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: PDE4C

Gene summary for PDE4C

Gene summary.

Gene information	Species	Human
	Gene symbol	PDE4C
	Gene ID	5143
	Gene name	phosphodiesterase 4C
	Gene Alias	DPDE1
	Cytomap	19p13.11
	Gene Type	protein-coding
	GO ID	GO:0006139
	UniProtAcc	O43849

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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
5143	PDE4C	HTA11_3410_2000001011	Human	Colorectum	AD	4.20e-02	9.73e-02	0.0155
5143	PDE4C	HTA11_2487_2000001011	Human	Colorectum	SER	1.18e-27	6.86e-01	-0.1808
5143	PDE4C	HTA11_1938_2000001011	Human	Colorectum	AD	3.41e-16	4.80e-01	-0.0811
5143	PDE4C	HTA11_78_2000001011	Human	Colorectum	AD	6.11e-04	1.68e-01	-0.1088
5143	PDE4C	HTA11_347_2000001011	Human	Colorectum	AD	2.14e-62	1.05e+00	-0.1954
5143	PDE4C	HTA11_411_2000001011	Human	Colorectum	SER	6.42e-18	1.29e+00	-0.2602
5143	PDE4C	HTA11_2112_2000001011	Human	Colorectum	SER	2.75e-12	6.59e-01	-0.2196
5143	PDE4C	HTA11_3361_2000001011	Human	Colorectum	AD	6.03e-08	3.50e-01	-0.1207
5143	PDE4C	HTA11_83_2000001011	Human	Colorectum	SER	2.83e-15	5.43e-01	-0.1526
5143	PDE4C	HTA11_696_2000001011	Human	Colorectum	AD	3.28e-34	6.47e-01	-0.1464
5143	PDE4C	HTA11_866_2000001011	Human	Colorectum	AD	2.71e-26	5.05e-01	-0.1001
5143	PDE4C	HTA11_1391_2000001011	Human	Colorectum	AD	4.56e-17	4.36e-01	-0.059
5143	PDE4C	HTA11_2992_2000001011	Human	Colorectum	SER	1.02e-19	8.95e-01	-0.1706
5143	PDE4C	HTA11_5212_2000001011	Human	Colorectum	AD	1.67e-10	4.78e-01	-0.2061
5143	PDE4C	HTA11_5216_2000001011	Human	Colorectum	SER	1.20e-12	6.52e-01	-0.1462
5143	PDE4C	HTA11_546_2000001011	Human	Colorectum	AD	1.19e-22	7.58e-01	-0.0842
5143	PDE4C	HTA11_866_3004761011	Human	Colorectum	AD	6.26e-04	1.18e-01	0.096
5143	PDE4C	HTA11_4255_2000001011	Human	Colorectum	SER	1.51e-11	5.15e-01	0.0446
5143	PDE4C	HTA11_9408_2000001011	Human	Colorectum	AD	4.54e-06	3.39e-01	0.0451
5143	PDE4C	HTA11_8622_2000001021	Human	Colorectum	SER	6.58e-13	5.44e-01	0.0528

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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
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

∗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:0009150	Colorectum	AD	purine ribonucleotide metabolic process	142/3918	368/18723	4.29e-15	1.17e-12	142
GO:0006163	Colorectum	AD	purine nucleotide metabolic process	149/3918	396/18723	1.08e-14	2.80e-12	149
GO:0072521	Colorectum	AD	purine-containing compound metabolic process	153/3918	416/18723	4.34e-14	1.01e-11	153
GO:0009259	Colorectum	AD	ribonucleotide metabolic process	144/3918	385/18723	5.25e-14	1.13e-11	144
GO:0019693	Colorectum	AD	ribose phosphate metabolic process	145/3918	396/18723	3.01e-13	5.71e-11	145
GO:0009117	Colorectum	AD	nucleotide metabolic process	168/3918	489/18723	2.20e-12	3.36e-10	168
GO:0006753	Colorectum	AD	nucleoside phosphate metabolic process	169/3918	497/18723	4.99e-12	6.98e-10	169
GO:0044270	Colorectum	AD	cellular nitrogen compound catabolic process	147/3918	451/18723	3.35e-09	2.23e-07	147
GO:0046700	Colorectum	AD	heterocycle catabolic process	145/3918	445/18723	4.37e-09	2.84e-07	145
GO:0034655	Colorectum	AD	nucleobase-containing compound catabolic process	133/3918	407/18723	1.56e-08	9.12e-07	133
GO:0019439	Colorectum	AD	aromatic compound catabolic process	146/3918	467/18723	7.48e-08	3.84e-06	146
GO:1901361	Colorectum	AD	organic cyclic compound catabolic process	153/3918	495/18723	8.23e-08	4.18e-06	153
GO:0006195	Colorectum	AD	purine nucleotide catabolic process	18/3918	46/18723	3.67e-03	2.60e-02	18
GO:0072523	Colorectum	AD	purine-containing compound catabolic process	19/3918	52/18723	6.92e-03	4.26e-02	19
GO:00061631	Colorectum	SER	purine nucleotide metabolic process	109/2897	396/18723	4.26e-10	5.44e-08	109
GO:00091501	Colorectum	SER	purine ribonucleotide metabolic process	103/2897	368/18723	4.69e-10	5.68e-08	103
GO:00725211	Colorectum	SER	purine-containing compound metabolic process	113/2897	416/18723	4.80e-10	5.68e-08	113
GO:00092591	Colorectum	SER	ribonucleotide metabolic process	104/2897	385/18723	3.27e-09	3.04e-07	104
GO:00196931	Colorectum	SER	ribose phosphate metabolic process	105/2897	396/18723	8.15e-09	7.14e-07	105
GO:00091171	Colorectum	SER	nucleotide metabolic process	122/2897	489/18723	2.50e-08	1.76e-06	122

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
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
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

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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

PDE4C

SNV

Missense_Mutation

c.1294N>A

p.His432Asn

p.H432N

Q08493

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-A2-A0CX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

PDE4C

SNV

Missense_Mutation

novel

c.292N>A

p.Gln98Lys

p.Q98K

Q08493

protein_coding

deleterious_low_confidence(0.01)

benign(0.062)

TCGA-A2-A0YK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

PDE4C

SNV

Missense_Mutation

rs759324714

c.1945N>A

p.Glu649Lys

p.E649K

Q08493

protein_coding

tolerated_low_confidence(0.09)

benign(0)

TCGA-A8-A09N-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

PDE4C

SNV

Missense_Mutation

c.418T>A

p.Ser140Thr

p.S140T

Q08493

protein_coding

deleterious(0.01)

possibly_damaging(0.5)

TCGA-AQ-A04J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

PDE4C

SNV

Missense_Mutation

novel

c.2002G>C

p.Glu668Gln

p.E668Q

Q08493

protein_coding

tolerated_low_confidence(0.14)

benign(0.007)

TCGA-AR-A2LH-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

PDE4C

SNV

Missense_Mutation

c.1780G>C

p.Glu594Gln

p.E594Q

Q08493

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-B6-A0RE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PDE4C

SNV

Missense_Mutation

c.1682C>T

p.Thr561Met

p.T561M

Q08493

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C8-A275-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PDE4C

SNV

Missense_Mutation

rs771418461

c.2132N>A

p.Arg711Lys

p.R711K

Q08493

protein_coding

deleterious_low_confidence(0)

benign(0.112)

TCGA-S3-AA0Z-01

Breast

breast invasive carcinoma

Female

<65

I/II

Ancillary

neulasta

PDE4C

insertion

Nonsense_Mutation

novel

c.1428_1429insAGCAGAGGGAACCCCACGTGAGGAGGC

p.Ile476_Phe477insSerArgGlyAsnProThrTerGlyGly

p.I476_F477insSRGNPT*GG

Q08493

protein_coding

TCGA-A2-A0D1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

PDE4C

insertion

In_Frame_Ins

novel

c.1851_1852insTGC

p.His617_Pro618insCys

p.H617_P618insC

Q08493

protein_coding

TCGA-A7-A0CJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

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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
5143	PDE4C	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL484785	CRISABOROLE
5143	PDE4C	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL1370561	AMINOPHYLLINE
5143	PDE4C	DRUGGABLE GENOME, ENZYME		CS-W011402
5143	PDE4C	DRUGGABLE GENOME, ENZYME		ETAZOLATE	ETAZOLATE
5143	PDE4C	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL1200578	THEOPHYLLINE SODIUM GLYCINATE
5143	PDE4C	DRUGGABLE GENOME, ENZYME		DYPHYLLINE	DYPHYLLINE
5143	PDE4C	DRUGGABLE GENOME, ENZYME		IBUDILAST	IBUDILAST
5143	PDE4C	DRUGGABLE GENOME, ENZYME		US10077269, Example 6
5143	PDE4C	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL628	PENTOXIFYLLINE
5143	PDE4C	DRUGGABLE GENOME, ENZYME	inhibitor	CHEMBL514800	APREMILAST

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