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: P4HB

Gene summary for P4HB

Gene summary.

Gene information	Species	Human
	Gene symbol	P4HB
	Gene ID	5034
	Gene name	prolyl 4-hydroxylase subunit beta
	Gene Alias	CLCRP1
	Cytomap	17q25.3
	Gene Type	protein-coding
	GO ID	GO:0000902
	UniProtAcc	A0A024R8S5

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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
5034	P4HB	GSM4909280	Human	Breast	Precancer	1.63e-02	-5.83e-01	0.0305
5034	P4HB	GSM4909281	Human	Breast	IDC	1.41e-29	5.87e-01	0.21
5034	P4HB	GSM4909282	Human	Breast	IDC	1.03e-08	4.05e-01	-0.0288
5034	P4HB	GSM4909285	Human	Breast	IDC	1.99e-09	4.53e-01	0.21
5034	P4HB	GSM4909287	Human	Breast	IDC	5.34e-16	3.77e-01	0.2057
5034	P4HB	GSM4909288	Human	Breast	IDC	2.14e-05	1.24e-01	0.0988
5034	P4HB	GSM4909289	Human	Breast	IDC	1.83e-07	5.09e-01	0.1064
5034	P4HB	GSM4909290	Human	Breast	IDC	8.47e-06	3.72e-01	0.2096
5034	P4HB	GSM4909294	Human	Breast	IDC	3.17e-14	-4.60e-01	0.2022
5034	P4HB	GSM4909296	Human	Breast	IDC	1.35e-17	-3.77e-01	0.1524
5034	P4HB	GSM4909297	Human	Breast	IDC	6.29e-27	-3.59e-01	0.1517
5034	P4HB	GSM4909301	Human	Breast	IDC	1.76e-03	-2.33e-01	0.1577
5034	P4HB	GSM4909306	Human	Breast	IDC	1.99e-02	-2.70e-01	0.1564
5034	P4HB	GSM4909309	Human	Breast	IDC	1.51e-05	-3.73e-01	0.0483
5034	P4HB	GSM4909311	Human	Breast	IDC	1.43e-41	-2.19e-01	0.1534
5034	P4HB	GSM4909312	Human	Breast	IDC	3.92e-11	8.87e-02	0.1552
5034	P4HB	GSM4909315	Human	Breast	IDC	7.49e-08	1.56e-01	0.21
5034	P4HB	GSM4909316	Human	Breast	IDC	7.66e-11	1.15e-01	0.21
5034	P4HB	GSM4909319	Human	Breast	IDC	3.04e-67	-1.97e-01	0.1563
5034	P4HB	GSM4909320	Human	Breast	IDC	3.73e-07	-1.26e-01	0.1575

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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
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:00971939	Breast	Precancer	intrinsic apoptotic signaling pathway	59/1080	288/18723	8.07e-18	3.60e-15	59
GO:20012339	Breast	Precancer	regulation of apoptotic signaling pathway	65/1080	356/18723	7.70e-17	3.17e-14	65
GO:20012429	Breast	Precancer	regulation of intrinsic apoptotic signaling pathway	41/1080	164/18723	6.48e-16	2.31e-13	41
GO:00069799	Breast	Precancer	response to oxidative stress	70/1080	446/18723	1.59e-14	4.26e-12	70
GO:00064578	Breast	Precancer	protein folding	43/1080	212/18723	3.48e-13	7.45e-11	43
GO:00362939	Breast	Precancer	response to decreased oxygen levels	53/1080	322/18723	4.09e-12	6.84e-10	53
GO:00016669	Breast	Precancer	response to hypoxia	51/1080	307/18723	7.33e-12	1.11e-09	51
GO:00704829	Breast	Precancer	response to oxygen levels	55/1080	347/18723	7.47e-12	1.11e-09	55
GO:00621979	Breast	Precancer	cellular response to chemical stress	51/1080	337/18723	2.40e-10	2.34e-08	51
GO:00160329	Breast	Precancer	viral process	58/1080	415/18723	3.42e-10	3.16e-08	58
GO:00190589	Breast	Precancer	viral life cycle	47/1080	317/18723	2.42e-09	1.99e-07	47
GO:00362948	Breast	Precancer	cellular response to decreased oxygen levels	31/1080	161/18723	2.61e-09	2.11e-07	31
GO:00714538	Breast	Precancer	cellular response to oxygen levels	32/1080	177/18723	7.32e-09	5.52e-07	32
GO:00714565	Breast	Precancer	cellular response to hypoxia	29/1080	151/18723	8.98e-09	6.50e-07	29
GO:00345999	Breast	Precancer	cellular response to oxidative stress	42/1080	288/18723	2.78e-08	1.79e-06	42
GO:00444039	Breast	Precancer	biological process involved in symbiotic interaction	42/1080	290/18723	3.40e-08	2.11e-06	42
GO:00349769	Breast	Precancer	response to endoplasmic reticulum stress	38/1080	256/18723	7.89e-08	4.60e-06	38
GO:00521269	Breast	Precancer	movement in host environment	29/1080	175/18723	2.59e-07	1.28e-05	29
GO:19021758	Breast	Precancer	regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	11/1080	29/18723	2.95e-07	1.44e-05	11
GO:00457859	Breast	Precancer	positive regulation of cell adhesion	52/1080	437/18723	5.74e-07	2.49e-05	52

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0414118	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0414119	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0414124	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0414134	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0414143	Breast	DCIS	Protein processing in endoplasmic reticulum	36/846	174/8465	1.60e-05	1.91e-04	1.41e-04	36
hsa0414153	Breast	DCIS	Protein processing in endoplasmic reticulum	36/846	174/8465	1.60e-05	1.91e-04	1.41e-04	36
hsa0414120	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa04141110	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa04141	Colorectum	AD	Protein processing in endoplasmic reticulum	80/2092	174/8465	5.96e-10	1.25e-08	7.96e-09	80
hsa041411	Colorectum	AD	Protein processing in endoplasmic reticulum	80/2092	174/8465	5.96e-10	1.25e-08	7.96e-09	80
hsa041414	Colorectum	MSS	Protein processing in endoplasmic reticulum	75/1875	174/8465	3.78e-10	8.44e-09	5.17e-09	75
hsa041415	Colorectum	MSS	Protein processing in endoplasmic reticulum	75/1875	174/8465	3.78e-10	8.44e-09	5.17e-09	75
hsa041416	Colorectum	MSI-H	Protein processing in endoplasmic reticulum	46/797	174/8465	4.53e-11	9.78e-10	8.19e-10	46
hsa041417	Colorectum	MSI-H	Protein processing in endoplasmic reticulum	46/797	174/8465	4.53e-11	9.78e-10	8.19e-10	46
hsa041418	Colorectum	FAP	Protein processing in endoplasmic reticulum	50/1404	174/8465	3.64e-05	3.68e-04	2.24e-04	50
hsa041419	Colorectum	FAP	Protein processing in endoplasmic reticulum	50/1404	174/8465	3.64e-05	3.68e-04	2.24e-04	50
hsa0414126	Endometrium	AEH	Protein processing in endoplasmic reticulum	62/1197	174/8465	5.97e-13	1.39e-11	1.01e-11	62
hsa04141111	Endometrium	AEH	Protein processing in endoplasmic reticulum	62/1197	174/8465	5.97e-13	1.39e-11	1.01e-11	62
hsa0414127	Endometrium	EEC	Protein processing in endoplasmic reticulum	64/1237	174/8465	2.17e-13	5.09e-12	3.80e-12	64
hsa0414136	Endometrium	EEC	Protein processing in endoplasmic reticulum	64/1237	174/8465	2.17e-13	5.09e-12	3.80e-12	64

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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

P4HB

SNV

Missense_Mutation

c.1439N>T

p.Asp480Val

p.D480V

P07237

protein_coding

tolerated(0.3)

possibly_damaging(0.454)

TCGA-A2-A0T0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

P4HB

SNV

Missense_Mutation

novel

c.431C>A

p.Ala144Glu

p.A144E

P07237

protein_coding

tolerated(1)

benign(0.003)

TCGA-A8-A06T-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

P4HB

SNV

Missense_Mutation

novel

c.431N>A

p.Ala144Glu

p.A144E

P07237

protein_coding

tolerated(1)

benign(0.003)

TCGA-A8-A08Z-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

P4HB

SNV

Missense_Mutation

rs138621837

c.430N>A

p.Ala144Thr

p.A144T

P07237

protein_coding

tolerated(0.51)

benign(0.003)

TCGA-A8-A08Z-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

P4HB

SNV

Missense_Mutation

novel

c.1089N>G

p.Asp363Glu

p.D363E

P07237

protein_coding

deleterious(0.02)

benign(0.036)

TCGA-AR-A2LR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

P4HB

SNV

Missense_Mutation

c.1163N>G

p.Val388Gly

p.V388G

P07237

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-B6-A0IA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

P4HB

insertion

Frame_Shift_Ins

novel

c.1453_1454insCCTGGAATCCCAGTGCTGGGGC

p.Glu485AlafsTer23

p.E485Afs*23

P07237

protein_coding

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

P4HB

deletion

Frame_Shift_Del

rs773547908

c.1160delN

p.Asn387ThrfsTer118

p.N387Tfs*118

P07237

protein_coding

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

P4HB

deletion

Frame_Shift_Del

rs773547908

c.1160delN

p.Asn387ThrfsTer118

p.N387Tfs*118

P07237

protein_coding

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

P4HB

SNV

Missense_Mutation

novel

c.649N>C

p.Glu217Gln

p.E217Q

P07237

protein_coding

deleterious(0.03)

possibly_damaging(0.556)

TCGA-C5-A8YQ-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
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		RALOXIFENE HYDROCHLORIDE	RALOXIFENE HYDROCHLORIDE
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		ASTRAGALIN	ASTRAGALIN
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		SYROSINGOPINE	SYROSINGOPINE
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		LIQUIRITIN	LIQUIRITIN
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		QUERCITRIN	QUERCITRIN
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE	inhibitor	CHEMBL2105662	LOMITAPIDE MESYLATE
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		NSC-19803	CHEMBL522983
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		DIHYDRODAPHNODORIN B	DIHYDRODAPHNODORIN B
5034	P4HB	THIOREDOXIN, DRUGGABLE GENOME, ENZYME, EXTERNAL SIDE OF PLASMA MEMBRANE		GNF-PF-2976	CHEMBL579956

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