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: CLK3

Gene summary for CLK3

Gene summary.

Gene information	Species	Human
	Gene symbol	CLK3
	Gene ID	1198
	Gene name	CDC like kinase 3
	Gene Alias	PHCLK3
	Cytomap	15q24.1
	Gene Type	protein-coding
	GO ID	GO:0006139
	UniProtAcc	B3KRI8

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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
1198	CLK3	LZE4T	Human	Esophagus	ESCC	1.61e-12	2.47e-01	0.0811
1198	CLK3	LZE7T	Human	Esophagus	ESCC	3.19e-09	3.49e-01	0.0667
1198	CLK3	LZE8T	Human	Esophagus	ESCC	6.96e-07	1.12e-01	0.067
1198	CLK3	LZE20T	Human	Esophagus	ESCC	2.92e-02	1.29e-01	0.0662
1198	CLK3	LZE22T	Human	Esophagus	ESCC	1.10e-02	1.38e-01	0.068
1198	CLK3	LZE24T	Human	Esophagus	ESCC	2.91e-18	2.25e-01	0.0596
1198	CLK3	LZE21T	Human	Esophagus	ESCC	4.80e-06	1.80e-01	0.0655
1198	CLK3	LZE6T	Human	Esophagus	ESCC	6.47e-09	2.68e-01	0.0845
1198	CLK3	P1T-E	Human	Esophagus	ESCC	1.01e-07	6.21e-01	0.0875
1198	CLK3	P2T-E	Human	Esophagus	ESCC	9.31e-27	2.76e-01	0.1177
1198	CLK3	P4T-E	Human	Esophagus	ESCC	1.80e-27	4.97e-01	0.1323
1198	CLK3	P5T-E	Human	Esophagus	ESCC	1.75e-14	2.14e-01	0.1327
1198	CLK3	P8T-E	Human	Esophagus	ESCC	5.41e-13	3.91e-01	0.0889
1198	CLK3	P9T-E	Human	Esophagus	ESCC	3.20e-19	3.10e-01	0.1131
1198	CLK3	P10T-E	Human	Esophagus	ESCC	3.28e-28	3.36e-01	0.116
1198	CLK3	P11T-E	Human	Esophagus	ESCC	5.67e-14	4.66e-01	0.1426
1198	CLK3	P12T-E	Human	Esophagus	ESCC	7.67e-24	4.59e-01	0.1122
1198	CLK3	P15T-E	Human	Esophagus	ESCC	1.44e-31	7.02e-01	0.1149
1198	CLK3	P16T-E	Human	Esophagus	ESCC	2.52e-29	5.32e-01	0.1153
1198	CLK3	P17T-E	Human	Esophagus	ESCC	4.01e-08	1.87e-01	0.1278

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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
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

∗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:0008380111	Esophagus	ESCC	RNA splicing	336/8552	434/18723	1.74e-42	3.67e-39	336
GO:0043484111	Esophagus	ESCC	regulation of RNA splicing	116/8552	148/18723	3.18e-16	2.38e-14	116
GO:004677710	Esophagus	ESCC	protein autophosphorylation	138/8552	227/18723	2.98e-06	3.38e-05	138
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:000838012	Liver	Cirrhotic	RNA splicing	229/4634	434/18723	9.13e-37	2.86e-33	229
GO:004348412	Liver	Cirrhotic	regulation of RNA splicing	85/4634	148/18723	2.03e-17	2.83e-15	85
GO:000838022	Liver	HCC	RNA splicing	313/7958	434/18723	1.36e-36	1.73e-33	313
GO:004348422	Liver	HCC	regulation of RNA splicing	113/7958	148/18723	4.32e-17	4.15e-15	113
GO:00467775	Liver	HCC	protein autophosphorylation	123/7958	227/18723	2.40e-04	1.80e-03	123
GO:000838020	Oral cavity	OSCC	RNA splicing	308/7305	434/18723	2.43e-42	7.70e-39	308
GO:004348420	Oral cavity	OSCC	regulation of RNA splicing	108/7305	148/18723	4.25e-17	3.69e-15	108
GO:00467779	Oral cavity	OSCC	protein autophosphorylation	123/7305	227/18723	2.31e-06	2.93e-05	123
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:0008380110	Oral cavity	LP	RNA splicing	237/4623	434/18723	1.82e-41	3.79e-38	237
GO:0043484110	Oral cavity	LP	regulation of RNA splicing	81/4623	148/18723	4.34e-15	5.79e-13	81
GO:0008380112	Skin	cSCC	RNA splicing	263/4864	434/18723	2.45e-53	5.13e-50	263
GO:004348429	Skin	cSCC	regulation of RNA splicing	97/4864	148/18723	4.66e-24	1.08e-21	97
GO:004677715	Skin	cSCC	protein autophosphorylation	84/4864	227/18723	1.53e-04	1.35e-03	84

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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

CLK3

SNV

Missense_Mutation

c.516G>T

p.Arg172Ser

p.R172S

P49761

protein_coding

deleterious(0.05)

probably_damaging(0.966)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CLK3

SNV

Missense_Mutation

novel

c.840N>G

p.Ser280Arg

p.S280R

P49761

protein_coding

tolerated(0.65)

benign(0.074)

TCGA-AO-A03P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

letrozole

CLK3

SNV

Missense_Mutation

novel

c.1270N>A

p.Glu424Lys

p.E424K

P49761

protein_coding

tolerated(0.06)

benign(0.04)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CLK3

SNV

Missense_Mutation

novel

c.535G>A

p.Glu179Lys

p.E179K

P49761

protein_coding

deleterious(0.02)

benign(0.081)

TCGA-BH-A0BM-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CLK3

SNV

Missense_Mutation

novel

c.464N>G

p.Tyr155Cys

p.Y155C

P49761

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.994)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CLK3

SNV

Missense_Mutation

novel

c.1810N>C

p.Asp604His

p.D604H

P49761

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-BH-A2L8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

CLK3

SNV

Missense_Mutation

c.913G>A

p.Glu305Lys

p.E305K

P49761

protein_coding

tolerated(0.2)

benign(0.303)

TCGA-D8-A13Y-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CLK3

insertion

Frame_Shift_Ins

novel

c.1335_1336insGGGATCCTTGAGCTGAAAAGTG

p.Thr446GlyfsTer12

p.T446Gfs*12

P49761

protein_coding

TCGA-BH-A0GZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

CLK3

deletion

Frame_Shift_Del

novel

c.1817delN

p.Gln607SerfsTer17

p.Q607Sfs*17

P49761

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

CLK3

SNV

Missense_Mutation

novel

c.1312N>A

p.Leu438Met

p.L438M

P49761

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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
1198	CLK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME, TYROSINE KINASE		HARMINE	HARMINE	22998443
1198	CLK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME, TYROSINE KINASE		LEUCETTAMINE B	LEUCETTAMINE B	22998443
1198	CLK3	KINASE, SERINE THREONINE KINASE, ENZYME, DRUGGABLE GENOME, TYROSINE KINASE	inhibitor	249565735

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