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: TNIK

Gene summary for TNIK

Gene summary.

Gene information	Species	Human
	Gene symbol	TNIK
	Gene ID	23043
	Gene name	TRAF2 and NCK interacting kinase
	Gene Alias	MRT54
	Cytomap	3q26.2-q26.31
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q9UKE5

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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
23043	TNIK	HTA11_3410_2000001011	Human	Colorectum	AD	4.71e-10	-4.18e-01	0.0155
23043	TNIK	HTA11_347_2000001011	Human	Colorectum	AD	5.54e-06	5.49e-01	-0.1954
23043	TNIK	HTA11_866_3004761011	Human	Colorectum	AD	4.30e-07	-5.18e-01	0.096
23043	TNIK	HTA11_4255_2000001011	Human	Colorectum	SER	2.89e-02	-5.16e-01	0.0446
23043	TNIK	HTA11_10711_2000001011	Human	Colorectum	AD	5.40e-05	-5.25e-01	0.0338
23043	TNIK	HTA11_99999973899_84307	Human	Colorectum	MSS	7.03e-08	-7.20e-01	0.2585
23043	TNIK	HTA11_99999974143_84620	Human	Colorectum	MSS	1.94e-18	-6.80e-01	0.3005
23043	TNIK	A015-C-203	Human	Colorectum	FAP	8.21e-28	-5.74e-01	-0.1294
23043	TNIK	A015-C-204	Human	Colorectum	FAP	1.15e-05	-3.16e-01	-0.0228
23043	TNIK	A014-C-040	Human	Colorectum	FAP	8.87e-11	-8.53e-01	-0.1184
23043	TNIK	A002-C-201	Human	Colorectum	FAP	1.01e-14	-4.99e-01	0.0324
23043	TNIK	A001-C-119	Human	Colorectum	FAP	8.54e-15	-7.73e-01	-0.1557
23043	TNIK	A001-C-108	Human	Colorectum	FAP	1.42e-13	-3.74e-01	-0.0272
23043	TNIK	A002-C-021	Human	Colorectum	FAP	2.75e-02	-2.41e-01	0.1171
23043	TNIK	A002-C-205	Human	Colorectum	FAP	2.55e-28	-6.85e-01	-0.1236
23043	TNIK	A001-C-104	Human	Colorectum	FAP	4.56e-02	-2.62e-01	0.0184
23043	TNIK	A015-C-005	Human	Colorectum	FAP	5.16e-05	-4.31e-01	-0.0336
23043	TNIK	A015-C-006	Human	Colorectum	FAP	1.06e-28	-9.00e-01	-0.0994
23043	TNIK	A015-C-106	Human	Colorectum	FAP	2.71e-16	-4.28e-01	-0.0511
23043	TNIK	A002-C-114	Human	Colorectum	FAP	5.31e-23	-6.45e-01	-0.1561

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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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
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:00463302	Esophagus	ESCC	positive regulation of JNK cascade	52/8552	89/18723	1.04e-02	3.56e-02	52
GO:00160556	Lung	IAC	Wnt signaling pathway	95/2061	444/18723	1.13e-10	2.80e-08	95
GO:01987386	Lung	IAC	cell-cell signaling by wnt	95/2061	446/18723	1.46e-10	3.48e-08	95
GO:00315327	Lung	IAC	actin cytoskeleton reorganization	35/2061	107/18723	1.44e-09	2.38e-07	35
GO:00310987	Lung	IAC	stress-activated protein kinase signaling cascade	57/2061	247/18723	3.95e-08	4.57e-06	57
GO:00163586	Lung	IAC	dendrite development	55/2061	243/18723	1.35e-07	1.18e-05	55
GO:00514037	Lung	IAC	stress-activated MAPK cascade	54/2061	239/18723	1.86e-07	1.56e-05	54
GO:00072544	Lung	IAC	JNK cascade	42/2061	167/18723	1.99e-07	1.62e-05	42
GO:00726598	Lung	IAC	protein localization to plasma membrane	60/2061	284/18723	4.74e-07	3.10e-05	60
GO:00467776	Lung	IAC	protein autophosphorylation	51/2061	227/18723	4.85e-07	3.10e-05	51
GO:00703026	Lung	IAC	regulation of stress-activated protein kinase signaling cascade	45/2061	195/18723	1.03e-06	5.65e-05	45
GO:19907787	Lung	IAC	protein localization to cell periphery	66/2061	333/18723	1.44e-06	7.22e-05	66
GO:00109756	Lung	IAC	regulation of neuron projection development	82/2061	445/18723	1.82e-06	8.78e-05	82
GO:00463284	Lung	IAC	regulation of JNK cascade	34/2061	133/18723	1.88e-06	8.87e-05	34
GO:00328726	Lung	IAC	regulation of stress-activated MAPK cascade	43/2061	192/18723	4.06e-06	1.66e-04	43
GO:00488134	Lung	IAC	dendrite morphogenesis	34/2061	146/18723	1.68e-05	4.79e-04	34
GO:00434103	Lung	IAC	positive regulation of MAPK cascade	78/2061	480/18723	2.72e-04	4.50e-03	78
GO:00300336	Lung	IAC	microvillus assembly	7/2061	16/18723	9.01e-04	1.11e-02	7
GO:00703042	Lung	IAC	positive regulation of stress-activated protein kinase signaling cascade	26/2061	128/18723	1.45e-03	1.55e-02	26
GO:00328742	Lung	IAC	positive regulation of stress-activated MAPK cascade	24/2061	126/18723	5.13e-03	3.91e-02	24

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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

TNIK

SNV

Missense_Mutation

novel

c.664N>C

p.Thr222Pro

p.T222P

Q9UKE5

protein_coding

deleterious(0.01)

probably_damaging(0.993)

TCGA-A2-A04Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

TNIK

SNV

Missense_Mutation

novel

c.1642N>C

p.Ser548Pro

p.S548P

Q9UKE5

protein_coding

deleterious(0.01)

probably_damaging(0.979)

TCGA-A2-A0D0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

TNIK

SNV

Missense_Mutation

c.335N>G

p.Ser112Cys

p.S112C

Q9UKE5

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TNIK

SNV

Missense_Mutation

c.1679N>T

p.Ser560Phe

p.S560F

Q9UKE5

protein_coding

deleterious_low_confidence(0.03)

possibly_damaging(0.887)

TCGA-AC-A3QQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

TNIK

SNV

Missense_Mutation

novel

c.1642N>C

p.Ser548Pro

p.S548P

Q9UKE5

protein_coding

deleterious(0.01)

probably_damaging(0.979)

TCGA-AR-A255-01

Breast

breast invasive carcinoma

Female

<65

I/II

Targeted Molecular therapy

trastuzumab

TNIK

SNV

Missense_Mutation

novel

c.1201N>G

p.Gln401Glu

p.Q401E

Q9UKE5

protein_coding

tolerated(0.22)

possibly_damaging(0.68)

TCGA-AR-A256-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

TNIK

SNV

Missense_Mutation

rs867347961

c.3086N>G

p.Asn1029Ser

p.N1029S

Q9UKE5

protein_coding

tolerated(0.08)

benign(0.325)

TCGA-AR-A2LN-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

letrozole

TNIK

SNV

Missense_Mutation

novel

c.664A>C

p.Thr222Pro

p.T222P

Q9UKE5

protein_coding

deleterious(0.01)

probably_damaging(0.993)

TCGA-B6-A0I5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

TNIK

SNV

Missense_Mutation

c.1763N>C

p.Val588Ala

p.V588A

Q9UKE5

protein_coding

deleterious(0.04)

benign(0.074)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TNIK

SNV

Missense_Mutation

c.1714N>C

p.Ser572Arg

p.S572R

Q9UKE5

protein_coding

deleterious_low_confidence(0.01)

possibly_damaging(0.791)

TCGA-C8-A1HN-01

Breast

breast invasive carcinoma

Female

<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
23043	TNIK	ENZYME, DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE		SB-202190	SB-202190	22951114
23043	TNIK	ENZYME, DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE	inhibitor	HESPERADIN	HESPERADIN	19035792
23043	TNIK	ENZYME, DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE	inhibitor	135652717	STAUROSPORINE
23043	TNIK	ENZYME, DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE	inhibitor	249565872
23043	TNIK	ENZYME, DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE		CEP-1347	CEP-1347	24044867

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