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: PDIA4

Gene summary for PDIA4

Gene summary.

Gene information	Species	Human
	Gene symbol	PDIA4
	Gene ID	9601
	Gene name	protein disulfide isomerase family A member 4
	Gene Alias	ERP70
	Cytomap	7q36.1
	Gene Type	protein-coding
	GO ID	GO:0006457
	UniProtAcc	A0A090N8Y2

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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
9601	PDIA4	P130T-E	Human	Esophagus	ESCC	1.04e-121	3.05e+00	0.1676
9601	PDIA4	S43	Human	Liver	Cirrhotic	3.44e-02	1.39e-01	-0.0187
9601	PDIA4	HCC1_Meng	Human	Liver	HCC	4.00e-88	6.04e-01	0.0246
9601	PDIA4	HCC2_Meng	Human	Liver	HCC	6.43e-40	3.62e-01	0.0107
9601	PDIA4	cirrhotic2	Human	Liver	Cirrhotic	4.97e-22	3.89e-01	0.0201
9601	PDIA4	cirrhotic3	Human	Liver	Cirrhotic	1.81e-08	2.00e-01	0.0215
9601	PDIA4	HCC1	Human	Liver	HCC	7.65e-26	5.83e+00	0.5336
9601	PDIA4	HCC2	Human	Liver	HCC	7.95e-39	5.87e+00	0.5341
9601	PDIA4	Pt13.a	Human	Liver	HCC	1.35e-04	2.56e-01	0.021
9601	PDIA4	Pt13.b	Human	Liver	HCC	9.05e-43	6.16e-01	0.0251
9601	PDIA4	Pt14.a	Human	Liver	HCC	2.39e-11	7.04e-01	0.0169
9601	PDIA4	Pt14.b	Human	Liver	HCC	2.02e-10	3.81e-01	0.018
9601	PDIA4	Pt14.d	Human	Liver	HCC	1.10e-08	3.90e-01	0.0143
9601	PDIA4	S014	Human	Liver	HCC	1.53e-43	2.53e+00	0.2254
9601	PDIA4	S015	Human	Liver	HCC	1.80e-49	3.03e+00	0.2375
9601	PDIA4	S016	Human	Liver	HCC	1.75e-58	2.73e+00	0.2243
9601	PDIA4	S027	Human	Liver	HCC	4.26e-25	2.31e+00	0.2446
9601	PDIA4	S028	Human	Liver	HCC	7.59e-48	2.65e+00	0.2503
9601	PDIA4	S029	Human	Liver	HCC	2.69e-45	2.68e+00	0.2581
9601	PDIA4	RNA-P17T-P17T-2	Human	Lung	IAC	1.67e-07	5.68e-01	0.3371

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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:0034976	Colorectum	AD	response to endoplasmic reticulum stress	90/3918	256/18723	8.48e-08	4.28e-06	90
GO:0006457	Colorectum	AD	protein folding	73/3918	212/18723	3.24e-06	9.10e-05	73
GO:0009306	Colorectum	AD	protein secretion	105/3918	359/18723	1.05e-04	1.57e-03	105
GO:0035592	Colorectum	AD	establishment of protein localization to extracellular region	105/3918	360/18723	1.18e-04	1.73e-03	105
GO:0071692	Colorectum	AD	protein localization to extracellular region	106/3918	368/18723	1.86e-04	2.49e-03	106
GO:0061077	Colorectum	AD	chaperone-mediated protein folding	26/3918	67/18723	6.20e-04	6.48e-03	26
GO:00349761	Colorectum	SER	response to endoplasmic reticulum stress	74/2897	256/18723	3.01e-08	2.05e-06	74
GO:00064571	Colorectum	SER	protein folding	54/2897	212/18723	1.04e-04	2.18e-03	54
GO:00093061	Colorectum	SER	protein secretion	79/2897	359/18723	5.99e-04	8.19e-03	79
GO:00355921	Colorectum	SER	establishment of protein localization to extracellular region	79/2897	360/18723	6.54e-04	8.77e-03	79
GO:00716921	Colorectum	SER	protein localization to extracellular region	80/2897	368/18723	8.13e-04	1.01e-02	80
GO:00610771	Colorectum	SER	chaperone-mediated protein folding	21/2897	67/18723	8.44e-04	1.04e-02	21
GO:00064572	Colorectum	MSS	protein folding	71/3467	212/18723	1.25e-07	5.91e-06	71
GO:00349762	Colorectum	MSS	response to endoplasmic reticulum stress	81/3467	256/18723	2.65e-07	1.10e-05	81
GO:00093062	Colorectum	MSS	protein secretion	98/3467	359/18723	2.43e-05	5.09e-04	98
GO:00355922	Colorectum	MSS	establishment of protein localization to extracellular region	98/3467	360/18723	2.75e-05	5.58e-04	98
GO:00716922	Colorectum	MSS	protein localization to extracellular region	99/3467	368/18723	4.17e-05	7.83e-04	99
GO:00610772	Colorectum	MSS	chaperone-mediated protein folding	26/3467	67/18723	8.06e-05	1.33e-03	26
GO:00349763	Colorectum	MSI-H	response to endoplasmic reticulum stress	39/1319	256/18723	4.12e-06	2.20e-04	39
GO:00064573	Colorectum	MSI-H	protein folding	33/1319	212/18723	1.40e-05	6.29e-04	33

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04141	Colorectum	AD	Protein processing in endoplasmic reticulum	80/2092	174/8465	5.96e-10	1.25e-08	7.96e-09	80
hsa05110	Colorectum	AD	Vibrio cholerae infection	29/2092	50/8465	5.10e-07	7.12e-06	4.54e-06	29
hsa041411	Colorectum	AD	Protein processing in endoplasmic reticulum	80/2092	174/8465	5.96e-10	1.25e-08	7.96e-09	80
hsa051101	Colorectum	AD	Vibrio cholerae infection	29/2092	50/8465	5.10e-07	7.12e-06	4.54e-06	29
hsa041412	Colorectum	SER	Protein processing in endoplasmic reticulum	60/1580	174/8465	4.20e-07	7.33e-06	5.32e-06	60
hsa051102	Colorectum	SER	Vibrio cholerae infection	24/1580	50/8465	2.17e-06	3.13e-05	2.28e-05	24
hsa041413	Colorectum	SER	Protein processing in endoplasmic reticulum	60/1580	174/8465	4.20e-07	7.33e-06	5.32e-06	60
hsa051103	Colorectum	SER	Vibrio cholerae infection	24/1580	50/8465	2.17e-06	3.13e-05	2.28e-05	24
hsa041414	Colorectum	MSS	Protein processing in endoplasmic reticulum	75/1875	174/8465	3.78e-10	8.44e-09	5.17e-09	75
hsa051104	Colorectum	MSS	Vibrio cholerae infection	27/1875	50/8465	8.58e-07	1.20e-05	7.34e-06	27
hsa041415	Colorectum	MSS	Protein processing in endoplasmic reticulum	75/1875	174/8465	3.78e-10	8.44e-09	5.17e-09	75
hsa051105	Colorectum	MSS	Vibrio cholerae infection	27/1875	50/8465	8.58e-07	1.20e-05	7.34e-06	27
hsa041416	Colorectum	MSI-H	Protein processing in endoplasmic reticulum	46/797	174/8465	4.53e-11	9.78e-10	8.19e-10	46
hsa051106	Colorectum	MSI-H	Vibrio cholerae infection	18/797	50/8465	2.77e-07	5.61e-06	4.70e-06	18
hsa041417	Colorectum	MSI-H	Protein processing in endoplasmic reticulum	46/797	174/8465	4.53e-11	9.78e-10	8.19e-10	46
hsa051107	Colorectum	MSI-H	Vibrio cholerae infection	18/797	50/8465	2.77e-07	5.61e-06	4.70e-06	18
hsa0414126	Endometrium	AEH	Protein processing in endoplasmic reticulum	62/1197	174/8465	5.97e-13	1.39e-11	1.01e-11	62
hsa0511018	Endometrium	AEH	Vibrio cholerae infection	18/1197	50/8465	9.09e-05	8.69e-04	6.36e-04	18
hsa04141111	Endometrium	AEH	Protein processing in endoplasmic reticulum	62/1197	174/8465	5.97e-13	1.39e-11	1.01e-11	62
hsa0511019	Endometrium	AEH	Vibrio cholerae infection	18/1197	50/8465	9.09e-05	8.69e-04	6.36e-04	18

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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

PDIA4

SNV

Missense_Mutation

novel

c.1904C>T

p.Ala635Val

p.A635V

P13667

protein_coding

deleterious(0.02)

benign(0.018)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDIA4

SNV

Missense_Mutation

c.1752C>A

p.Asp584Glu

p.D584E

P13667

protein_coding

deleterious(0)

probably_damaging(0.949)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDIA4

SNV

Missense_Mutation

c.118N>A

p.Asp40Asn

p.D40N

P13667

protein_coding

tolerated_low_confidence(0.07)

benign(0.071)

TCGA-BH-A0BZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

PDIA4

SNV

Missense_Mutation

c.151N>A

p.Glu51Lys

p.E51K

P13667

protein_coding

tolerated(0.68)

benign(0.025)

TCGA-C8-A274-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PDIA4

insertion

In_Frame_Ins

novel

c.1634_1635insTGGTCGGGG

p.Asp545_Val546insGlyArgGly

p.D545_V546insGRG

P13667

protein_coding

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

PDIA4

insertion

Frame_Shift_Ins

novel

c.1633_1634insTGGGAGGAGGCAGACGCCCTGCGTGGCCC

p.Asp545ValfsTer27

p.D545Vfs*27

P13667

protein_coding

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

PDIA4

SNV

Missense_Mutation

rs757482634

c.1223G>A

p.Arg408His

p.R408H

P13667

protein_coding

deleterious(0.01)

probably_damaging(0.947)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PDIA4

SNV

Missense_Mutation

novel

c.715G>A

p.Ala239Thr

p.A239T

P13667

protein_coding

tolerated(0.36)

benign(0.267)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PDIA4

SNV

Missense_Mutation

novel

c.491T>C

p.Val164Ala

p.V164A

P13667

protein_coding

deleterious(0.04)

possibly_damaging(0.729)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PDIA4

SNV

Missense_Mutation

rs144700814

c.160N>C

p.Asp54His

p.D54H

P13667

protein_coding

deleterious(0.01)

possibly_damaging(0.65)

TCGA-C5-A8YR-01

Cervix

cervical & endocervical cancer

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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