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: ENPP2

Gene summary for ENPP2

Gene summary.

Gene information	Species	Human
	Gene symbol	ENPP2
	Gene ID	5168
	Gene name	ectonucleotide pyrophosphatase/phosphodiesterase 2
	Gene Alias	ATX
	Cytomap	8q24.12
	Gene Type	protein-coding
	GO ID	GO:0000902
	UniProtAcc	Q13822

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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
5168	ENPP2	HCC1_Meng	Human	Liver	HCC	5.20e-80	3.34e-01	0.0246
5168	ENPP2	HCC2_Meng	Human	Liver	HCC	1.93e-02	-1.54e-01	0.0107
5168	ENPP2	cirrhotic2	Human	Liver	Cirrhotic	1.75e-11	2.17e-01	0.0201
5168	ENPP2	HCC1	Human	Liver	HCC	3.65e-25	9.61e-01	0.5336
5168	ENPP2	HCC2	Human	Liver	HCC	3.55e-03	1.51e+00	0.5341
5168	ENPP2	S014	Human	Liver	HCC	2.03e-23	1.28e+00	0.2254
5168	ENPP2	S015	Human	Liver	HCC	8.19e-20	1.45e+00	0.2375
5168	ENPP2	S016	Human	Liver	HCC	2.87e-35	1.54e+00	0.2243
5168	ENPP2	S028	Human	Liver	HCC	6.78e-08	5.66e-01	0.2503
5168	ENPP2	S029	Human	Liver	HCC	7.60e-10	6.37e-01	0.2581
5168	ENPP2	HTA12-15-2	Human	Pancreas	PDAC	4.61e-06	5.22e-01	0.2315
5168	ENPP2	HTA12-25-1	Human	Pancreas	PDAC	3.47e-04	5.22e-01	0.313
5168	ENPP2	HTA12-26-1	Human	Pancreas	PDAC	3.84e-09	4.77e-01	0.3728
5168	ENPP2	HTA12-29-1	Human	Pancreas	PDAC	9.76e-28	6.54e-01	0.3722

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		NAFLD: Non-alcoholic fatty liver disease

∗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:002260412	Liver	Cirrhotic	regulation of cell morphogenesis	127/4634	309/18723	1.45e-10	7.44e-09	127
GO:004424212	Liver	Cirrhotic	cellular lipid catabolic process	82/4634	214/18723	6.91e-06	1.08e-04	82
GO:001604212	Liver	Cirrhotic	lipid catabolic process	112/4634	320/18723	2.31e-05	3.03e-04	112
GO:009758111	Liver	Cirrhotic	lamellipodium organization	40/4634	90/18723	3.48e-05	4.26e-04	40
GO:190274511	Liver	Cirrhotic	positive regulation of lamellipodium organization	19/4634	37/18723	4.39e-04	3.57e-03	19
GO:190274311	Liver	Cirrhotic	regulation of lamellipodium organization	25/4634	54/18723	4.63e-04	3.75e-03	25
GO:0006643	Liver	Cirrhotic	membrane lipid metabolic process	69/4634	203/18723	1.89e-03	1.19e-02	69
GO:000166712	Liver	Cirrhotic	ameboidal-type cell migration	145/4634	475/18723	2.23e-03	1.36e-02	145
GO:00106327	Liver	Cirrhotic	regulation of epithelial cell migration	93/4634	292/18723	3.46e-03	1.92e-02	93
GO:00106317	Liver	Cirrhotic	epithelial cell migration	110/4634	357/18723	5.14e-03	2.65e-02	110
GO:00901327	Liver	Cirrhotic	epithelium migration	110/4634	360/18723	6.79e-03	3.35e-02	110
GO:00901307	Liver	Cirrhotic	tissue migration	111/4634	365/18723	7.66e-03	3.61e-02	111
GO:00464341	Liver	Cirrhotic	organophosphate catabolic process	52/4634	155/18723	8.42e-03	3.91e-02	52
GO:00106346	Liver	Cirrhotic	positive regulation of epithelial cell migration	58/4634	176/18723	8.54e-03	3.96e-02	58
GO:002260422	Liver	HCC	regulation of cell morphogenesis	188/7958	309/18723	4.84e-11	1.82e-09	188
GO:004424222	Liver	HCC	cellular lipid catabolic process	134/7958	214/18723	2.07e-09	5.79e-08	134
GO:00066444	Liver	HCC	phospholipid metabolic process	214/7958	383/18723	7.25e-08	1.48e-06	214
GO:0090305	Liver	HCC	nucleic acid phosphodiester bond hydrolysis	152/7958	261/18723	1.90e-07	3.46e-06	152
GO:004648611	Liver	HCC	glycerolipid metabolic process	215/7958	392/18723	4.54e-07	7.49e-06	215
GO:003134611	Liver	HCC	positive regulation of cell projection organization	193/7958	353/18723	2.28e-06	3.08e-05	193

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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

ENPP2

SNV

Missense_Mutation

novel

c.1153G>A

p.Asp385Asn

p.D385N

Q13822

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-3C-AALI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Poly E

Complete Response

ENPP2

SNV

Missense_Mutation

c.1754N>G

p.His585Arg

p.H585R

Q13822

protein_coding

deleterious(0)

possibly_damaging(0.524)

TCGA-A2-A04Y-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ENPP2

SNV

Missense_Mutation

novel

c.1307N>A

p.Thr436Asn

p.T436N

Q13822

protein_coding

tolerated(0.22)

benign(0.124)

TCGA-A7-A6VV-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

ENPP2

SNV

Missense_Mutation

rs746187066

c.606N>T

p.Met202Ile

p.M202I

Q13822

protein_coding

deleterious(0.01)

probably_damaging(0.993)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ENPP2

SNV

Missense_Mutation

novel

c.2168N>C

p.Lys723Thr

p.K723T

Q13822

protein_coding

tolerated(0.16)

benign(0.22)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ENPP2

SNV

Missense_Mutation

c.1073N>T

p.Arg358Ile

p.R358I

Q13822

protein_coding

deleterious_low_confidence(0.02)

possibly_damaging(0.474)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ENPP2

SNV

Missense_Mutation

rs746442526

c.95N>A

p.Arg32Gln

p.R32Q

Q13822

protein_coding

deleterious(0.01)

probably_damaging(0.968)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ENPP2

SNV

Missense_Mutation

c.1450N>T

p.Arg484Cys

p.R484C

Q13822

protein_coding

deleterious(0)

probably_damaging(0.96)

TCGA-AQ-A1H2-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

herceptin

ENPP2

SNV

Missense_Mutation

novel

c.1340N>T

p.Ser447Phe

p.S447F

Q13822

protein_coding

deleterious(0)

benign(0.346)

TCGA-AR-A0TX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ENPP2

SNV

Missense_Mutation

c.2741A>G

p.Glu914Gly

p.E914G

Q13822

protein_coding

deleterious(0.02)

probably_damaging(0.94)

TCGA-BH-A0BW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

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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
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING	inhibitor	315661229
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING		NSC-12188	CHEMBL1089321	20349977
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING		(S)-CARBA CYCLIC-PHOSPHATIDIC ACID	CHEMBL1630084	21051230
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING		NSC-1741	CHEMBL483302	20349977
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING	inhibitor	354702264
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING	inhibitor	315661228
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING		NSC-34937	CHEMBL1092743	20349977
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING		NSC-1698	CHEMBL1093490	20349977
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING	inhibitor	315661227
5168	ENPP2	ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR BINDING	inhibitor	336446947	ZIRITAXESTAT

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