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: TLK2

Gene summary for TLK2

Gene summary.

Gene information	Species	Human
	Gene symbol	TLK2
	Gene ID	11011
	Gene name	tousled like kinase 2
	Gene Alias	HsHPK
	Cytomap	17q23.2
	Gene Type	protein-coding
	GO ID	GO:0001672
	UniProtAcc	Q86UE8

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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
11011	TLK2	HTA11_3410_2000001011	Human	Colorectum	AD	3.18e-13	-5.25e-01	0.0155
11011	TLK2	HTA11_866_3004761011	Human	Colorectum	AD	1.73e-06	-4.26e-01	0.096
11011	TLK2	HTA11_8622_2000001021	Human	Colorectum	SER	4.43e-02	-5.96e-01	0.0528
11011	TLK2	HTA11_7696_3000711011	Human	Colorectum	AD	7.67e-09	-4.17e-01	0.0674
11011	TLK2	HTA11_6818_2000001021	Human	Colorectum	AD	8.39e-03	-5.00e-01	0.0588
11011	TLK2	HTA11_99999970781_79442	Human	Colorectum	MSS	7.10e-12	-4.87e-01	0.294
11011	TLK2	HTA11_99999965104_69814	Human	Colorectum	MSS	1.41e-11	7.63e-01	0.281
11011	TLK2	HTA11_99999974143_84620	Human	Colorectum	MSS	1.28e-06	-3.86e-01	0.3005
11011	TLK2	F007	Human	Colorectum	FAP	4.14e-03	-3.20e-01	0.1176
11011	TLK2	A002-C-010	Human	Colorectum	FAP	2.04e-02	-2.33e-01	0.242
11011	TLK2	A001-C-207	Human	Colorectum	FAP	1.43e-04	-3.15e-01	0.1278
11011	TLK2	A015-C-203	Human	Colorectum	FAP	5.79e-31	-4.22e-01	-0.1294
11011	TLK2	A015-C-204	Human	Colorectum	FAP	2.35e-09	-3.33e-01	-0.0228
11011	TLK2	A014-C-040	Human	Colorectum	FAP	3.56e-05	-3.44e-01	-0.1184
11011	TLK2	A002-C-201	Human	Colorectum	FAP	6.92e-20	-4.24e-01	0.0324
11011	TLK2	A002-C-203	Human	Colorectum	FAP	1.51e-04	-2.36e-01	0.2786
11011	TLK2	A001-C-119	Human	Colorectum	FAP	1.11e-09	-3.90e-01	-0.1557
11011	TLK2	A001-C-108	Human	Colorectum	FAP	3.21e-19	-3.45e-01	-0.0272
11011	TLK2	A002-C-205	Human	Colorectum	FAP	3.18e-26	-4.21e-01	-0.1236
11011	TLK2	A001-C-104	Human	Colorectum	FAP	8.62e-07	-3.07e-01	0.0184

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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:20000591	Colorectum	SER	negative regulation of ubiquitin-dependent protein catabolic process	17/2897	48/18723	5.46e-04	7.63e-03	17
GO:00181051	Colorectum	SER	peptidyl-serine phosphorylation	66/2897	315/18723	5.47e-03	4.06e-02	66
GO:00421762	Colorectum	MSS	regulation of protein catabolic process	145/3467	391/18723	2.03e-18	1.17e-15	145
GO:19033622	Colorectum	MSS	regulation of cellular protein catabolic process	99/3467	255/18723	1.90e-14	5.37e-12	99
GO:00104982	Colorectum	MSS	proteasomal protein catabolic process	157/3467	490/18723	2.39e-13	5.25e-11	157
GO:00313302	Colorectum	MSS	negative regulation of cellular catabolic process	96/3467	262/18723	2.67e-12	4.63e-10	96
GO:00098952	Colorectum	MSS	negative regulation of catabolic process	110/3467	320/18723	7.88e-12	1.20e-09	110
GO:19030502	Colorectum	MSS	regulation of proteolysis involved in cellular protein catabolic process	82/3467	221/18723	4.97e-11	5.64e-09	82
GO:00431612	Colorectum	MSS	proteasome-mediated ubiquitin-dependent protein catabolic process	127/3467	412/18723	7.70e-10	6.32e-08	127
GO:20000582	Colorectum	MSS	regulation of ubiquitin-dependent protein catabolic process	61/3467	164/18723	1.28e-08	7.61e-07	61
GO:00611362	Colorectum	MSS	regulation of proteasomal protein catabolic process	67/3467	187/18723	1.45e-08	8.47e-07	67
GO:19033632	Colorectum	MSS	negative regulation of cellular protein catabolic process	34/3467	75/18723	8.96e-08	4.44e-06	34
GO:00421772	Colorectum	MSS	negative regulation of protein catabolic process	47/3467	121/18723	1.28e-07	6.01e-06	47
GO:00105062	Colorectum	MSS	regulation of autophagy	95/3467	317/18723	4.36e-07	1.71e-05	95
GO:00324342	Colorectum	MSS	regulation of proteasomal ubiquitin-dependent protein catabolic process	49/3467	134/18723	6.02e-07	2.26e-05	49
GO:20000592	Colorectum	MSS	negative regulation of ubiquitin-dependent protein catabolic process	22/3467	48/18723	1.33e-05	3.07e-04	22
GO:00458612	Colorectum	MSS	negative regulation of proteolysis	97/3467	351/18723	1.57e-05	3.54e-04	97
GO:19030512	Colorectum	MSS	negative regulation of proteolysis involved in cellular protein catabolic process	26/3467	64/18723	3.19e-05	6.30e-04	26
GO:00324352	Colorectum	MSS	negative regulation of proteasomal ubiquitin-dependent protein catabolic process	17/3467	35/18723	5.07e-05	9.12e-04	17
GO:00063252	Colorectum	MSS	chromatin organization	107/3467	409/18723	7.22e-05	1.21e-03	107

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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

TLK2

SNV

Missense_Mutation

novel

c.1820N>C

p.Gly607Ala

p.G607A

Q86UE8

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-3C-AALI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Poly E

Complete Response

TLK2

SNV

Missense_Mutation

c.1219N>C

p.Glu407Gln

p.E407Q

Q86UE8

protein_coding

deleterious(0.01)

benign(0.371)

TCGA-A2-A0CX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

TLK2

SNV

Missense_Mutation

c.1730N>T

p.Ala577Val

p.A577V

Q86UE8

protein_coding

deleterious(0)

probably_damaging(0.926)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TLK2

SNV

Missense_Mutation

c.1658A>G

p.Asp553Gly

p.D553G

Q86UE8

protein_coding

deleterious(0)

possibly_damaging(0.685)

TCGA-D8-A1XC-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

TLK2

SNV

Missense_Mutation

novel

c.93N>G

p.Asn31Lys

p.N31K

Q86UE8

protein_coding

deleterious_low_confidence(0.02)

benign(0.007)

TCGA-PE-A5DC-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

TLK2

SNV

Missense_Mutation

novel

c.1703G>A

p.Arg568Gln

p.R568Q

Q86UE8

protein_coding

deleterious(0)

probably_damaging(0.909)

TCGA-UL-AAZ6-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

herceptin

TLK2

SNV

Missense_Mutation

rs200158456

c.127N>A

p.Gly43Arg

p.G43R

Q86UE8

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TLK2

SNV

Missense_Mutation

novel

c.1864G>T

p.Asp622Tyr

p.D622Y

Q86UE8

protein_coding

deleterious(0)

probably_damaging(0.928)

TCGA-C5-A8XI-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

cisplatin

TLK2

SNV

Missense_Mutation

c.857G>C

p.Arg286Thr

p.R286T

Q86UE8

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-JX-A3Q0-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

TLK2

SNV

Missense_Mutation

c.1801N>C

p.Val601Leu

p.V601L

Q86UE8

protein_coding

tolerated(0.24)

probably_damaging(0.981)

TCGA-Q1-A73O-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
11011	TLK2	DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE, ENZYME		GO6983		27694828
11011	TLK2	DRUGGABLE GENOME, SERINE THREONINE KINASE, KINASE, ENZYME		GF109203X		27694828

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