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: MARK2

Gene summary for MARK2

Gene summary.

Gene information	Species	Human
	Gene symbol	MARK2
	Gene ID	2011
	Gene name	microtubule affinity regulating kinase 2
	Gene Alias	EMK-1
	Cytomap	11q13.1
	Gene Type	protein-coding
	GO ID	GO:0000226
	UniProtAcc	Q7KZI7

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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
2011	MARK2	HTA11_3410_2000001011	Human	Colorectum	AD	1.23e-03	-3.02e-01	0.0155
2011	MARK2	HTA11_2951_2000001011	Human	Colorectum	AD	1.13e-02	-6.04e-01	0.0216
2011	MARK2	HTA11_347_2000001011	Human	Colorectum	AD	1.35e-04	3.86e-01	-0.1954
2011	MARK2	HTA11_411_2000001011	Human	Colorectum	SER	3.99e-02	7.08e-01	-0.2602
2011	MARK2	HTA11_99999970781_79442	Human	Colorectum	MSS	3.18e-08	-3.25e-01	0.294
2011	MARK2	A002-C-010	Human	Colorectum	FAP	3.76e-02	-2.31e-01	0.242
2011	MARK2	A015-C-203	Human	Colorectum	FAP	9.59e-26	-3.69e-01	-0.1294
2011	MARK2	A015-C-204	Human	Colorectum	FAP	4.99e-06	-3.54e-01	-0.0228
2011	MARK2	A014-C-040	Human	Colorectum	FAP	1.26e-02	-4.15e-01	-0.1184
2011	MARK2	A002-C-201	Human	Colorectum	FAP	3.54e-08	-2.95e-01	0.0324
2011	MARK2	A002-C-203	Human	Colorectum	FAP	2.71e-04	-1.91e-01	0.2786
2011	MARK2	A001-C-119	Human	Colorectum	FAP	1.00e-03	-2.80e-01	-0.1557
2011	MARK2	A001-C-108	Human	Colorectum	FAP	3.21e-16	-3.24e-01	-0.0272
2011	MARK2	A002-C-205	Human	Colorectum	FAP	4.03e-16	-4.09e-01	-0.1236
2011	MARK2	A001-C-104	Human	Colorectum	FAP	3.90e-06	-2.25e-01	0.0184
2011	MARK2	A015-C-005	Human	Colorectum	FAP	2.53e-05	-3.62e-01	-0.0336
2011	MARK2	A015-C-006	Human	Colorectum	FAP	5.18e-08	-2.55e-01	-0.0994
2011	MARK2	A015-C-106	Human	Colorectum	FAP	4.33e-15	-2.22e-01	-0.0511
2011	MARK2	A002-C-114	Human	Colorectum	FAP	1.13e-12	-3.80e-01	-0.1561
2011	MARK2	A015-C-104	Human	Colorectum	FAP	1.67e-28	-3.65e-01	-0.1899

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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
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
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:001820917	Thyroid	ATC	peptidyl-serine modification	161/6293	338/18723	5.23e-08	9.44e-07	161
GO:003367427	Thyroid	ATC	positive regulation of kinase activity	212/6293	467/18723	5.89e-08	1.05e-06	212
GO:0030010111	Thyroid	ATC	establishment of cell polarity	79/6293	143/18723	8.08e-08	1.40e-06	79
GO:004677717	Thyroid	ATC	protein autophosphorylation	114/6293	227/18723	1.54e-07	2.49e-06	114
GO:005077011	Thyroid	ATC	regulation of axonogenesis	80/6293	154/18723	1.95e-06	2.34e-05	80
GO:001810718	Thyroid	ATC	peptidyl-threonine phosphorylation	63/6293	116/18723	3.47e-06	3.89e-05	63
GO:003288613	Thyroid	ATC	regulation of microtubule-based process	114/6293	240/18723	5.17e-06	5.59e-05	114
GO:001821018	Thyroid	ATC	peptidyl-threonine modification	66/6293	125/18723	7.36e-06	7.56e-05	66
GO:001097614	Thyroid	ATC	positive regulation of neuron projection development	82/6293	163/18723	7.43e-06	7.61e-05	82
GO:003214711	Thyroid	ATC	activation of protein kinase activity	65/6293	134/18723	2.44e-04	1.57e-03	65
GO:003508815	Thyroid	ATC	establishment or maintenance of apical/basal cell polarity	27/6293	49/18723	1.58e-03	7.99e-03	27
GO:006124515	Thyroid	ATC	establishment or maintenance of bipolar cell polarity	27/6293	49/18723	1.58e-03	7.99e-03	27
GO:004519715	Thyroid	ATC	establishment or maintenance of epithelial cell apical/basal polarity	24/6293	44/18723	3.39e-03	1.52e-02	24
GO:005164612	Thyroid	ATC	mitochondrion localization	25/6293	50/18723	1.20e-02	4.27e-02	25

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

MARK2

SNV

Missense_Mutation

c.2144N>A

p.Arg715His

p.R715H

Q7KZI7

protein_coding

deleterious(0)

probably_damaging(0.915)

TCGA-A7-A6VX-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

MARK2

SNV

Missense_Mutation

c.2050G>C

p.Glu684Gln

p.E684Q

Q7KZI7

protein_coding

tolerated(0.08)

benign(0)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

MARK2

SNV

Missense_Mutation

novel

c.1312G>C

p.Glu438Gln

p.E438Q

Q7KZI7

protein_coding

tolerated(0.23)

benign(0.018)

TCGA-AC-A5XS-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

femara

MARK2

SNV

Missense_Mutation

c.1075C>A

p.Leu359Met

p.L359M

Q7KZI7

protein_coding

deleterious(0.01)

possibly_damaging(0.654)

TCGA-B6-A0IK-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

MARK2

SNV

Missense_Mutation

c.316N>C

p.Val106Leu

p.V106L

Q7KZI7

protein_coding

tolerated(0.79)

benign(0)

TCGA-BH-A18Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

MARK2

SNV

Missense_Mutation

rs368859674

c.1307N>A

p.Arg436Gln

p.R436Q

Q7KZI7

protein_coding

tolerated(0.79)

benign(0.007)

TCGA-D8-A1Y1-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

MARK2

SNV

Missense_Mutation

rs199684279

c.905N>A

p.Arg302Gln

p.R302Q

Q7KZI7

protein_coding

deleterious(0)

possibly_damaging(0.606)

TCGA-XX-A899-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

MARK2

insertion

Nonsense_Mutation

novel

c.908_909insCCCCAGAACTCTTCCAGGGCAAAAAATATGATGGACCC

p.Trp303CysfsTer11

p.W303Cfs*11

Q7KZI7

protein_coding

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

MARK2

insertion

Frame_Shift_Ins

novel

c.876_877insTCCTCTC

p.Gly293SerfsTer21

p.G293Sfs*21

Q7KZI7

protein_coding

TCGA-B6-A0IK-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

MARK2

insertion

Nonsense_Mutation

novel

c.879_880insCTCTGGTCTTAGCCCTGACCTCCTGCCTTTGCC

p.Gly293_Thr294insLeuTrpSerTerProTerProProAlaPheAla

p.G293_T294insLWS*P*PPAFA

Q7KZI7

protein_coding

TCGA-B6-A0IK-01

Breast

breast invasive carcinoma

Female

<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
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		TOZASERTIB	TOZASERTIB
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		LINIFANIB	LINIFANIB
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		DOVITINIB	DOVITINIB
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		GSK-269962A	GSK-269962A
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		TYROSINE KINASE INHIBITORS		15811957
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		GNF-PF-2301	CHEMBL578061
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		KENPAULLONE	KENPAULLONE
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		CENISERTIB	CENISERTIB
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		ALSTERPAULLONE	ALSTERPAULLONE
2011	MARK2	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		AZD-1080	AZD-1080

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