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: CLIC4

Gene summary for CLIC4

Gene summary.

Gene information	Species	Human
	Gene symbol	CLIC4
	Gene ID	25932
	Gene name	chloride intracellular channel 4
	Gene Alias	CLIC4L
	Cytomap	1p36.11
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	Q6FIC5

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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
25932	CLIC4	LZE2T	Human	Esophagus	ESCC	2.30e-02	3.06e-01	0.082
25932	CLIC4	LZE4T	Human	Esophagus	ESCC	1.72e-08	1.72e-01	0.0811
25932	CLIC4	LZE7T	Human	Esophagus	ESCC	3.31e-06	7.16e-01	0.0667
25932	CLIC4	LZE8T	Human	Esophagus	ESCC	2.52e-03	-3.04e-02	0.067
25932	CLIC4	LZE20T	Human	Esophagus	ESCC	4.73e-05	2.28e-01	0.0662
25932	CLIC4	LZE22T	Human	Esophagus	ESCC	1.93e-07	4.43e-01	0.068
25932	CLIC4	LZE24T	Human	Esophagus	ESCC	4.01e-19	5.98e-01	0.0596
25932	CLIC4	LZE6T	Human	Esophagus	ESCC	3.65e-07	2.69e-01	0.0845
25932	CLIC4	P1T-E	Human	Esophagus	ESCC	8.16e-07	6.66e-01	0.0875
25932	CLIC4	P2T-E	Human	Esophagus	ESCC	2.04e-83	1.52e+00	0.1177
25932	CLIC4	P4T-E	Human	Esophagus	ESCC	1.92e-40	1.04e+00	0.1323
25932	CLIC4	P5T-E	Human	Esophagus	ESCC	2.67e-60	1.28e+00	0.1327
25932	CLIC4	P8T-E	Human	Esophagus	ESCC	8.76e-11	3.63e-01	0.0889
25932	CLIC4	P9T-E	Human	Esophagus	ESCC	3.92e-14	6.62e-01	0.1131
25932	CLIC4	P10T-E	Human	Esophagus	ESCC	2.55e-32	8.49e-01	0.116
25932	CLIC4	P11T-E	Human	Esophagus	ESCC	1.56e-30	1.53e+00	0.1426
25932	CLIC4	P12T-E	Human	Esophagus	ESCC	1.31e-26	7.34e-01	0.1122
25932	CLIC4	P15T-E	Human	Esophagus	ESCC	1.77e-23	8.07e-01	0.1149
25932	CLIC4	P16T-E	Human	Esophagus	ESCC	1.51e-35	7.77e-01	0.1153
25932	CLIC4	P17T-E	Human	Esophagus	ESCC	4.37e-14	1.29e+00	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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
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:001003829	Skin	cSCC	response to metal ion	132/4864	373/18723	3.11e-05	3.42e-04	132
GO:000206426	Skin	cSCC	epithelial cell development	84/4864	220/18723	4.33e-05	4.56e-04	84
GO:003508814	Skin	cSCC	establishment or maintenance of apical/basal cell polarity	26/4864	49/18723	4.78e-05	4.96e-04	26
GO:006124514	Skin	cSCC	establishment or maintenance of bipolar cell polarity	26/4864	49/18723	4.78e-05	4.96e-04	26
GO:000991324	Skin	cSCC	epidermal cell differentiation	78/4864	202/18723	5.12e-05	5.28e-04	78
GO:000188525	Skin	cSCC	endothelial cell development	30/4864	64/18723	2.50e-04	2.04e-03	30
GO:00070354	Skin	cSCC	vacuolar acidification	13/4864	24/18723	3.02e-03	1.67e-02	13
GO:000315824	Skin	cSCC	endothelium development	49/4864	136/18723	6.00e-03	2.95e-02	49
GO:005159217	Skin	cSCC	response to calcium ion	52/4864	149/18723	9.63e-03	4.31e-02	52
GO:0007163111	Thyroid	PTC	establishment or maintenance of cell polarity	115/5968	218/18723	1.15e-10	3.90e-09	115
GO:006056219	Thyroid	PTC	epithelial tube morphogenesis	141/5968	325/18723	7.52e-06	8.73e-05	141
GO:0002064112	Thyroid	PTC	epithelial cell development	101/5968	220/18723	8.53e-06	9.74e-05	101
GO:000188519	Thyroid	PTC	endothelial cell development	37/5968	64/18723	1.62e-05	1.70e-04	37
GO:0010038112	Thyroid	PTC	response to metal ion	157/5968	373/18723	1.80e-05	1.86e-04	157
GO:0003158111	Thyroid	PTC	endothelium development	62/5968	136/18723	5.45e-04	3.48e-03	62
GO:004544619	Thyroid	PTC	endothelial cell differentiation	55/5968	118/18723	5.64e-04	3.59e-03	55
GO:005159219	Thyroid	PTC	response to calcium ion	65/5968	149/18723	1.67e-03	9.16e-03	65
GO:003508810	Thyroid	PTC	establishment or maintenance of apical/basal cell polarity	26/5968	49/18723	1.68e-03	9.20e-03	26
GO:006124510	Thyroid	PTC	establishment or maintenance of bipolar cell polarity	26/5968	49/18723	1.68e-03	9.20e-03	26
GO:00070355	Thyroid	PTC	vacuolar acidification	15/5968	24/18723	1.95e-03	1.05e-02	15

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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

CLIC4

SNV

Missense_Mutation

rs779954576

c.257N>T

p.Thr86Met

p.T86M

Q9Y696

protein_coding

deleterious(0.02)

probably_damaging(0.999)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CLIC4

SNV

Missense_Mutation

novel

c.16N>A

p.Pro6Thr

p.P6T

Q9Y696

protein_coding

deleterious_low_confidence(0.03)

benign(0.151)

TCGA-Q1-A5R2-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CLIC4

SNV

Missense_Mutation

c.647G>A

p.Gly216Asp

p.G216D

Q9Y696

protein_coding

deleterious(0)

possibly_damaging(0.826)

TCGA-CK-5913-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Unknown

CLIC4

SNV

Missense_Mutation

c.283C>A

p.Leu95Ile

p.L95I

Q9Y696

protein_coding

deleterious(0.04)

probably_damaging(0.997)

TCGA-AG-A002-01

Colorectum

rectum adenocarcinoma

Male

<65

I/II

Unknown

CLIC4

SNV

Missense_Mutation

novel

c.468N>G

p.Asn156Lys

p.N156K

Q9Y696

protein_coding

tolerated(0.29)

benign(0.054)

TCGA-EI-6917-01

Colorectum

rectum adenocarcinoma

Male

<65

III/IV

Chemotherapy

5fluorouracil+oxaciplatina+l-folinian

CLIC4

SNV

Missense_Mutation

rs144375143

c.617G>A

p.Arg206His

p.R206H

Q9Y696

protein_coding

tolerated(0.06)

benign(0.009)

TCGA-AJ-A3EK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

CLIC4

SNV

Missense_Mutation

c.375N>A

p.Phe125Leu

p.F125L

Q9Y696

protein_coding

deleterious(0.04)

benign(0.166)

TCGA-AX-A05Z-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

CLIC4

SNV

Missense_Mutation

c.109T>C

p.Phe37Leu

p.F37L

Q9Y696

protein_coding

deleterious(0.04)

probably_damaging(0.92)

TCGA-D1-A167-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

CLIC4

SNV

Missense_Mutation

novel

c.307N>G

p.Lys103Glu

p.K103E

Q9Y696

protein_coding

tolerated(0.11)

possibly_damaging(0.795)

TCGA-E6-A1LX-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

CLIC4

deletion

Frame_Shift_Del

c.612delA

p.Lys204AsnfsTer11

p.K204Nfs*11

Q9Y696

protein_coding

TCGA-AX-A3FT-01

Endometrium

uterine corpus endometrioid 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

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