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: PCK2

Gene summary for PCK2

Gene summary.

Gene information	Species	Human
	Gene symbol	PCK2
	Gene ID	5106
	Gene name	phosphoenolpyruvate carboxykinase 2, mitochondrial
	Gene Alias	PEPCK
	Cytomap	14q11.2-q12
	Gene Type	protein-coding
	GO ID	GO:0001678
	UniProtAcc	A0A0A0MS74

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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
5106	PCK2	HTA11_3410_2000001011	Human	Colorectum	AD	1.83e-14	3.88e-01	0.0155
5106	PCK2	HTA11_2487_2000001011	Human	Colorectum	SER	5.48e-23	7.73e-01	-0.1808
5106	PCK2	HTA11_2951_2000001011	Human	Colorectum	AD	1.47e-02	4.14e-01	0.0216
5106	PCK2	HTA11_1938_2000001011	Human	Colorectum	AD	6.37e-14	7.46e-01	-0.0811
5106	PCK2	HTA11_78_2000001011	Human	Colorectum	AD	2.17e-10	5.61e-01	-0.1088
5106	PCK2	HTA11_347_2000001011	Human	Colorectum	AD	1.42e-35	8.68e-01	-0.1954
5106	PCK2	HTA11_411_2000001011	Human	Colorectum	SER	4.99e-11	1.29e+00	-0.2602
5106	PCK2	HTA11_3361_2000001011	Human	Colorectum	AD	1.46e-16	8.61e-01	-0.1207
5106	PCK2	HTA11_83_2000001011	Human	Colorectum	SER	2.63e-13	7.60e-01	-0.1526
5106	PCK2	HTA11_696_2000001011	Human	Colorectum	AD	8.15e-28	8.18e-01	-0.1464
5106	PCK2	HTA11_866_2000001011	Human	Colorectum	AD	5.84e-17	5.95e-01	-0.1001
5106	PCK2	HTA11_1391_2000001011	Human	Colorectum	AD	7.95e-22	7.24e-01	-0.059
5106	PCK2	HTA11_2992_2000001011	Human	Colorectum	SER	5.26e-10	1.05e+00	-0.1706
5106	PCK2	HTA11_5212_2000001011	Human	Colorectum	AD	1.43e-14	8.47e-01	-0.2061
5106	PCK2	HTA11_5216_2000001011	Human	Colorectum	SER	1.27e-11	8.99e-01	-0.1462
5106	PCK2	HTA11_546_2000001011	Human	Colorectum	AD	7.53e-11	6.04e-01	-0.0842
5106	PCK2	HTA11_7862_2000001011	Human	Colorectum	AD	7.10e-14	5.93e-01	-0.0179
5106	PCK2	HTA11_866_3004761011	Human	Colorectum	AD	6.71e-21	6.60e-01	0.096
5106	PCK2	HTA11_8622_2000001021	Human	Colorectum	SER	1.27e-05	6.46e-01	0.0528
5106	PCK2	HTA11_7663_2000001011	Human	Colorectum	SER	6.90e-06	6.05e-01	0.0131

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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
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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma

∗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:00342842	Colorectum	MSS	response to monosaccharide	70/3467	225/18723	3.27e-06	9.57e-05	70
GO:00610082	Colorectum	MSS	hepaticobiliary system development	51/3467	150/18723	4.33e-06	1.23e-04	51
GO:00018892	Colorectum	MSS	liver development	50/3467	147/18723	5.28e-06	1.44e-04	50
GO:00713222	Colorectum	MSS	cellular response to carbohydrate stimulus	53/3467	163/18723	1.23e-05	2.87e-04	53
GO:00316672	Colorectum	MSS	response to nutrient levels	125/3467	474/18723	1.24e-05	2.88e-04	125
GO:00335002	Colorectum	MSS	carbohydrate homeostasis	76/3467	259/18723	1.37e-05	3.14e-04	76
GO:00507082	Colorectum	MSS	regulation of protein secretion	78/3467	268/18723	1.47e-05	3.33e-04	78
GO:00097462	Colorectum	MSS	response to hexose	66/3467	219/18723	1.94e-05	4.18e-04	66
GO:00425932	Colorectum	MSS	glucose homeostasis	75/3467	258/18723	2.22e-05	4.69e-04	75
GO:00097492	Colorectum	MSS	response to glucose	64/3467	212/18723	2.43e-05	5.09e-04	64
GO:00093062	Colorectum	MSS	protein secretion	98/3467	359/18723	2.43e-05	5.09e-04	98
GO:00713332	Colorectum	MSS	cellular response to glucose stimulus	49/3467	151/18723	2.73e-05	5.58e-04	49
GO:00355922	Colorectum	MSS	establishment of protein localization to extracellular region	98/3467	360/18723	2.75e-05	5.58e-04	98
GO:00016782	Colorectum	MSS	cellular glucose homeostasis	54/3467	172/18723	3.11e-05	6.25e-04	54
GO:00713312	Colorectum	MSS	cellular response to hexose stimulus	49/3467	153/18723	4.01e-05	7.61e-04	49
GO:00716922	Colorectum	MSS	protein localization to extracellular region	99/3467	368/18723	4.17e-05	7.83e-04	99
GO:00060902	Colorectum	MSS	pyruvate metabolic process	37/3467	106/18723	4.48e-05	8.28e-04	37
GO:00713262	Colorectum	MSS	cellular response to monosaccharide stimulus	49/3467	154/18723	4.84e-05	8.80e-04	49
GO:19016542	Colorectum	MSS	response to ketone	58/3467	194/18723	7.70e-05	1.28e-03	58
GO:00507962	Colorectum	MSS	regulation of insulin secretion	50/3467	165/18723	1.61e-04	2.31e-03	50

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa00620	Colorectum	AD	Pyruvate metabolism	28/2092	47/8465	3.71e-07	5.41e-06	3.45e-06	28
hsa00020	Colorectum	AD	Citrate cycle (TCA cycle)	20/2092	30/8465	1.43e-06	1.77e-05	1.13e-05	20
hsa00010	Colorectum	AD	Glycolysis / Gluconeogenesis	34/2092	67/8465	3.63e-06	4.34e-05	2.77e-05	34
hsa04152	Colorectum	AD	AMPK signaling pathway	47/2092	121/8465	3.74e-04	2.82e-03	1.80e-03	47
hsa04922	Colorectum	AD	Glucagon signaling pathway	41/2092	107/8465	1.18e-03	7.75e-03	4.94e-03	41
hsa04964	Colorectum	AD	Proximal tubule bicarbonate reclamation	11/2092	23/8465	1.35e-02	4.86e-02	3.10e-02	11
hsa006201	Colorectum	AD	Pyruvate metabolism	28/2092	47/8465	3.71e-07	5.41e-06	3.45e-06	28
hsa000201	Colorectum	AD	Citrate cycle (TCA cycle)	20/2092	30/8465	1.43e-06	1.77e-05	1.13e-05	20
hsa000101	Colorectum	AD	Glycolysis / Gluconeogenesis	34/2092	67/8465	3.63e-06	4.34e-05	2.77e-05	34
hsa041521	Colorectum	AD	AMPK signaling pathway	47/2092	121/8465	3.74e-04	2.82e-03	1.80e-03	47
hsa049221	Colorectum	AD	Glucagon signaling pathway	41/2092	107/8465	1.18e-03	7.75e-03	4.94e-03	41
hsa049641	Colorectum	AD	Proximal tubule bicarbonate reclamation	11/2092	23/8465	1.35e-02	4.86e-02	3.10e-02	11
hsa006202	Colorectum	SER	Pyruvate metabolism	22/1580	47/8465	9.62e-06	1.33e-04	9.67e-05	22
hsa000202	Colorectum	SER	Citrate cycle (TCA cycle)	16/1580	30/8465	2.06e-05	2.74e-04	1.99e-04	16
hsa049222	Colorectum	SER	Glucagon signaling pathway	38/1580	107/8465	2.57e-05	3.28e-04	2.38e-04	38
hsa000102	Colorectum	SER	Glycolysis / Gluconeogenesis	24/1580	67/8465	6.62e-04	5.36e-03	3.89e-03	24
hsa049642	Colorectum	SER	Proximal tubule bicarbonate reclamation	10/1580	23/8465	5.33e-03	3.28e-02	2.38e-02	10
hsa006203	Colorectum	SER	Pyruvate metabolism	22/1580	47/8465	9.62e-06	1.33e-04	9.67e-05	22
hsa000203	Colorectum	SER	Citrate cycle (TCA cycle)	16/1580	30/8465	2.06e-05	2.74e-04	1.99e-04	16
hsa049223	Colorectum	SER	Glucagon signaling pathway	38/1580	107/8465	2.57e-05	3.28e-04	2.38e-04	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

PCK2

SNV

Missense_Mutation

c.1014N>C

p.Glu338Asp

p.E338D

Q16822

protein_coding

tolerated(1)

benign(0.003)

TCGA-BH-A0E2-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

PCK2

SNV

Missense_Mutation

rs559309673

c.1285C>T

p.Arg429Cys

p.R429C

Q16822

protein_coding

deleterious(0.02)

possibly_damaging(0.785)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PCK2

SNV

Missense_Mutation

c.1270N>C

p.Phe424Leu

p.F424L

Q16822

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-D8-A1JK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PCK2

SNV

Missense_Mutation

novel

c.530N>G

p.Gln177Arg

p.Q177R

Q16822

protein_coding

deleterious(0.02)

probably_damaging(0.993)

TCGA-E9-A1ND-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

aromasin

PCK2

SNV

Missense_Mutation

c.1334N>A

p.Pro445His

p.P445H

Q16822

protein_coding

deleterious(0)

possibly_damaging(0.456)

TCGA-E9-A22E-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphane

PCK2

insertion

Nonsense_Mutation

novel

c.1621_1622insTTTACTAACACCATCATTAA

p.Gly541ValfsTer3

p.G541Vfs*3

Q16822

protein_coding

TCGA-A8-A092-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

PCK2

SNV

Missense_Mutation

rs201059299

c.157N>T

p.Arg53Cys

p.R53C

Q16822

protein_coding

deleterious(0.01)

possibly_damaging(0.606)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PCK2

SNV

Missense_Mutation

c.996N>C

p.Trp332Cys

p.W332C

Q16822

protein_coding

deleterious(0)

probably_damaging(0.987)

TCGA-JX-A3Q0-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

PCK2

SNV

Missense_Mutation

rs2229660

c.92N>A

p.Arg31Gln

p.R31Q

Q16822

protein_coding

tolerated(0.54)

benign(0.011)

TCGA-MU-A8JM-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

PCK2

SNV

Missense_Mutation

rs765912476

c.311G>A

p.Arg104Gln

p.R104Q

Q16822

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AA-3663-01

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

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