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: DYRK4

Gene summary for DYRK4

Gene summary.

Gene information	Species	Human
	Gene symbol	DYRK4
	Gene ID	8798
	Gene name	dual specificity tyrosine phosphorylation regulated kinase 4
	Gene Alias	DYRK4
	Cytomap	12p13.32
	Gene Type	protein-coding
	GO ID	GO:0006464
	UniProtAcc	D3JEN2

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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
8798	DYRK4	HTA11_3410_2000001011	Human	Colorectum	AD	3.66e-02	1.24e-01	0.0155
8798	DYRK4	HTA11_1938_2000001011	Human	Colorectum	AD	2.30e-02	1.94e-01	-0.0811
8798	DYRK4	HTA11_347_2000001011	Human	Colorectum	AD	5.50e-03	1.47e-01	-0.1954
8798	DYRK4	HTA11_696_2000001011	Human	Colorectum	AD	3.85e-04	1.55e-01	-0.1464
8798	DYRK4	HTA11_866_2000001011	Human	Colorectum	AD	2.05e-06	1.97e-01	-0.1001
8798	DYRK4	HTA11_1391_2000001011	Human	Colorectum	AD	2.63e-07	2.58e-01	-0.059
8798	DYRK4	HTA11_7696_3000711011	Human	Colorectum	AD	2.07e-08	1.77e-01	0.0674
8798	DYRK4	HTA11_99999965062_69753	Human	Colorectum	MSI-H	9.21e-04	5.32e-01	0.3487
8798	DYRK4	HTA11_99999974143_84620	Human	Colorectum	MSS	9.04e-05	1.29e-01	0.3005
8798	DYRK4	LZE7T	Human	Esophagus	ESCC	5.37e-05	2.78e-01	0.0667
8798	DYRK4	LZE24T	Human	Esophagus	ESCC	1.61e-10	3.29e-01	0.0596
8798	DYRK4	P2T-E	Human	Esophagus	ESCC	3.15e-55	9.69e-01	0.1177
8798	DYRK4	P4T-E	Human	Esophagus	ESCC	3.05e-44	9.47e-01	0.1323
8798	DYRK4	P5T-E	Human	Esophagus	ESCC	6.53e-18	2.43e-01	0.1327
8798	DYRK4	P8T-E	Human	Esophagus	ESCC	1.76e-13	1.76e-01	0.0889
8798	DYRK4	P9T-E	Human	Esophagus	ESCC	3.18e-12	2.52e-01	0.1131
8798	DYRK4	P10T-E	Human	Esophagus	ESCC	1.47e-21	3.59e-01	0.116
8798	DYRK4	P11T-E	Human	Esophagus	ESCC	5.68e-11	4.70e-01	0.1426
8798	DYRK4	P12T-E	Human	Esophagus	ESCC	3.96e-53	8.84e-01	0.1122
8798	DYRK4	P16T-E	Human	Esophagus	ESCC	1.75e-20	3.84e-01	0.1153

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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
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:0018105	Colorectum	AD	peptidyl-serine phosphorylation	88/3918	315/18723	1.73e-03	1.43e-02	88
GO:0018210	Colorectum	AD	peptidyl-threonine modification	40/3918	125/18723	2.44e-03	1.88e-02	40
GO:0018209	Colorectum	AD	peptidyl-serine modification	92/3918	338/18723	3.19e-03	2.36e-02	92
GO:0018107	Colorectum	AD	peptidyl-threonine phosphorylation	37/3918	116/18723	3.68e-03	2.61e-02	37
GO:00181052	Colorectum	MSS	peptidyl-serine phosphorylation	81/3467	315/18723	8.92e-04	9.12e-03	81
GO:00182091	Colorectum	MSS	peptidyl-serine modification	84/3467	338/18723	2.12e-03	1.79e-02	84
GO:00181071	Colorectum	MSS	peptidyl-threonine phosphorylation	34/3467	116/18723	3.08e-03	2.34e-02	34
GO:00182101	Colorectum	MSS	peptidyl-threonine modification	36/3467	125/18723	3.28e-03	2.49e-02	36
GO:00182099	Esophagus	ESCC	peptidyl-serine modification	196/8552	338/18723	3.07e-06	3.47e-05	196
GO:001810515	Esophagus	ESCC	peptidyl-serine phosphorylation	184/8552	315/18723	3.22e-06	3.61e-05	184
GO:00182124	Esophagus	ESCC	peptidyl-tyrosine modification	202/8552	378/18723	1.34e-03	6.39e-03	202
GO:00181084	Esophagus	ESCC	peptidyl-tyrosine phosphorylation	200/8552	375/18723	1.60e-03	7.45e-03	200
GO:001810710	Esophagus	ESCC	peptidyl-threonine phosphorylation	66/8552	116/18723	9.76e-03	3.37e-02	66
GO:001821010	Esophagus	ESCC	peptidyl-threonine modification	70/8552	125/18723	1.29e-02	4.25e-02	70
GO:00182098	Oral cavity	OSCC	peptidyl-serine modification	175/7305	338/18723	1.09e-06	1.46e-05	175
GO:001810510	Oral cavity	OSCC	peptidyl-serine phosphorylation	164/7305	315/18723	1.51e-06	1.99e-05	164
GO:00182123	Oral cavity	OSCC	peptidyl-tyrosine modification	180/7305	378/18723	3.63e-04	2.22e-03	180
GO:00181083	Oral cavity	OSCC	peptidyl-tyrosine phosphorylation	177/7305	375/18723	6.86e-04	3.83e-03	177
GO:00181079	Oral cavity	OSCC	peptidyl-threonine phosphorylation	60/7305	116/18723	3.59e-03	1.50e-02	60
GO:00182109	Oral cavity	OSCC	peptidyl-threonine modification	64/7305	125/18723	3.68e-03	1.52e-02	64

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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

DYRK4

SNV

Missense_Mutation

c.1176C>A

p.Asp392Glu

p.D392E

Q9NR20

protein_coding

tolerated(0.31)

benign(0.006)

TCGA-D8-A1JL-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DYRK4

SNV

Missense_Mutation

c.606C>A

p.Phe202Leu

p.F202L

Q9NR20

protein_coding

deleterious(0.02)

benign(0.107)

TCGA-E9-A1QZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

DYRK4

insertion

Nonsense_Mutation

novel

c.1303_1304insCATTAGCATTATTATTTTATCTTGGTTGGTGTTAAGCCATTTA

p.His435ProfsTer12

p.H435Pfs*12

Q9NR20

protein_coding

TCGA-A8-A085-01

Breast

breast invasive carcinoma

Male

<65

I/II

Hormone Therapy

tamoxiphen

DYRK4

insertion

In_Frame_Ins

novel

c.380_381insAACAGAAGTCTTGTTCCCTATAAGTCTTTTTCT

p.Asn127delinsLysThrGluValLeuPheProIleSerLeuPheLeu

p.N127delinsKTEVLFPISLFL

Q9NR20

protein_coding

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DYRK4

deletion

Frame_Shift_Del

novel

c.498delN

p.Val167CysfsTer3

p.V167Cfs*3

Q9NR20

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

DYRK4

SNV

Missense_Mutation

rs149277354

c.697N>T

p.Pro233Ser

p.P233S

Q9NR20

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

DYRK4

SNV

Missense_Mutation

novel

c.734N>T

p.Ser245Phe

p.S245F

Q9NR20

protein_coding

deleterious(0)

possibly_damaging(0.657)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

DYRK4

SNV

Missense_Mutation

rs766865898

c.220N>A

p.Asp74Asn

p.D74N

Q9NR20

protein_coding

tolerated(0.71)

benign(0)

TCGA-AA-3811-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

DYRK4

SNV

Missense_Mutation

c.377N>T

p.Asn126Ile

p.N126I

Q9NR20

protein_coding

deleterious(0.03)

benign(0.091)

TCGA-AA-3818-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

DYRK4

SNV

Missense_Mutation

novel

c.1486N>C

p.Glu496Gln

p.E496Q

Q9NR20

protein_coding

tolerated_low_confidence(0.07)

benign(0.01)

TCGA-AA-3979-01

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
8798	DYRK4	ENZYME, KINASE, DRUGGABLE GENOME, TYROSINE KINASE, SERINE THREONINE KINASE	inhibitor	249565847
8798	DYRK4	ENZYME, KINASE, DRUGGABLE GENOME, TYROSINE KINASE, SERINE THREONINE KINASE		TAMATINIB	R-406
8798	DYRK4	ENZYME, KINASE, DRUGGABLE GENOME, TYROSINE KINASE, SERINE THREONINE KINASE		PHA-767491	CHEMBL225519

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