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: SIK2

Gene summary for SIK2

Gene summary.

Gene information	Species	Human
	Gene symbol	SIK2
	Gene ID	23235
	Gene name	salt inducible kinase 2
	Gene Alias	LOH11CR1I
	Cytomap	11q23.1
	Gene Type	protein-coding
	GO ID	GO:0006464
	UniProtAcc	A0A024R3G7

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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
23235	SIK2	HTA11_3410_2000001011	Human	Colorectum	AD	1.71e-02	-3.52e-01	0.0155
23235	SIK2	HTA11_347_2000001011	Human	Colorectum	AD	6.43e-07	4.04e-01	-0.1954
23235	SIK2	HTA11_99999974143_84620	Human	Colorectum	MSS	4.48e-09	-4.24e-01	0.3005
23235	SIK2	A015-C-203	Human	Colorectum	FAP	5.64e-27	-5.21e-01	-0.1294
23235	SIK2	A015-C-204	Human	Colorectum	FAP	5.93e-05	-3.45e-01	-0.0228
23235	SIK2	A014-C-040	Human	Colorectum	FAP	5.51e-05	-5.58e-01	-0.1184
23235	SIK2	A002-C-201	Human	Colorectum	FAP	2.21e-13	-3.98e-01	0.0324
23235	SIK2	A002-C-203	Human	Colorectum	FAP	7.77e-03	-1.50e-01	0.2786
23235	SIK2	A001-C-119	Human	Colorectum	FAP	8.85e-04	-3.36e-01	-0.1557
23235	SIK2	A001-C-108	Human	Colorectum	FAP	1.91e-13	-3.14e-01	-0.0272
23235	SIK2	A002-C-205	Human	Colorectum	FAP	2.92e-22	-4.97e-01	-0.1236
23235	SIK2	A001-C-104	Human	Colorectum	FAP	2.44e-02	-2.17e-01	0.0184
23235	SIK2	A015-C-005	Human	Colorectum	FAP	9.91e-04	-2.62e-01	-0.0336
23235	SIK2	A015-C-006	Human	Colorectum	FAP	8.85e-16	-6.14e-01	-0.0994
23235	SIK2	A015-C-106	Human	Colorectum	FAP	7.25e-11	-3.18e-01	-0.0511
23235	SIK2	A002-C-114	Human	Colorectum	FAP	2.89e-20	-6.00e-01	-0.1561
23235	SIK2	A015-C-104	Human	Colorectum	FAP	1.59e-29	-4.81e-01	-0.1899
23235	SIK2	A001-C-014	Human	Colorectum	FAP	1.09e-12	-3.45e-01	0.0135
23235	SIK2	A002-C-016	Human	Colorectum	FAP	3.54e-21	-4.32e-01	0.0521
23235	SIK2	A015-C-002	Human	Colorectum	FAP	3.71e-11	-5.14e-01	-0.0763

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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
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

∗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:007137513	Endometrium	EEC	cellular response to peptide hormone stimulus	52/2168	290/18723	8.77e-04	8.01e-03	52
GO:003286914	Endometrium	EEC	cellular response to insulin stimulus	39/2168	203/18723	9.93e-04	8.79e-03	39
GO:003166816	Endometrium	EEC	cellular response to extracellular stimulus	45/2168	246/18723	1.24e-03	1.03e-02	45
GO:000828613	Endometrium	EEC	insulin receptor signaling pathway	25/2168	116/18723	1.50e-03	1.21e-02	25
GO:000926715	Endometrium	EEC	cellular response to starvation	31/2168	156/18723	1.80e-03	1.39e-02	31
GO:003286814	Endometrium	EEC	response to insulin	46/2168	264/18723	3.01e-03	2.10e-02	46
GO:004259414	Endometrium	EEC	response to starvation	36/2168	197/18723	3.66e-03	2.45e-02	36
GO:00467777	Endometrium	EEC	protein autophosphorylation	39/2168	227/18723	7.52e-03	4.21e-02	39
GO:00713755	Liver	NAFLD	cellular response to peptide hormone stimulus	65/1882	290/18723	3.95e-10	9.62e-08	65
GO:19016536	Liver	NAFLD	cellular response to peptide	71/1882	359/18723	1.82e-08	2.09e-06	71
GO:00328695	Liver	NAFLD	cellular response to insulin stimulus	47/1882	203/18723	3.60e-08	3.63e-06	47
GO:00316677	Liver	NAFLD	response to nutrient levels	85/1882	474/18723	8.23e-08	7.09e-06	85
GO:00434346	Liver	NAFLD	response to peptide hormone	76/1882	414/18723	1.51e-07	1.09e-05	76
GO:00328685	Liver	NAFLD	response to insulin	53/1882	264/18723	6.99e-07	3.95e-05	53
GO:00082863	Liver	NAFLD	insulin receptor signaling pathway	27/1882	116/18723	2.50e-05	6.76e-04	27
GO:00714967	Liver	NAFLD	cellular response to external stimulus	51/1882	320/18723	6.21e-04	8.18e-03	51
GO:0046626	Liver	NAFLD	regulation of insulin receptor signaling pathway	16/1882	66/18723	6.66e-04	8.61e-03	16
GO:00425945	Liver	NAFLD	response to starvation	33/1882	197/18723	2.35e-03	2.21e-02	33
GO:004259412	Liver	Cirrhotic	response to starvation	87/4634	197/18723	1.85e-09	7.78e-08	87
GO:003166712	Liver	Cirrhotic	response to nutrient levels	174/4634	474/18723	3.08e-09	1.27e-07	174

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04922	Colorectum	AD	Glucagon signaling pathway	41/2092	107/8465	1.18e-03	7.75e-03	4.94e-03	41
hsa049221	Colorectum	AD	Glucagon signaling pathway	41/2092	107/8465	1.18e-03	7.75e-03	4.94e-03	41
hsa049226	Colorectum	FAP	Glucagon signaling pathway	32/1404	107/8465	4.08e-04	3.10e-03	1.89e-03	32
hsa049227	Colorectum	FAP	Glucagon signaling pathway	32/1404	107/8465	4.08e-04	3.10e-03	1.89e-03	32
hsa049228	Colorectum	CRC	Glucagon signaling pathway	24/1091	107/8465	4.21e-03	2.47e-02	1.67e-02	24
hsa049229	Colorectum	CRC	Glucagon signaling pathway	24/1091	107/8465	4.21e-03	2.47e-02	1.67e-02	24
hsa0492210	Liver	NAFLD	Glucagon signaling pathway	24/1043	107/8465	2.33e-03	2.46e-02	1.99e-02	24
hsa0492211	Liver	NAFLD	Glucagon signaling pathway	24/1043	107/8465	2.33e-03	2.46e-02	1.99e-02	24
hsa0492221	Liver	Cirrhotic	Glucagon signaling pathway	43/2530	107/8465	1.42e-02	4.35e-02	2.68e-02	43
hsa0492231	Liver	Cirrhotic	Glucagon signaling pathway	43/2530	107/8465	1.42e-02	4.35e-02	2.68e-02	43
hsa0492241	Liver	HCC	Glucagon signaling pathway	64/4020	107/8465	6.70e-03	1.87e-02	1.04e-02	64
hsa0492251	Liver	HCC	Glucagon signaling pathway	64/4020	107/8465	6.70e-03	1.87e-02	1.04e-02	64

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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

SIK2

SNV

Missense_Mutation

c.1006N>T

p.Arg336Cys

p.R336C

Q9H0K1

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

SIK2

SNV

Missense_Mutation

c.2608N>A

p.Asp870Asn

p.D870N

Q9H0K1

protein_coding

tolerated_low_confidence(0.14)

benign(0.001)

TCGA-D8-A1XW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin+cyclophosphamide

SIK2

insertion

Nonsense_Mutation

novel

c.2713_2714insATTCCTTATAGGCAAGTAGCTTT

p.Gly905AspfsTer4

p.G905Dfs*4

Q9H0K1

protein_coding

TCGA-A8-A07G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

5-fluorouracil

SIK2

insertion

Frame_Shift_Ins

novel

c.2338_2339insAAGATCTAACTCCACCTTTCTCATTG

p.Pro780GlnfsTer107

p.P780Qfs*107

Q9H0K1

protein_coding

TCGA-AO-A0JJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophospamide

SIK2

insertion

Frame_Shift_Ins

novel

c.2428_2429insACCTGGCTTCTTTCTTT

p.Ala810AspfsTer74

p.A810Dfs*74

Q9H0K1

protein_coding

TCGA-BH-A0B8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

SIK2

deletion

Frame_Shift_Del

novel

c.1749delN

p.Arg584AlafsTer13

p.R584Afs*13

Q9H0K1

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

SIK2

SNV

Missense_Mutation

c.498N>G

p.Phe166Leu

p.F166L

Q9H0K1

protein_coding

deleterious(0.04)

possibly_damaging(0.884)

TCGA-DR-A0ZL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

SIK2

SNV

Missense_Mutation

c.1879N>A

p.Glu627Lys

p.E627K

Q9H0K1

protein_coding

tolerated(0.35)

benign(0.014)

TCGA-DR-A0ZM-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unspecific

Cisplatin

SIK2

SNV

Missense_Mutation

c.243A>T

p.Lys81Asn

p.K81N

Q9H0K1

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-EA-A5FO-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

SIK2

SNV

Missense_Mutation

novel

c.820N>A

p.Glu274Lys

p.E274K

Q9H0K1

protein_coding

deleterious(0.03)

benign(0.277)

TCGA-IR-A3LK-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

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
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	340590212
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		PF-562271	PF-00562271
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	178102336	BOSUTINIB
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	249565729
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		TAMATINIB	R-406
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		JNJ-7706621	JNJ-7706621
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		DASATINIB	DASATINIB
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		DOVITINIB	DOVITINIB
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		GEFITINIB	GEFITINIB
23235	SIK2	SERINE THREONINE KINASE, KINASE, DRUGGABLE GENOME, ENZYME		SB-203580	SB-203580

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