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: PDE4D

Gene summary for PDE4D

Gene summary.

Gene information	Species	Human
	Gene symbol	PDE4D
	Gene ID	5144
	Gene name	phosphodiesterase 4D
	Gene Alias	ACRDYS2
	Cytomap	5q11.2-q12.1
	Gene Type	protein-coding
	GO ID	GO:0001816
	UniProtAcc	A0A140VJR0

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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
5144	PDE4D	P48T-E	Human	Esophagus	ESCC	1.28e-18	2.65e-01	0.0959
5144	PDE4D	P49T-E	Human	Esophagus	ESCC	1.18e-10	8.64e-01	0.1768
5144	PDE4D	P52T-E	Human	Esophagus	ESCC	3.18e-11	1.93e-01	0.1555
5144	PDE4D	P54T-E	Human	Esophagus	ESCC	1.11e-16	3.76e-01	0.0975
5144	PDE4D	P57T-E	Human	Esophagus	ESCC	5.53e-12	2.32e-01	0.0926
5144	PDE4D	P61T-E	Human	Esophagus	ESCC	3.03e-03	1.43e-01	0.099
5144	PDE4D	P62T-E	Human	Esophagus	ESCC	1.25e-16	3.62e-01	0.1302
5144	PDE4D	P74T-E	Human	Esophagus	ESCC	2.79e-14	4.16e-01	0.1479
5144	PDE4D	P75T-E	Human	Esophagus	ESCC	2.59e-21	2.82e-01	0.1125
5144	PDE4D	P76T-E	Human	Esophagus	ESCC	9.82e-04	1.24e-01	0.1207
5144	PDE4D	P79T-E	Human	Esophagus	ESCC	1.18e-08	1.10e-01	0.1154
5144	PDE4D	P82T-E	Human	Esophagus	ESCC	4.18e-09	2.82e-01	0.1072
5144	PDE4D	P83T-E	Human	Esophagus	ESCC	3.51e-09	2.80e-01	0.1738
5144	PDE4D	P89T-E	Human	Esophagus	ESCC	3.54e-03	2.38e-01	0.1752
5144	PDE4D	P104T-E	Human	Esophagus	ESCC	2.71e-04	3.52e-01	0.0931
5144	PDE4D	P107T-E	Human	Esophagus	ESCC	8.40e-09	2.38e-01	0.171
5144	PDE4D	P127T-E	Human	Esophagus	ESCC	9.75e-06	1.72e-01	0.0826
5144	PDE4D	P128T-E	Human	Esophagus	ESCC	1.01e-12	4.24e-01	0.1241
5144	PDE4D	P130T-E	Human	Esophagus	ESCC	1.59e-25	8.63e-01	0.1676
5144	PDE4D	NAFLD1	Human	Liver	NAFLD	8.54e-07	9.28e-01	-0.04

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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:003297010	Cervix	CC	regulation of actin filament-based process	96/2311	397/18723	4.00e-11	8.54e-09	96
GO:00512359	Cervix	CC	maintenance of location	78/2311	327/18723	5.18e-09	4.92e-07	78
GO:005165110	Cervix	CC	maintenance of location in cell	55/2311	214/18723	6.63e-08	3.85e-06	55
GO:00027644	Cervix	CC	immune response-regulating signaling pathway	97/2311	468/18723	1.49e-07	7.07e-06	97
GO:00018197	Cervix	CC	positive regulation of cytokine production	95/2311	467/18723	4.88e-07	1.85e-05	95
GO:004593610	Cervix	CC	negative regulation of phosphate metabolic process	88/2311	441/18723	2.92e-06	8.27e-05	88
GO:001056310	Cervix	CC	negative regulation of phosphorus metabolic process	88/2311	442/18723	3.21e-06	8.77e-05	88
GO:004232610	Cervix	CC	negative regulation of phosphorylation	77/2311	385/18723	1.09e-05	2.38e-04	77
GO:000193310	Cervix	CC	negative regulation of protein phosphorylation	69/2311	342/18723	2.29e-05	4.01e-04	69
GO:00181057	Cervix	CC	peptidyl-serine phosphorylation	63/2311	315/18723	6.65e-05	9.47e-04	63
GO:00022533	Cervix	CC	activation of immune response	72/2311	375/18723	8.26e-05	1.11e-03	72
GO:00182096	Cervix	CC	peptidyl-serine modification	66/2311	338/18723	9.58e-05	1.25e-03	66
GO:00106444	Cervix	CC	cell communication by electrical coupling	12/2311	32/18723	2.53e-04	2.79e-03	12
GO:00106494	Cervix	CC	regulation of cell communication by electrical coupling	8/2311	16/18723	2.73e-04	2.99e-03	8
GO:00467008	Cervix	CC	heterocycle catabolic process	80/2311	445/18723	3.23e-04	3.42e-03	80
GO:00346559	Cervix	CC	nucleobase-containing compound catabolic process	74/2311	407/18723	3.77e-04	3.88e-03	74
GO:000206410	Cervix	CC	epithelial cell development	45/2311	220/18723	4.14e-04	4.21e-03	45
GO:00196939	Cervix	CC	ribose phosphate metabolic process	72/2311	396/18723	4.49e-04	4.48e-03	72
GO:00092599	Cervix	CC	ribonucleotide metabolic process	70/2311	385/18723	5.35e-04	5.18e-03	70
GO:0002768	Cervix	CC	immune response-regulating cell surface receptor signaling pathway	59/2311	315/18723	6.64e-04	6.11e-03	59

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0492812	Cervix	CC	Parathyroid hormone synthesis, secretion and action	27/1267	106/8465	3.12e-03	1.19e-02	7.03e-03	27
hsa0492813	Cervix	CC	Parathyroid hormone synthesis, secretion and action	27/1267	106/8465	3.12e-03	1.19e-02	7.03e-03	27
hsa04928	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38
hsa049281	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38
hsa049282	Colorectum	SER	Parathyroid hormone synthesis, secretion and action	31/1580	106/8465	5.20e-03	3.28e-02	2.38e-02	31
hsa049283	Colorectum	SER	Parathyroid hormone synthesis, secretion and action	31/1580	106/8465	5.20e-03	3.28e-02	2.38e-02	31
hsa049284	Colorectum	MSS	Parathyroid hormone synthesis, secretion and action	37/1875	106/8465	1.72e-03	9.13e-03	5.59e-03	37
hsa049285	Colorectum	MSS	Parathyroid hormone synthesis, secretion and action	37/1875	106/8465	1.72e-03	9.13e-03	5.59e-03	37
hsa049286	Colorectum	FAP	Parathyroid hormone synthesis, secretion and action	29/1404	106/8465	3.37e-03	1.44e-02	8.77e-03	29
hsa04024	Colorectum	FAP	cAMP signaling pathway	51/1404	225/8465	1.02e-02	3.68e-02	2.24e-02	51
hsa049287	Colorectum	FAP	Parathyroid hormone synthesis, secretion and action	29/1404	106/8465	3.37e-03	1.44e-02	8.77e-03	29
hsa040241	Colorectum	FAP	cAMP signaling pathway	51/1404	225/8465	1.02e-02	3.68e-02	2.24e-02	51
hsa040242	Colorectum	CRC	cAMP signaling pathway	47/1091	225/8465	4.57e-04	4.77e-03	3.23e-03	47
hsa049288	Colorectum	CRC	Parathyroid hormone synthesis, secretion and action	24/1091	106/8465	3.71e-03	2.29e-02	1.55e-02	24
hsa040243	Colorectum	CRC	cAMP signaling pathway	47/1091	225/8465	4.57e-04	4.77e-03	3.23e-03	47
hsa049289	Colorectum	CRC	Parathyroid hormone synthesis, secretion and action	24/1091	106/8465	3.71e-03	2.29e-02	1.55e-02	24
hsa0492816	Esophagus	ESCC	Parathyroid hormone synthesis, secretion and action	66/4205	106/8465	5.86e-03	1.47e-02	7.51e-03	66
hsa0492817	Esophagus	ESCC	Parathyroid hormone synthesis, secretion and action	66/4205	106/8465	5.86e-03	1.47e-02	7.51e-03	66
hsa0492810	Lung	IAC	Parathyroid hormone synthesis, secretion and action	26/1053	106/8465	4.34e-04	4.03e-03	2.68e-03	26
hsa0492811	Lung	IAC	Parathyroid hormone synthesis, secretion and action	26/1053	106/8465	4.34e-04	4.03e-03	2.68e-03	26

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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

PDE4D

SNV

Missense_Mutation

c.647T>C

p.Ile216Thr

p.I216T

Q08499

protein_coding

tolerated_low_confidence(0.29)

possibly_damaging(0.84)

TCGA-A8-A09C-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDE4D

SNV

Missense_Mutation

c.1895N>A

p.Arg632His

p.R632H

Q08499

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.985)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDE4D

SNV

Missense_Mutation

c.1904N>T

p.Thr635Met

p.T635M

Q08499

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-AN-A0AJ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDE4D

SNV

Missense_Mutation

c.896N>A

p.Ser299Tyr

p.S299Y

Q08499

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.974)

TCGA-BH-A0BP-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDE4D

SNV

Missense_Mutation

c.1691N>G

p.Lys564Arg

p.K564R

Q08499

protein_coding

tolerated_low_confidence(0.27)

probably_damaging(0.97)

TCGA-BH-A18T-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PDE4D

SNV

Missense_Mutation

c.1291N>T

p.Arg431Trp

p.R431W

Q08499

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.994)

TCGA-C8-A1HL-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

PDE4D

SNV

Missense_Mutation

c.2221G>C

p.Glu741Gln

p.E741Q

Q08499

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.954)

TCGA-E2-A159-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

PDE4D

insertion

Nonsense_Mutation

novel

c.1924_1925insGTTGTTGTTGAAAATAGTGACAATTTTACCAAACTAAGTTTAG

p.Phe642CysfsTer4

p.F642Cfs*4

Q08499

protein_coding

TCGA-A2-A0D1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

PDE4D

deletion

Frame_Shift_Del

novel

c.2148delN

p.Ser717LeufsTer22

p.S717Lfs*22

Q08499

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

PDE4D

SNV

Missense_Mutation

novel

c.359N>T

p.Ala120Val

p.A120V

Q08499

protein_coding

tolerated_low_confidence(0.24)

benign(0.058)

TCGA-VS-A8EH-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

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
5144	PDE4D	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL932	DIPYRIDAMOLE
5144	PDE4D	DRUGGABLE GENOME, ENZYME		GPD-1116
5144	PDE4D	DRUGGABLE GENOME, ENZYME		DENBUFYLLINE	DENBUFYLLINE
5144	PDE4D	DRUGGABLE GENOME, ENZYME		BPN14770	BPN-14770
5144	PDE4D	DRUGGABLE GENOME, ENZYME		ROLIPRAM	ROLIPRAM
5144	PDE4D	DRUGGABLE GENOME, ENZYME		Oglemilast	OGLEMILAST	18660832
5144	PDE4D	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL1370561	AMINOPHYLLINE
5144	PDE4D	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL484785	CRISABOROLE
5144	PDE4D	DRUGGABLE GENOME, ENZYME		AN-2898
5144	PDE4D	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL193240	ROFLUMILAST

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