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: CLDN4

Gene summary for CLDN4

Gene summary.

Gene information	Species	Human
	Gene symbol	CLDN4
	Gene ID	1364
	Gene name	claudin 4
	Gene Alias	CPE-R
	Cytomap	7q11.23
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	O14493

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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
1364	CLDN4	GSM4909280	Human	Breast	Precancer	3.36e-04	3.43e-01	0.0305
1364	CLDN4	GSM4909281	Human	Breast	IDC	1.63e-14	-4.12e-01	0.21
1364	CLDN4	GSM4909282	Human	Breast	IDC	2.01e-13	4.11e-01	-0.0288
1364	CLDN4	GSM4909285	Human	Breast	IDC	5.90e-09	-2.32e-01	0.21
1364	CLDN4	GSM4909286	Human	Breast	IDC	1.55e-23	-5.52e-01	0.1081
1364	CLDN4	GSM4909288	Human	Breast	IDC	7.42e-03	-4.43e-01	0.0988
1364	CLDN4	GSM4909290	Human	Breast	IDC	1.28e-20	-7.92e-01	0.2096
1364	CLDN4	GSM4909294	Human	Breast	IDC	2.42e-17	-5.94e-01	0.2022
1364	CLDN4	GSM4909297	Human	Breast	IDC	6.95e-14	-4.57e-01	0.1517
1364	CLDN4	GSM4909298	Human	Breast	IDC	7.84e-08	-3.63e-01	0.1551
1364	CLDN4	GSM4909300	Human	Breast	IDC	3.38e-07	4.00e-01	0.0334
1364	CLDN4	GSM4909302	Human	Breast	IDC	7.19e-06	-4.40e-01	0.1545
1364	CLDN4	GSM4909304	Human	Breast	IDC	1.12e-14	-4.36e-01	0.1636
1364	CLDN4	GSM4909305	Human	Breast	IDC	7.25e-07	3.33e-01	0.0436
1364	CLDN4	GSM4909307	Human	Breast	IDC	1.04e-06	-4.16e-01	0.1569
1364	CLDN4	GSM4909308	Human	Breast	IDC	2.92e-19	-5.81e-01	0.158
1364	CLDN4	GSM4909311	Human	Breast	IDC	6.44e-37	-6.24e-01	0.1534
1364	CLDN4	GSM4909313	Human	Breast	IDC	6.80e-06	1.84e-01	0.0391
1364	CLDN4	GSM4909315	Human	Breast	IDC	2.60e-36	-9.18e-01	0.21
1364	CLDN4	GSM4909316	Human	Breast	IDC	2.27e-15	-1.02e+00	0.21

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
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
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
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:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00485459	Breast	Precancer	response to steroid hormone	53/1080	339/18723	3.07e-11	3.66e-09	53
GO:00458629	Breast	Precancer	positive regulation of proteolysis	51/1080	372/18723	7.77e-09	5.70e-07	51
GO:00109529	Breast	Precancer	positive regulation of peptidase activity	33/1080	197/18723	3.01e-08	1.89e-06	33
GO:00075653	Breast	Precancer	female pregnancy	29/1080	193/18723	2.07e-06	7.31e-05	29
GO:00447063	Breast	Precancer	multi-multicellular organism process	31/1080	220/18723	3.73e-06	1.19e-04	31
GO:00420609	Breast	Precancer	wound healing	48/1080	422/18723	5.48e-06	1.63e-04	48
GO:00508789	Breast	Precancer	regulation of body fluid levels	40/1080	379/18723	1.68e-04	2.77e-03	40
GO:00702933	Breast	Precancer	renal absorption	6/1080	17/18723	2.59e-04	3.83e-03	6
GO:19030367	Breast	Precancer	positive regulation of response to wounding	12/1080	72/18723	7.90e-04	9.30e-03	12
GO:00903036	Breast	Precancer	positive regulation of wound healing	10/1080	59/18723	1.86e-03	1.81e-02	10
GO:19016549	Breast	Precancer	response to ketone	22/1080	194/18723	1.89e-03	1.84e-02	22
GO:19030348	Breast	Precancer	regulation of response to wounding	19/1080	167/18723	3.60e-03	2.98e-02	19
GO:00226049	Breast	Precancer	regulation of cell morphogenesis	29/1080	309/18723	6.88e-03	4.67e-02	29
GO:005254714	Breast	IDC	regulation of peptidase activity	96/1434	461/18723	7.58e-20	6.15e-17	96
GO:004854514	Breast	IDC	response to steroid hormone	70/1434	339/18723	1.34e-14	4.23e-12	70
GO:004586214	Breast	IDC	positive regulation of proteolysis	66/1434	372/18723	9.76e-11	1.29e-08	66
GO:001095214	Breast	IDC	positive regulation of peptidase activity	40/1434	197/18723	1.04e-08	7.67e-07	40
GO:000756511	Breast	IDC	female pregnancy	39/1434	193/18723	1.81e-08	1.27e-06	39
GO:00447061	Breast	IDC	multi-multicellular organism process	41/1434	220/18723	8.58e-08	5.19e-06	41

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0513018	Breast	Precancer	Pathogenic Escherichia coli infection	38/684	197/8465	3.12e-07	5.81e-06	4.45e-06	38
hsa0453018	Breast	Precancer	Tight junction	31/684	169/8465	1.13e-05	1.26e-04	9.64e-05	31
hsa0513019	Breast	Precancer	Pathogenic Escherichia coli infection	38/684	197/8465	3.12e-07	5.81e-06	4.45e-06	38
hsa0453019	Breast	Precancer	Tight junction	31/684	169/8465	1.13e-05	1.26e-04	9.64e-05	31
hsa0453024	Breast	IDC	Tight junction	38/867	169/8465	2.07e-06	3.20e-05	2.39e-05	38
hsa0513024	Breast	IDC	Pathogenic Escherichia coli infection	42/867	197/8465	2.66e-06	3.92e-05	2.94e-05	42
hsa0467024	Breast	IDC	Leukocyte transendothelial migration	21/867	114/8465	5.41e-03	3.13e-02	2.34e-02	21
hsa0453034	Breast	IDC	Tight junction	38/867	169/8465	2.07e-06	3.20e-05	2.39e-05	38
hsa0513034	Breast	IDC	Pathogenic Escherichia coli infection	42/867	197/8465	2.66e-06	3.92e-05	2.94e-05	42
hsa0467034	Breast	IDC	Leukocyte transendothelial migration	21/867	114/8465	5.41e-03	3.13e-02	2.34e-02	21
hsa0513043	Breast	DCIS	Pathogenic Escherichia coli infection	42/846	197/8465	1.40e-06	2.15e-05	1.59e-05	42
hsa0453044	Breast	DCIS	Tight junction	37/846	169/8465	3.07e-06	4.20e-05	3.09e-05	37
hsa0513053	Breast	DCIS	Pathogenic Escherichia coli infection	42/846	197/8465	1.40e-06	2.15e-05	1.59e-05	42
hsa0453054	Breast	DCIS	Tight junction	37/846	169/8465	3.07e-06	4.20e-05	3.09e-05	37
hsa0513020	Cervix	CC	Pathogenic Escherichia coli infection	63/1267	197/8465	9.28e-10	2.00e-08	1.19e-08	63
hsa0453020	Cervix	CC	Tight junction	49/1267	169/8465	1.87e-06	1.78e-05	1.05e-05	49
hsa0467020	Cervix	CC	Leukocyte transendothelial migration	36/1267	114/8465	5.22e-06	4.83e-05	2.86e-05	36
hsa045147	Cervix	CC	Cell adhesion molecules	36/1267	157/8465	4.94e-03	1.67e-02	9.86e-03	36
hsa05130110	Cervix	CC	Pathogenic Escherichia coli infection	63/1267	197/8465	9.28e-10	2.00e-08	1.19e-08	63
hsa04530110	Cervix	CC	Tight junction	49/1267	169/8465	1.87e-06	1.78e-05	1.05e-05	49

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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

CLDN4

deletion

Frame_Shift_Del

c.537delG

p.Leu180CysfsTer115

p.L180Cfs*115

O14493

protein_coding

TCGA-CG-4306-01

Stomach

stomach adenocarcinoma

Male

>=65

III/IV

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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