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: HIPK2

Gene summary for HIPK2

Gene summary.

Gene information	Species	Human
	Gene symbol	HIPK2
	Gene ID	28996
	Gene name	homeodomain interacting protein kinase 2
	Gene Alias	PRO0593
	Cytomap	7q34
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	Q9H2X6

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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
28996	HIPK2	HTA11_1938_2000001011	Human	Colorectum	AD	1.64e-02	4.24e-01	-0.0811
28996	HIPK2	HTA11_78_2000001011	Human	Colorectum	AD	4.10e-04	5.89e-01	-0.1088
28996	HIPK2	HTA11_347_2000001011	Human	Colorectum	AD	3.08e-07	5.58e-01	-0.1954
28996	HIPK2	HTA11_696_2000001011	Human	Colorectum	AD	3.85e-03	3.64e-01	-0.1464
28996	HIPK2	HTA11_1391_2000001011	Human	Colorectum	AD	2.51e-03	5.17e-01	-0.059
28996	HIPK2	HTA11_7696_3000711011	Human	Colorectum	AD	9.47e-03	3.65e-01	0.0674
28996	HIPK2	HTA11_99999965062_69753	Human	Colorectum	MSI-H	6.35e-03	9.82e-01	0.3487
28996	HIPK2	A015-C-203	Human	Colorectum	FAP	3.47e-13	-1.54e-01	-0.1294
28996	HIPK2	A015-C-204	Human	Colorectum	FAP	3.93e-02	-1.25e-01	-0.0228
28996	HIPK2	A002-C-201	Human	Colorectum	FAP	1.24e-05	-4.85e-02	0.0324
28996	HIPK2	A002-C-203	Human	Colorectum	FAP	1.28e-02	2.25e-01	0.2786
28996	HIPK2	A001-C-108	Human	Colorectum	FAP	5.44e-07	-9.74e-02	-0.0272
28996	HIPK2	A002-C-021	Human	Colorectum	FAP	8.78e-03	2.96e-01	0.1171
28996	HIPK2	A002-C-205	Human	Colorectum	FAP	1.32e-12	-1.10e-01	-0.1236
28996	HIPK2	A015-C-006	Human	Colorectum	FAP	3.04e-10	-2.84e-01	-0.0994
28996	HIPK2	A015-C-106	Human	Colorectum	FAP	3.60e-04	-3.09e-02	-0.0511
28996	HIPK2	A002-C-114	Human	Colorectum	FAP	9.32e-11	-6.80e-02	-0.1561
28996	HIPK2	A015-C-104	Human	Colorectum	FAP	6.74e-16	-6.46e-02	-0.1899
28996	HIPK2	A001-C-014	Human	Colorectum	FAP	1.36e-04	-1.06e-01	0.0135
28996	HIPK2	A002-C-016	Human	Colorectum	FAP	1.35e-09	-1.54e-01	0.0521

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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
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
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:005140316	Oral cavity	OSCC	stress-activated MAPK cascade	134/7305	239/18723	6.02e-08	1.09e-06	134
GO:00715598	Oral cavity	OSCC	response to transforming growth factor beta	140/7305	256/18723	2.34e-07	3.70e-06	140
GO:00715608	Oral cavity	OSCC	cellular response to transforming growth factor beta stimulus	137/7305	250/18723	2.68e-07	4.15e-06	137
GO:007030210	Oral cavity	OSCC	regulation of stress-activated protein kinase signaling cascade	111/7305	195/18723	2.82e-07	4.34e-06	111
GO:003021820	Oral cavity	OSCC	erythrocyte differentiation	74/7305	120/18723	4.09e-07	6.06e-06	74
GO:005140217	Oral cavity	OSCC	neuron apoptotic process	134/7305	246/18723	5.65e-07	8.19e-06	134
GO:003287210	Oral cavity	OSCC	regulation of stress-activated MAPK cascade	108/7305	192/18723	8.97e-07	1.22e-05	108
GO:00510907	Oral cavity	OSCC	regulation of DNA-binding transcription factor activity	221/7305	440/18723	9.06e-07	1.23e-05	221
GO:004586120	Oral cavity	OSCC	negative regulation of proteolysis	181/7305	351/18723	1.01e-06	1.37e-05	181
GO:00182098	Oral cavity	OSCC	peptidyl-serine modification	175/7305	338/18723	1.09e-06	1.46e-05	175
GO:001810510	Oral cavity	OSCC	peptidyl-serine phosphorylation	164/7305	315/18723	1.51e-06	1.99e-05	164
GO:200005919	Oral cavity	OSCC	negative regulation of ubiquitin-dependent protein catabolic process	35/7305	48/18723	1.93e-06	2.47e-05	35
GO:00071798	Oral cavity	OSCC	transforming growth factor beta receptor signaling pathway	109/7305	198/18723	3.21e-06	3.86e-05	109
GO:190336317	Oral cavity	OSCC	negative regulation of cellular protein catabolic process	49/7305	75/18723	3.49e-06	4.15e-05	49
GO:003209210	Oral cavity	OSCC	positive regulation of protein binding	54/7305	85/18723	4.05e-06	4.71e-05	54
GO:007145317	Oral cavity	OSCC	cellular response to oxygen levels	98/7305	177/18723	7.10e-06	7.75e-05	98
GO:003033018	Oral cavity	OSCC	DNA damage response, signal transduction by p53 class mediator	46/7305	72/18723	1.66e-05	1.64e-04	46
GO:00714569	Oral cavity	OSCC	cellular response to hypoxia	84/7305	151/18723	2.46e-05	2.30e-04	84
GO:00510917	Oral cavity	OSCC	positive regulation of DNA-binding transcription factor activity	134/7305	260/18723	2.52e-05	2.35e-04	134
GO:003629417	Oral cavity	OSCC	cellular response to decreased oxygen levels	88/7305	161/18723	3.91e-05	3.43e-04	88

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04218	Colorectum	AD	Cellular senescence	53/2092	156/8465	5.55e-03	2.48e-02	1.58e-02	53
hsa042181	Colorectum	AD	Cellular senescence	53/2092	156/8465	5.55e-03	2.48e-02	1.58e-02	53
hsa042184	Colorectum	FAP	Cellular senescence	42/1404	156/8465	6.79e-04	4.63e-03	2.82e-03	42
hsa042185	Colorectum	FAP	Cellular senescence	42/1404	156/8465	6.79e-04	4.63e-03	2.82e-03	42
hsa0421816	Endometrium	AEH	Cellular senescence	37/1197	156/8465	8.49e-04	5.52e-03	4.04e-03	37
hsa0421817	Endometrium	AEH	Cellular senescence	37/1197	156/8465	8.49e-04	5.52e-03	4.04e-03	37
hsa0421825	Endometrium	EEC	Cellular senescence	40/1237	156/8465	1.89e-04	1.68e-03	1.25e-03	40
hsa0421835	Endometrium	EEC	Cellular senescence	40/1237	156/8465	1.89e-04	1.68e-03	1.25e-03	40
hsa0421829	Esophagus	ESCC	Cellular senescence	119/4205	156/8465	5.89e-12	9.40e-11	4.81e-11	119
hsa0421838	Esophagus	ESCC	Cellular senescence	119/4205	156/8465	5.89e-12	9.40e-11	4.81e-11	119
hsa042187	Liver	Cirrhotic	Cellular senescence	66/2530	156/8465	5.94e-04	3.60e-03	2.22e-03	66
hsa0421812	Liver	Cirrhotic	Cellular senescence	66/2530	156/8465	5.94e-04	3.60e-03	2.22e-03	66
hsa0421822	Liver	HCC	Cellular senescence	102/4020	156/8465	4.18e-06	3.59e-05	2.00e-05	102
hsa0421832	Liver	HCC	Cellular senescence	102/4020	156/8465	4.18e-06	3.59e-05	2.00e-05	102
hsa042188	Lung	IAC	Cellular senescence	40/1053	156/8465	4.44e-06	1.44e-04	9.59e-05	40
hsa0421813	Lung	IAC	Cellular senescence	40/1053	156/8465	4.44e-06	1.44e-04	9.59e-05	40
hsa0421823	Lung	AIS	Cellular senescence	35/961	156/8465	5.09e-05	7.85e-04	5.03e-04	35
hsa0421833	Lung	AIS	Cellular senescence	35/961	156/8465	5.09e-05	7.85e-04	5.03e-04	35
hsa0421820	Oral cavity	OSCC	Cellular senescence	112/3704	156/8465	8.04e-13	1.42e-11	7.21e-12	112
hsa04218110	Oral cavity	OSCC	Cellular senescence	112/3704	156/8465	8.04e-13	1.42e-11	7.21e-12	112

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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

HIPK2

SNV

Missense_Mutation

c.1945N>C

p.Asp649His

p.D649H

Q9H2X6

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-A7-A26H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

HIPK2

SNV

Missense_Mutation

rs764542823

c.350G>A

p.Arg117Gln

p.R117Q

Q9H2X6

protein_coding

tolerated(0.2)

probably_damaging(0.978)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HIPK2

SNV

Missense_Mutation

novel

c.2665N>G

p.Thr889Ala

p.T889A

Q9H2X6

protein_coding

deleterious(0)

probably_damaging(0.952)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

HIPK2

SNV

Missense_Mutation

c.1477N>A

p.Glu493Lys

p.E493K

Q9H2X6

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-AR-A0TZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

Doxorubicin

HIPK2

SNV

Missense_Mutation

c.2108C>G

p.Ala703Gly

p.A703G

Q9H2X6

protein_coding

deleterious(0)

benign(0.108)

TCGA-AR-A0U2-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

tamoxiphen

HIPK2

SNV

Missense_Mutation

rs747709692

c.280N>A

p.Val94Met

p.V94M

Q9H2X6

protein_coding

deleterious(0.01)

probably_damaging(0.994)

TCGA-AR-A2LN-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

letrozole

HIPK2

SNV

Missense_Mutation

c.47N>G

p.Ser16Cys

p.S16C

Q9H2X6

protein_coding

deleterious(0.02)

probably_damaging(0.993)

TCGA-B6-A3ZX-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

HIPK2

SNV

Missense_Mutation

c.2220N>C

p.Glu740Asp

p.E740D

Q9H2X6

protein_coding

tolerated(0.99)

benign(0.001)

TCGA-BH-A18P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HIPK2

SNV

Missense_Mutation

rs773782325

c.140N>C

p.His47Pro

p.H47P

Q9H2X6

protein_coding

tolerated(0.1)

possibly_damaging(0.71)

TCGA-C8-A1HO-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

5-fluorouracil

HIPK2

SNV

Missense_Mutation

rs773782325

c.140N>C

p.His47Pro

p.H47P

Q9H2X6

protein_coding

tolerated(0.1)

possibly_damaging(0.71)

TCGA-D8-A1JI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

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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
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME	inhibitor	249565808
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		TAMATINIB	R-406
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		PI-103	PI-103
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		GSK-269962A	GSK-269962A
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		CENISERTIB	CENISERTIB
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		BAY-613606	CHEMBL541400
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		ILORASERTIB	ILORASERTIB
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		PF-562271	PF-00562271
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		PHA-767491	CHEMBL225519
28996	HIPK2	TYROSINE KINASE, SERINE THREONINE KINASE, TUMOR SUPPRESSOR, KINASE, TRANSCRIPTION FACTOR, DRUGGABLE GENOME, ENZYME		SP-600125	SP-600125

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