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: CDK12

Gene summary for CDK12

Gene summary.

Gene information	Species	Human
	Gene symbol	CDK12
	Gene ID	51755
	Gene name	cyclin dependent kinase 12
	Gene Alias	CRK7
	Cytomap	17q12
	Gene Type	protein-coding
	GO ID	GO:0001932
	UniProtAcc	Q9NYV4

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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
51755	CDK12	GSM4909291	Human	Breast	IDC	9.76e-47	1.04e+00	0.1753
51755	CDK12	GSM4909292	Human	Breast	IDC	8.11e-07	7.04e-01	0.1236
51755	CDK12	GSM4909293	Human	Breast	IDC	1.19e-68	9.90e-01	0.1581
51755	CDK12	GSM4909294	Human	Breast	IDC	2.27e-06	2.80e-01	0.2022
51755	CDK12	GSM4909296	Human	Breast	IDC	7.93e-03	-9.45e-02	0.1524
51755	CDK12	GSM4909311	Human	Breast	IDC	7.73e-08	-1.57e-01	0.1534
51755	CDK12	GSM4909312	Human	Breast	IDC	1.05e-02	-1.31e-02	0.1552
51755	CDK12	GSM4909317	Human	Breast	IDC	3.01e-05	2.11e-01	0.1355
51755	CDK12	GSM4909319	Human	Breast	IDC	2.84e-09	-8.96e-02	0.1563
51755	CDK12	GSM4909321	Human	Breast	IDC	4.34e-05	-6.52e-03	0.1559
51755	CDK12	DCIS2	Human	Breast	DCIS	5.07e-62	2.48e-01	0.0085
51755	CDK12	LZE4T	Human	Esophagus	ESCC	7.87e-22	5.84e-01	0.0811
51755	CDK12	LZE5T	Human	Esophagus	ESCC	1.75e-02	2.51e-01	0.0514
51755	CDK12	LZE7T	Human	Esophagus	ESCC	8.96e-15	5.87e-01	0.0667
51755	CDK12	LZE8T	Human	Esophagus	ESCC	1.29e-09	1.95e-01	0.067
51755	CDK12	LZE20T	Human	Esophagus	ESCC	5.75e-08	2.50e-01	0.0662
51755	CDK12	LZE21D1	Human	Esophagus	HGIN	3.29e-07	3.74e-01	0.0632
51755	CDK12	LZE22T	Human	Esophagus	ESCC	5.93e-07	2.78e-01	0.068
51755	CDK12	LZE24T	Human	Esophagus	ESCC	9.48e-29	6.81e-01	0.0596
51755	CDK12	LZE21T	Human	Esophagus	ESCC	2.29e-10	5.10e-01	0.0655

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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
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
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:000838014	Breast	IDC	RNA splicing	73/1434	434/18723	1.27e-10	1.57e-08	73
GO:004348414	Breast	IDC	regulation of RNA splicing	36/1434	148/18723	3.32e-10	3.77e-08	36
GO:000838024	Breast	DCIS	RNA splicing	73/1390	434/18723	3.05e-11	5.08e-09	73
GO:004348424	Breast	DCIS	regulation of RNA splicing	36/1390	148/18723	1.40e-10	1.69e-08	36
GO:000838026	Esophagus	HGIN	RNA splicing	160/2587	434/18723	3.74e-34	1.12e-30	160
GO:004348427	Esophagus	HGIN	regulation of RNA splicing	59/2587	148/18723	3.61e-15	7.22e-13	59
GO:00063687	Esophagus	HGIN	transcription elongation from RNA polymerase II promoter	24/2587	69/18723	8.93e-06	2.64e-04	24
GO:20007375	Esophagus	HGIN	negative regulation of stem cell differentiation	12/2587	23/18723	1.45e-05	4.02e-04	12
GO:20007365	Esophagus	HGIN	regulation of stem cell differentiation	20/2587	58/18723	5.65e-05	1.33e-03	20
GO:00063548	Esophagus	HGIN	DNA-templated transcription, elongation	27/2587	91/18723	6.62e-05	1.52e-03	27
GO:00342435	Esophagus	HGIN	regulation of transcription elongation from RNA polymerase II promoter	13/2587	32/18723	1.72e-04	3.32e-03	13
GO:00327866	Esophagus	HGIN	positive regulation of DNA-templated transcription, elongation	11/2587	27/18723	5.28e-04	7.56e-03	11
GO:00329685	Esophagus	HGIN	positive regulation of transcription elongation from RNA polymerase II promoter	7/2587	13/18723	7.61e-04	1.00e-02	7
GO:00327844	Esophagus	HGIN	regulation of DNA-templated transcription, elongation	16/2587	53/18723	1.58e-03	1.79e-02	16
GO:00708162	Esophagus	HGIN	phosphorylation of RNA polymerase II C-terminal domain	6/2587	12/18723	3.03e-03	2.88e-02	6
GO:0008380111	Esophagus	ESCC	RNA splicing	336/8552	434/18723	1.74e-42	3.67e-39	336
GO:0043484111	Esophagus	ESCC	regulation of RNA splicing	116/8552	148/18723	3.18e-16	2.38e-14	116
GO:000635414	Esophagus	ESCC	DNA-templated transcription, elongation	76/8552	91/18723	8.35e-14	4.11e-12	76
GO:007190016	Esophagus	ESCC	regulation of protein serine/threonine kinase activity	227/8552	359/18723	1.12e-11	4.10e-10	227
GO:000636814	Esophagus	ESCC	transcription elongation from RNA polymerase II promoter	56/8552	69/18723	1.40e-09	3.30e-08	56

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

CDK12

SNV

Missense_Mutation

c.3280N>T

p.Val1094Leu

p.V1094L

Q9NYV4

protein_coding

tolerated(0.3)

benign(0.01)

TCGA-A2-A0CW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

CDK12

SNV

Missense_Mutation

c.530N>T

p.Ser177Phe

p.S177F

Q9NYV4

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.966)

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

CDK12

SNV

Missense_Mutation

c.3436N>C

p.Met1146Leu

p.M1146L

Q9NYV4

protein_coding

deleterious(0.01)

benign(0)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CDK12

SNV

Missense_Mutation

rs778399102

c.4136N>G

p.Ser1379Cys

p.S1379C

Q9NYV4

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.926)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CDK12

SNV

Missense_Mutation

novel

c.2776N>A

p.Leu926Ile

p.L926I

Q9NYV4

protein_coding

deleterious(0.01)

probably_damaging(0.998)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CDK12

SNV

Missense_Mutation

c.122N>C

p.Lys41Thr

p.K41T

Q9NYV4

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.968)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CDK12

SNV

Missense_Mutation

c.256N>A

p.Asp86Asn

p.D86N

Q9NYV4

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.98)

TCGA-BH-A1FJ-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

CDK12

SNV

Missense_Mutation

c.3430N>T

p.Pro1144Ser

p.P1144S

Q9NYV4

protein_coding

tolerated(0.1)

possibly_damaging(0.877)

TCGA-C8-A12W-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

CDK12

SNV

Missense_Mutation

c.2705N>C

p.Arg902Pro

p.R902P

Q9NYV4

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-E2-A1LG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CDK12

SNV

Missense_Mutation

rs773007495

c.2816A>G

p.Asn939Ser

p.N939S

Q9NYV4

protein_coding

deleterious(0.03)

benign(0.185)

TCGA-E9-A1NH-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

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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
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE	inhibitor	375973251
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE		Cemiplimab	CEMIPLIMAB
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE	inhibitor	CHEMBL445813	AT-7519
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE		Nivolumab	NIVOLUMAB
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE		OLAPARIB	OLAPARIB	24240700
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE		Pembrolizumab	PEMBROLIZUMAB
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE	inhibitor	CHEMBL3544942	RONICICLIB
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE	inhibitor	CHEMBL488436	AZD-5438
51755	CDK12	KINASE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, ENZYME, TUMOR SUPPRESSOR, SERINE THREONINE KINASE	inhibitor	CHEMBL1230607	PHA-793887

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