A

p.Arg84His

p.R84H

P27361

protein_coding

deleterious(0.03)

probably_damaging(0.963)

TCGA-AD-5900-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

MAPK3

SNV

Missense_Mutation

rs764219989

c.631N>T

p.Arg211Trp

p.R211W

P27361

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-DM-A1HB-01

Colorectum

colon adenocarcinoma

Male

>=65

III/IV

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
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		(+)-ISOBICYCLOGERMACRENAL	CHEMBL2333548
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		ETOPOSIDE	ETOPOSIDE	23999041
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		BENZOTHIAZOL-2-YLAMINE	CHEMBL329785	22982122
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		YUANHUADINE	YUANHUADINE	21916433
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		CIMIRACEMATE A	CIMIRACEMATE A	19835377
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		SELENIUM		14744887
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		NSC-753574	CHEMBL2088730	22982122
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		PD-153035	CHEMBL29197	17681471
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		MADOLIN A	MADOLIN A
5595	MAPK3	TRANSCRIPTION FACTOR, KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, ENZYME		VOLVALERENAL D	VOLVALERENAL D

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