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: CLCN3

Gene summary for CLCN3

Gene summary.

Gene information	Species	Human
	Gene symbol	CLCN3
	Gene ID	1182
	Gene name	chloride voltage-gated channel 3
	Gene Alias	CLC3
	Cytomap	4q33
	Gene Type	protein-coding
	GO ID	GO:0001894
	UniProtAcc	P51790

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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
1182	CLCN3	HTA11_3410_2000001011	Human	Colorectum	AD	1.17e-06	-3.97e-01	0.0155
1182	CLCN3	HTA11_347_2000001011	Human	Colorectum	AD	6.21e-03	3.35e-01	-0.1954
1182	CLCN3	HTA11_866_2000001011	Human	Colorectum	AD	7.40e-04	-3.11e-01	-0.1001
1182	CLCN3	HTA11_99999974143_84620	Human	Colorectum	MSS	3.42e-04	-3.38e-01	0.3005
1182	CLCN3	A015-C-203	Human	Colorectum	FAP	3.87e-24	-5.05e-01	-0.1294
1182	CLCN3	A015-C-204	Human	Colorectum	FAP	4.40e-07	-2.95e-01	-0.0228
1182	CLCN3	A002-C-201	Human	Colorectum	FAP	5.90e-08	-2.28e-01	0.0324
1182	CLCN3	A001-C-119	Human	Colorectum	FAP	2.48e-07	-3.55e-01	-0.1557
1182	CLCN3	A001-C-108	Human	Colorectum	FAP	1.94e-09	-1.91e-01	-0.0272
1182	CLCN3	A002-C-205	Human	Colorectum	FAP	7.35e-15	-2.81e-01	-0.1236
1182	CLCN3	A015-C-006	Human	Colorectum	FAP	9.90e-13	-4.73e-01	-0.0994
1182	CLCN3	A015-C-106	Human	Colorectum	FAP	3.57e-08	-1.93e-01	-0.0511
1182	CLCN3	A002-C-114	Human	Colorectum	FAP	1.11e-13	-3.72e-01	-0.1561
1182	CLCN3	A015-C-104	Human	Colorectum	FAP	3.02e-22	-4.39e-01	-0.1899
1182	CLCN3	A001-C-014	Human	Colorectum	FAP	2.60e-10	-1.33e-01	0.0135
1182	CLCN3	A002-C-016	Human	Colorectum	FAP	2.23e-15	-1.84e-01	0.0521
1182	CLCN3	A015-C-002	Human	Colorectum	FAP	2.11e-10	-5.13e-01	-0.0763
1182	CLCN3	A001-C-203	Human	Colorectum	FAP	4.05e-06	-1.56e-01	-0.0481
1182	CLCN3	A002-C-116	Human	Colorectum	FAP	1.25e-26	-2.64e-01	-0.0452
1182	CLCN3	A014-C-008	Human	Colorectum	FAP	3.37e-09	-3.72e-01	-0.191

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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
Prostate		BPH: Benign Prostatic Hyperplasia
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:0032535	Colorectum	AD	regulation of cellular component size	142/3918	383/18723	1.74e-13	3.41e-11	142
GO:1902600	Colorectum	AD	proton transmembrane transport	66/3918	157/18723	1.59e-09	1.17e-07	66
GO:0016050	Colorectum	AD	vesicle organization	101/3918	300/18723	1.65e-07	7.17e-06	101
GO:0007032	Colorectum	AD	endosome organization	33/3918	82/18723	5.30e-05	9.01e-04	33
GO:0060249	Colorectum	AD	anatomical structure homeostasis	94/3918	314/18723	9.37e-05	1.42e-03	94
GO:0001894	Colorectum	AD	tissue homeostasis	81/3918	268/18723	1.96e-04	2.62e-03	81
GO:0072593	Colorectum	AD	reactive oxygen species metabolic process	73/3918	239/18723	2.79e-04	3.42e-03	73
GO:2000379	Colorectum	AD	positive regulation of reactive oxygen species metabolic process	29/3918	76/18723	4.31e-04	4.82e-03	29
GO:0030004	Colorectum	AD	cellular monovalent inorganic cation homeostasis	36/3918	103/18723	6.80e-04	6.95e-03	36
GO:0008361	Colorectum	AD	regulation of cell size	56/3918	181/18723	9.61e-04	9.07e-03	56
GO:0030641	Colorectum	AD	regulation of cellular pH	29/3918	81/18723	1.42e-03	1.22e-02	29
GO:2000377	Colorectum	AD	regulation of reactive oxygen species metabolic process	48/3918	157/18723	2.77e-03	2.09e-02	48
GO:0051453	Colorectum	AD	regulation of intracellular pH	26/3918	75/18723	4.04e-03	2.82e-02	26
GO:0006885	Colorectum	AD	regulation of pH	30/3918	91/18723	4.95e-03	3.32e-02	30
GO:0055067	Colorectum	AD	monovalent inorganic cation homeostasis	45/3918	151/18723	6.19e-03	3.88e-02	45
GO:0099003	Colorectum	AD	vesicle-mediated transport in synapse	57/3918	200/18723	6.53e-03	4.06e-02	57
GO:0015698	Colorectum	AD	inorganic anion transport	52/3918	180/18723	6.83e-03	4.22e-02	52
GO:00325352	Colorectum	MSS	regulation of cellular component size	127/3467	383/18723	3.44e-12	5.79e-10	127
GO:19026002	Colorectum	MSS	proton transmembrane transport	57/3467	157/18723	1.00e-07	4.81e-06	57
GO:00160502	Colorectum	MSS	vesicle organization	93/3467	300/18723	1.04e-07	4.97e-06	93

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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

CLCN3

SNV

Missense_Mutation

c.2106N>T

p.Arg702Ser

p.R702S

P51790

protein_coding

tolerated(0.34)

possibly_damaging(0.474)

TCGA-AO-A0JG-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

CLCN3

SNV

Missense_Mutation

c.2309N>G

p.Ile770Ser

p.I770S

P51790

protein_coding

deleterious(0.03)

benign(0.125)

TCGA-AR-A0TV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CLCN3

SNV

Missense_Mutation

c.1769N>T

p.Thr590Ile

p.T590I

P51790

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-C8-A12Z-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

CLCN3

SNV

Missense_Mutation

c.2296N>G

p.Thr766Ala

p.T766A

P51790

protein_coding

deleterious(0.01)

possibly_damaging(0.63)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

CLCN3

SNV

Missense_Mutation

novel

c.226N>T

p.Asp76Tyr

p.D76Y

P51790

protein_coding

deleterious(0)

possibly_damaging(0.521)

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

CLCN3

SNV

Missense_Mutation

c.670C>A

p.Leu224Ile

p.L224I

P51790

protein_coding

tolerated(0.12)

benign(0.101)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CLCN3

SNV

Missense_Mutation

novel

c.1213G>A

p.Ala405Thr

p.A405T

P51790

protein_coding

tolerated(0.45)

benign(0.31)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CLCN3

SNV

Missense_Mutation

c.719N>T

p.Gly240Val

p.G240V

P51790

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-C5-A905-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CLCN3

SNV

Missense_Mutation

novel

c.115N>G

p.Gln39Glu

p.Q39E

P51790

protein_coding

tolerated(0.71)

benign(0.012)

TCGA-IR-A3LH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CLCN3

SNV

Missense_Mutation

c.1228N>A

p.Ala410Thr

p.A410T

P51790

protein_coding

tolerated(0.19)

benign(0.111)

TCGA-AA-3977-01

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
1182	CLCN3	DRUGGABLE GENOME, ION CHANNEL, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, KINASE, TRANSPORTER	blocker	178101102	PHLORETIN
1182	CLCN3	DRUGGABLE GENOME, ION CHANNEL, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, KINASE, TRANSPORTER		DESACETYLBUFOTALIN	DESACETYLBUFOTALIN	23799775
1182	CLCN3	DRUGGABLE GENOME, ION CHANNEL, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, KINASE, TRANSPORTER		CINOBUFAGIN	CINOBUFAGIN	23799775
1182	CLCN3	DRUGGABLE GENOME, ION CHANNEL, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, KINASE, TRANSPORTER		BUFALIN	BUFALIN	23799775

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