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: PRKAG2

Gene summary for PRKAG2

Gene summary.

Gene information	Species	Human
	Gene symbol	PRKAG2
	Gene ID	51422
	Gene name	protein kinase AMP-activated non-catalytic subunit gamma 2
	Gene Alias	AAKG
	Cytomap	7q36.1
	Gene Type	protein-coding
	GO ID	GO:0001932
	UniProtAcc	Q9UGJ0

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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
51422	PRKAG2	HTA11_3410_2000001011	Human	Colorectum	AD	8.29e-20	-7.16e-01	0.0155
51422	PRKAG2	HTA11_2487_2000001011	Human	Colorectum	SER	1.35e-02	-4.90e-01	-0.1808
51422	PRKAG2	HTA11_2951_2000001011	Human	Colorectum	AD	2.19e-07	-9.48e-01	0.0216
51422	PRKAG2	HTA11_1938_2000001011	Human	Colorectum	AD	1.97e-06	-5.77e-01	-0.0811
51422	PRKAG2	HTA11_3361_2000001011	Human	Colorectum	AD	2.09e-05	-6.06e-01	-0.1207
51422	PRKAG2	HTA11_696_2000001011	Human	Colorectum	AD	7.22e-03	-1.89e-01	-0.1464
51422	PRKAG2	HTA11_5212_2000001011	Human	Colorectum	AD	1.14e-06	-7.61e-01	-0.2061
51422	PRKAG2	HTA11_5216_2000001011	Human	Colorectum	SER	3.42e-02	-6.06e-01	-0.1462
51422	PRKAG2	HTA11_9341_2000001011	Human	Colorectum	SER	3.05e-03	-4.85e-01	-0.00410000000000005
51422	PRKAG2	HTA11_866_3004761011	Human	Colorectum	AD	4.24e-29	-8.72e-01	0.096
51422	PRKAG2	HTA11_8622_2000001021	Human	Colorectum	SER	2.43e-02	-4.01e-01	0.0528
51422	PRKAG2	HTA11_10711_2000001011	Human	Colorectum	AD	1.51e-10	-6.98e-01	0.0338
51422	PRKAG2	HTA11_7696_3000711011	Human	Colorectum	AD	8.42e-09	-5.21e-01	0.0674
51422	PRKAG2	HTA11_6818_2000001021	Human	Colorectum	AD	2.58e-05	-6.29e-01	0.0588
51422	PRKAG2	HTA11_99999970781_79442	Human	Colorectum	MSS	6.88e-58	-1.07e+00	0.294
51422	PRKAG2	HTA11_99999965104_69814	Human	Colorectum	MSS	1.88e-08	-5.47e-01	0.281
51422	PRKAG2	HTA11_99999971662_82457	Human	Colorectum	MSS	2.85e-47	-9.96e-01	0.3859
51422	PRKAG2	HTA11_99999973899_84307	Human	Colorectum	MSS	2.38e-16	-1.02e+00	0.2585
51422	PRKAG2	HTA11_99999974143_84620	Human	Colorectum	MSS	6.62e-68	-1.17e+00	0.3005
51422	PRKAG2	F007	Human	Colorectum	FAP	6.31e-21	-9.90e-01	0.1176

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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
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
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:0046034	Colorectum	AD	ATP metabolic process	142/3918	277/18723	2.64e-29	8.26e-26	142
GO:0006091	Colorectum	AD	generation of precursor metabolites and energy	209/3918	490/18723	3.17e-28	6.61e-25	209
GO:0015980	Colorectum	AD	energy derivation by oxidation of organic compounds	143/3918	318/18723	2.78e-22	2.49e-19	143
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:0009144	Colorectum	AD	purine nucleoside triphosphate metabolic process	43/3918	88/18723	5.05e-09	3.19e-07	43
GO:0009135	Colorectum	AD	purine nucleoside diphosphate metabolic process	47/3918	103/18723	1.61e-08	9.22e-07	47
GO:0009179	Colorectum	AD	purine ribonucleoside diphosphate metabolic process	47/3918	103/18723	1.61e-08	9.22e-07	47
GO:0006090	Colorectum	AD	pyruvate metabolic process	47/3918	106/18723	4.85e-08	2.55e-06	47
GO:0009185	Colorectum	AD	ribonucleoside diphosphate metabolic process	47/3918	106/18723	4.85e-08	2.55e-06	47
GO:0009205	Colorectum	AD	purine ribonucleoside triphosphate metabolic process	39/3918	82/18723	6.58e-08	3.40e-06	39
GO:0009141	Colorectum	AD	nucleoside triphosphate metabolic process	48/3918	112/18723	1.27e-07	6.02e-06	48
GO:0006754	Colorectum	AD	ATP biosynthetic process	30/3918	57/18723	1.27e-07	6.02e-06	30
GO:0046031	Colorectum	AD	ADP metabolic process	41/3918	90/18723	1.37e-07	6.42e-06	41
GO:0006096	Colorectum	AD	glycolytic process	38/3918	81/18723	1.52e-07	6.78e-06	38

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04714	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa04932	Colorectum	AD	Non-alcoholic fatty liver disease	90/2092	155/8465	4.83e-19	1.80e-17	1.15e-17	90
hsa04530	Colorectum	AD	Tight junction	76/2092	169/8465	5.49e-09	9.69e-08	6.18e-08	76
hsa04152	Colorectum	AD	AMPK signaling pathway	47/2092	121/8465	3.74e-04	2.82e-03	1.80e-03	47
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
hsa04211	Colorectum	AD	Longevity regulating pathway	33/2092	89/8465	6.15e-03	2.68e-02	1.71e-02	33
hsa047141	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa049321	Colorectum	AD	Non-alcoholic fatty liver disease	90/2092	155/8465	4.83e-19	1.80e-17	1.15e-17	90
hsa045301	Colorectum	AD	Tight junction	76/2092	169/8465	5.49e-09	9.69e-08	6.18e-08	76
hsa041521	Colorectum	AD	AMPK signaling pathway	47/2092	121/8465	3.74e-04	2.82e-03	1.80e-03	47
hsa042131	Colorectum	AD	Longevity regulating pathway - multiple species	27/2092	62/8465	8.72e-04	5.96e-03	3.80e-03	27
hsa049221	Colorectum	AD	Glucagon signaling pathway	41/2092	107/8465	1.18e-03	7.75e-03	4.94e-03	41
hsa042111	Colorectum	AD	Longevity regulating pathway	33/2092	89/8465	6.15e-03	2.68e-02	1.71e-02	33
hsa047142	Colorectum	SER	Thermogenesis	106/1580	232/8465	1.15e-21	6.34e-20	4.61e-20	106
hsa049322	Colorectum	SER	Non-alcoholic fatty liver disease	75/1580	155/8465	2.16e-17	5.99e-16	4.35e-16	75
hsa045302	Colorectum	SER	Tight junction	59/1580	169/8465	3.24e-07	5.98e-06	4.34e-06	59
hsa049222	Colorectum	SER	Glucagon signaling pathway	38/1580	107/8465	2.57e-05	3.28e-04	2.38e-04	38
hsa042132	Colorectum	SER	Longevity regulating pathway - multiple species	20/1580	62/8465	7.15e-03	3.77e-02	2.74e-02	20
hsa047143	Colorectum	SER	Thermogenesis	106/1580	232/8465	1.15e-21	6.34e-20	4.61e-20	106

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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

PRKAG2

SNV

Missense_Mutation

novel

c.1024N>A

p.Glu342Lys

p.E342K

Q9UGJ0

protein_coding

deleterious(0.01)

probably_damaging(0.944)

TCGA-AC-A62V-01

Breast

breast invasive carcinoma

Male

<65

III/IV

Targeted Molecular therapy

denosumab

PRKAG2

SNV

Missense_Mutation

c.64G>A

p.Gly22Ser

p.G22S

Q9UGJ0

protein_coding

tolerated_low_confidence(0.89)

benign(0.01)

TCGA-BH-A0W4-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PRKAG2

SNV

Missense_Mutation

novel

c.257C>A

p.Ser86Tyr

p.S86Y

Q9UGJ0

protein_coding

deleterious_low_confidence(0)

possibly_damaging(0.735)

TCGA-C8-A8HQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PRKAG2

insertion

Frame_Shift_Ins

novel

c.1024_1025insTA

p.Glu342ValfsTer21

p.E342Vfs*21

Q9UGJ0

protein_coding

TCGA-A8-A0A4-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

PRKAG2

insertion

Frame_Shift_Ins

novel

c.1023_1024insCCCACAAAAGAATCCTCAAGTTCCTCCAGCTTTTT

p.Glu342ProfsTer32

p.E342Pfs*32

Q9UGJ0

protein_coding

TCGA-A8-A0A4-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

PRKAG2

SNV

Missense_Mutation

c.1240G>C

p.Asp414His

p.D414H

Q9UGJ0

protein_coding

deleterious(0.03)

benign(0.007)

TCGA-DR-A0ZM-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unspecific

Cisplatin

PRKAG2

SNV

Missense_Mutation

c.769N>C

p.Glu257Gln

p.E257Q

Q9UGJ0

protein_coding

tolerated(0.07)

benign(0.109)

TCGA-FU-A23L-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PRKAG2

SNV

Missense_Mutation

c.223N>A

p.Gly75Arg

p.G75R

Q9UGJ0

protein_coding

deleterious_low_confidence(0)

benign(0.352)

TCGA-R2-A69V-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PRKAG2

SNV

Missense_Mutation

rs730880970

c.202G>A

p.Gly68Ser

p.G68S

Q9UGJ0

protein_coding

tolerated_low_confidence(0.51)

benign(0)

TCGA-AU-6004-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

PRKAG2

SNV

Missense_Mutation

rs397517269

c.313N>A

p.Val105Met

p.V105M

Q9UGJ0

protein_coding

deleterious_low_confidence(0.04)

benign(0.031)

TCGA-CM-5862-01

Colorectum

colon adenocarcinoma

Male

>=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
51422	PRKAG2	ENZYME, KINASE		SAPONARIN	SAPONARIN	26471090
51422	PRKAG2	ENZYME, KINASE		METFORMIN	METFORMIN	26471090
51422	PRKAG2	ENZYME, KINASE		hydrochlorothiazide	HYDROCHLOROTHIAZIDE	31327267
51422	PRKAG2	ENZYME, KINASE		metformin	METFORMIN	22722338

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