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: PRKACA

Gene summary for PRKACA

Gene summary.

Gene information	Species	Human
	Gene symbol	PRKACA
	Gene ID	5566
	Gene name	protein kinase cAMP-activated catalytic subunit alpha
	Gene Alias	CAFD1
	Cytomap	19p13.12
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P17612

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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
5566	PRKACA	HTA11_3410_2000001011	Human	Colorectum	AD	1.58e-03	1.40e-01	0.0155
5566	PRKACA	HTA11_2487_2000001011	Human	Colorectum	SER	3.84e-04	2.99e-01	-0.1808
5566	PRKACA	HTA11_1938_2000001011	Human	Colorectum	AD	1.53e-04	2.50e-01	-0.0811
5566	PRKACA	HTA11_347_2000001011	Human	Colorectum	AD	2.01e-09	3.61e-01	-0.1954
5566	PRKACA	HTA11_411_2000001011	Human	Colorectum	SER	1.20e-04	7.42e-01	-0.2602
5566	PRKACA	HTA11_3361_2000001011	Human	Colorectum	AD	4.12e-04	4.35e-01	-0.1207
5566	PRKACA	HTA11_83_2000001011	Human	Colorectum	SER	2.63e-03	3.08e-01	-0.1526
5566	PRKACA	HTA11_696_2000001011	Human	Colorectum	AD	1.25e-14	4.49e-01	-0.1464
5566	PRKACA	HTA11_866_2000001011	Human	Colorectum	AD	7.60e-09	2.83e-01	-0.1001
5566	PRKACA	HTA11_1391_2000001011	Human	Colorectum	AD	1.85e-12	5.14e-01	-0.059
5566	PRKACA	HTA11_2992_2000001011	Human	Colorectum	SER	1.07e-07	5.67e-01	-0.1706
5566	PRKACA	HTA11_5212_2000001011	Human	Colorectum	AD	1.12e-04	4.04e-01	-0.2061
5566	PRKACA	HTA11_5216_2000001011	Human	Colorectum	SER	6.82e-03	4.04e-01	-0.1462
5566	PRKACA	HTA11_866_3004761011	Human	Colorectum	AD	5.27e-04	1.93e-01	0.096
5566	PRKACA	HTA11_10711_2000001011	Human	Colorectum	AD	4.27e-02	1.91e-01	0.0338
5566	PRKACA	HTA11_7696_3000711011	Human	Colorectum	AD	4.69e-13	4.69e-01	0.0674
5566	PRKACA	HTA11_6818_2000001011	Human	Colorectum	AD	3.38e-02	2.82e-01	0.0112
5566	PRKACA	HTA11_99999971662_82457	Human	Colorectum	MSS	6.29e-11	3.76e-01	0.3859
5566	PRKACA	HTA11_99999973899_84307	Human	Colorectum	MSS	1.24e-04	2.88e-01	0.2585
5566	PRKACA	HTA11_99999974143_84620	Human	Colorectum	MSS	5.24e-07	2.33e-01	0.3005

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
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:004217622	Liver	HCC	regulation of protein catabolic process	267/7958	391/18723	2.45e-25	7.38e-23	267
GO:003238621	Liver	HCC	regulation of intracellular transport	231/7958	337/18723	1.99e-22	3.40e-20	231
GO:001623621	Liver	HCC	macroautophagy	204/7958	291/18723	8.66e-22	1.41e-19	204
GO:000691322	Liver	HCC	nucleocytoplasmic transport	208/7958	301/18723	5.51e-21	8.12e-19	208
GO:005116922	Liver	HCC	nuclear transport	208/7958	301/18723	5.51e-21	8.12e-19	208
GO:190336222	Liver	HCC	regulation of cellular protein catabolic process	182/7958	255/18723	5.91e-21	8.52e-19	182
GO:003315721	Liver	HCC	regulation of intracellular protein transport	165/7958	229/18723	8.37e-20	1.15e-17	165
GO:003238821	Liver	HCC	positive regulation of intracellular transport	148/7958	202/18723	5.15e-19	6.66e-17	148
GO:190305022	Liver	HCC	regulation of proteolysis involved in cellular protein catabolic process	157/7958	221/18723	5.93e-18	6.83e-16	157
GO:001050621	Liver	HCC	regulation of autophagy	210/7958	317/18723	7.59e-18	8.45e-16	210
GO:009031621	Liver	HCC	positive regulation of intracellular protein transport	121/7958	160/18723	1.27e-17	1.39e-15	121
GO:190495122	Liver	HCC	positive regulation of establishment of protein localization	207/7958	319/18723	3.95e-16	3.29e-14	207
GO:006113622	Liver	HCC	regulation of proteasomal protein catabolic process	134/7958	187/18723	5.03e-16	4.09e-14	134
GO:005116822	Liver	HCC	nuclear export	113/7958	154/18723	6.30e-15	4.39e-13	113
GO:005122222	Liver	HCC	positive regulation of protein transport	194/7958	303/18723	2.41e-14	1.56e-12	194
GO:005109822	Liver	HCC	regulation of binding	225/7958	363/18723	3.78e-14	2.37e-12	225
GO:004682221	Liver	HCC	regulation of nucleocytoplasmic transport	81/7958	106/18723	1.11e-12	5.52e-11	81
GO:004339322	Liver	HCC	regulation of protein binding	129/7958	196/18723	3.27e-11	1.26e-09	129
GO:001624111	Liver	HCC	regulation of macroautophagy	96/7958	141/18723	6.82e-10	2.14e-08	96
GO:003460512	Liver	HCC	cellular response to heat	53/7958	69/18723	6.62e-09	1.70e-07	53

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05012	Colorectum	AD	Parkinson disease	147/2092	266/8465	2.53e-27	8.48e-25	5.41e-25	147
hsa04714	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa05020	Colorectum	AD	Prion disease	133/2092	273/8465	2.47e-18	8.29e-17	5.29e-17	133
hsa04530	Colorectum	AD	Tight junction	76/2092	169/8465	5.49e-09	9.69e-08	6.18e-08	76
hsa05110	Colorectum	AD	Vibrio cholerae infection	29/2092	50/8465	5.10e-07	7.12e-06	4.54e-06	29
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa04723	Colorectum	AD	Retrograde endocannabinoid signaling	59/2092	148/8465	2.94e-05	2.73e-04	1.74e-04	59
hsa04961	Colorectum	AD	Endocrine and other factor-regulated calcium reabsorption	24/2092	53/8465	8.49e-04	5.93e-03	3.78e-03	24
hsa04213	Colorectum	AD	Longevity regulating pathway - multiple species	27/2092	62/8465	8.72e-04	5.96e-03	3.80e-03	27
hsa04922	Colorectum	AD	Glucagon signaling pathway	41/2092	107/8465	1.18e-03	7.75e-03	4.94e-03	41
hsa05205	Colorectum	AD	Proteoglycans in cancer	70/2092	205/8465	1.37e-03	8.46e-03	5.39e-03	70
hsa05163	Colorectum	AD	Human cytomegalovirus infection	75/2092	225/8465	2.00e-03	1.10e-02	7.01e-03	75
hsa04912	Colorectum	AD	GnRH signaling pathway	35/2092	93/8465	3.69e-03	1.90e-02	1.21e-02	35
hsa04140	Colorectum	AD	Autophagy - animal	49/2092	141/8465	4.58e-03	2.20e-02	1.40e-02	49
hsa05166	Colorectum	AD	Human T-cell leukemia virus 1 infection	72/2092	222/8465	5.24e-03	2.44e-02	1.55e-02	72
hsa04962	Colorectum	AD	Vasopressin-regulated water reabsorption	19/2092	44/8465	5.48e-03	2.48e-02	1.58e-02	19
hsa04728	Colorectum	AD	Dopaminergic synapse	46/2092	132/8465	5.55e-03	2.48e-02	1.58e-02	46
hsa04211	Colorectum	AD	Longevity regulating pathway	33/2092	89/8465	6.15e-03	2.68e-02	1.71e-02	33
hsa04971	Colorectum	AD	Gastric acid secretion	29/2092	76/8465	6.25e-03	2.68e-02	1.71e-02	29
hsa04928	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38

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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

PRKACA

SNV

Missense_Mutation

c.382N>C

p.Glu128Gln

p.E128Q

P17612

protein_coding

deleterious(0)

probably_damaging(0.989)

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

PRKACA

SNV

Missense_Mutation

c.656N>T

p.Ala219Val

p.A219V

P17612

protein_coding

deleterious(0)

probably_damaging(0.962)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

PRKACA

SNV

Missense_Mutation

c.248T>C

p.Leu83Pro

p.L83P

P17612

protein_coding

deleterious(0)

probably_damaging(0.925)

TCGA-E2-A15L-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

PRKACA

SNV

Missense_Mutation

c.589N>A

p.Trp197Arg

p.W197R

P17612

protein_coding

deleterious(0)

probably_damaging(0.91)

TCGA-E2-A1IU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

PRKACA

SNV

Missense_Mutation

c.376N>A

p.Gly126Ser

p.G126S

P17612

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-GM-A2DO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PRKACA

deletion

Frame_Shift_Del

novel

c.871delN

p.Asp291IlefsTer99

p.D291Ifs*99

P17612

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PRKACA

SNV

Missense_Mutation

c.710C>T

p.Pro237Leu

p.P237L

P17612

protein_coding

deleterious(0)

probably_damaging(0.99)

TCGA-C5-A7CH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unspecific

PRKACA

SNV

Missense_Mutation

c.450G>T

p.Gln150His

p.Q150H

P17612

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PRKACA

SNV

Missense_Mutation

c.700N>A

p.Ala234Thr

p.A234T

P17612

protein_coding

deleterious(0.04)

possibly_damaging(0.567)

TCGA-CK-5913-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Unknown

PRKACA

SNV

Missense_Mutation

c.442N>A

p.Ala148Thr

p.A148T

P17612

protein_coding

deleterious(0.02)

probably_damaging(0.951)

TCGA-AJ-A23O-01

Endometrium

uterine corpus endometrioid carcinoma

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
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		ALISERTIB	ALISERTIB
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		TCMDC-125758	CHEMBL546797
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		CYC-116	CYC-116
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		AG-1879	CHEMBL406845
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		CENISERTIB	CENISERTIB
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		GO-6976	GO-6976
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	CHEMBL494089	GSK-690693
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		PD-0166285	PD-0166285
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	178102606	CHEMBL104264
5566	PRKACA	SERINE THREONINE KINASE, TUMOR SUPPRESSOR, DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		FASUDIL	FASUDIL

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