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: ASL

Gene summary for ASL

Gene summary.

Gene information	Species	Human
	Gene symbol	ASL
	Gene ID	435
	Gene name	argininosuccinate lyase
	Gene Alias	ASAL
	Cytomap	7q11.21
	Gene Type	protein-coding
	GO ID	GO:0000050
	UniProtAcc	A0A024RDL8

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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
435	ASL	P52T-E	Human	Esophagus	ESCC	2.06e-23	5.06e-01	0.1555
435	ASL	P54T-E	Human	Esophagus	ESCC	1.82e-26	5.51e-01	0.0975
435	ASL	P56T-E	Human	Esophagus	ESCC	4.22e-03	3.74e-01	0.1613
435	ASL	P57T-E	Human	Esophagus	ESCC	1.44e-16	3.48e-01	0.0926
435	ASL	P61T-E	Human	Esophagus	ESCC	3.68e-33	6.01e-01	0.099
435	ASL	P62T-E	Human	Esophagus	ESCC	4.09e-29	5.44e-01	0.1302
435	ASL	P65T-E	Human	Esophagus	ESCC	3.46e-49	9.06e-01	0.0978
435	ASL	P74T-E	Human	Esophagus	ESCC	9.59e-30	6.86e-01	0.1479
435	ASL	P75T-E	Human	Esophagus	ESCC	3.05e-61	1.01e+00	0.1125
435	ASL	P76T-E	Human	Esophagus	ESCC	1.79e-23	4.26e-01	0.1207
435	ASL	P79T-E	Human	Esophagus	ESCC	3.53e-14	3.02e-01	0.1154
435	ASL	P80T-E	Human	Esophagus	ESCC	1.12e-23	6.86e-01	0.155
435	ASL	P82T-E	Human	Esophagus	ESCC	8.83e-27	1.07e+00	0.1072
435	ASL	P83T-E	Human	Esophagus	ESCC	1.37e-55	1.46e+00	0.1738
435	ASL	P84T-E	Human	Esophagus	ESCC	6.60e-04	3.12e-01	0.0933
435	ASL	P89T-E	Human	Esophagus	ESCC	1.71e-27	1.45e+00	0.1752
435	ASL	P91T-E	Human	Esophagus	ESCC	3.73e-09	5.77e-01	0.1828
435	ASL	P94T-E	Human	Esophagus	ESCC	1.69e-12	1.45e+00	0.0879
435	ASL	P104T-E	Human	Esophagus	ESCC	1.17e-23	1.04e+00	0.0931
435	ASL	P107T-E	Human	Esophagus	ESCC	2.14e-13	3.17e-01	0.171

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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
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
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:0007015	Colorectum	AD	actin filament organization	167/3918	442/18723	1.65e-16	7.94e-14	167
GO:0032535	Colorectum	AD	regulation of cellular component size	142/3918	383/18723	1.74e-13	3.41e-11	142
GO:1902903	Colorectum	AD	regulation of supramolecular fiber organization	139/3918	383/18723	2.01e-12	3.19e-10	139
GO:0032970	Colorectum	AD	regulation of actin filament-based process	142/3918	397/18723	4.05e-12	5.90e-10	142
GO:0110053	Colorectum	AD	regulation of actin filament organization	108/3918	278/18723	5.02e-12	6.98e-10	108
GO:0008154	Colorectum	AD	actin polymerization or depolymerization	90/3918	218/18723	6.14e-12	8.23e-10	90
GO:0032271	Colorectum	AD	regulation of protein polymerization	94/3918	233/18723	1.01e-11	1.29e-09	94
GO:0030041	Colorectum	AD	actin filament polymerization	81/3918	191/18723	1.35e-11	1.69e-09	81
GO:0051258	Colorectum	AD	protein polymerization	112/3918	297/18723	1.85e-11	2.27e-09	112
GO:0043254	Colorectum	AD	regulation of protein-containing complex assembly	148/3918	428/18723	2.64e-11	3.18e-09	148
GO:0008064	Colorectum	AD	regulation of actin polymerization or depolymerization	79/3918	188/18723	4.17e-11	4.74e-09	79
GO:0030833	Colorectum	AD	regulation of actin filament polymerization	74/3918	172/18723	4.50e-11	5.03e-09	74
GO:0030832	Colorectum	AD	regulation of actin filament length	79/3918	189/18723	5.71e-11	6.27e-09	79
GO:1902905	Colorectum	AD	positive regulation of supramolecular fiber organization	85/3918	209/18723	5.95e-11	6.33e-09	85
GO:0032956	Colorectum	AD	regulation of actin cytoskeleton organization	127/3918	358/18723	1.03e-10	1.04e-08	127
GO:0051495	Colorectum	AD	positive regulation of cytoskeleton organization	89/3918	226/18723	1.61e-10	1.56e-08	89
GO:0032273	Colorectum	AD	positive regulation of protein polymerization	62/3918	138/18723	1.94e-10	1.76e-08	62
GO:0031334	Colorectum	AD	positive regulation of protein-containing complex assembly	91/3918	237/18723	4.78e-10	3.99e-08	91
GO:0030838	Colorectum	AD	positive regulation of actin filament polymerization	48/3918	99/18723	9.21e-10	7.03e-08	48
GO:0051656	Colorectum	AD	establishment of organelle localization	131/3918	390/18723	3.00e-09	2.06e-07	131

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa01230	Colorectum	AD	Biosynthesis of amino acids	28/2092	75/8465	9.99e-03	3.89e-02	2.48e-02	28
hsa012301	Colorectum	AD	Biosynthesis of amino acids	28/2092	75/8465	9.99e-03	3.89e-02	2.48e-02	28
hsa012302	Colorectum	SER	Biosynthesis of amino acids	23/1580	75/8465	8.11e-03	4.14e-02	3.01e-02	23
hsa012303	Colorectum	SER	Biosynthesis of amino acids	23/1580	75/8465	8.11e-03	4.14e-02	3.01e-02	23
hsa0123023	Esophagus	ESCC	Biosynthesis of amino acids	49/4205	75/8465	4.35e-03	1.12e-02	5.74e-03	49
hsa0123033	Esophagus	ESCC	Biosynthesis of amino acids	49/4205	75/8465	4.35e-03	1.12e-02	5.74e-03	49
hsa012304	Liver	Cirrhotic	Biosynthesis of amino acids	35/2530	75/8465	1.54e-03	7.83e-03	4.83e-03	35
hsa0123011	Liver	Cirrhotic	Biosynthesis of amino acids	35/2530	75/8465	1.54e-03	7.83e-03	4.83e-03	35
hsa0123021	Liver	HCC	Biosynthesis of amino acids	53/4020	75/8465	3.79e-05	2.11e-04	1.18e-04	53
hsa0123031	Liver	HCC	Biosynthesis of amino acids	53/4020	75/8465	3.79e-05	2.11e-04	1.18e-04	53
hsa012305	Oral cavity	OSCC	Biosynthesis of amino acids	45/3704	75/8465	3.27e-03	8.23e-03	4.19e-03	45
hsa0123012	Oral cavity	OSCC	Biosynthesis of amino acids	45/3704	75/8465	3.27e-03	8.23e-03	4.19e-03	45
hsa00220	Stomach	GC	Arginine biosynthesis	6/708	22/8465	7.81e-03	4.10e-02	2.88e-02	6
hsa002201	Stomach	GC	Arginine biosynthesis	6/708	22/8465	7.81e-03	4.10e-02	2.88e-02	6

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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

ASL

SNV

Missense_Mutation

c.22N>T

p.Leu8Phe

p.L8F

P04424

protein_coding

deleterious(0)

probably_damaging(0.912)

TCGA-A1-A0SH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

ASL

SNV

Missense_Mutation

c.1188N>G

p.Phe396Leu

p.F396L

P04424

protein_coding

tolerated(0.69)

benign(0.003)

TCGA-A8-A09G-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

ASL

SNV

Missense_Mutation

c.653C>T

p.Ala218Val

p.A218V

P04424

protein_coding

tolerated(0.08)

benign(0.01)

TCGA-D8-A1XW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin+cyclophosphamide

ASL

SNV

Missense_Mutation

c.219N>C

p.Glu73Asp

p.E73D

P04424

protein_coding

deleterious(0.04)

probably_damaging(1)

TCGA-E2-A14R-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ASL

SNV

Missense_Mutation

c.491N>T

p.Ala164Val

p.A164V

P04424

protein_coding

deleterious(0)

probably_damaging(0.971)

TCGA-E2-A15M-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ASL

SNV

Missense_Mutation

c.1188N>G

p.Phe396Leu

p.F396L

P04424

protein_coding

tolerated(0.69)

benign(0.003)

TCGA-XX-A89A-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ASL

insertion

Frame_Shift_Ins

novel

c.1285_1286insAA

p.Asp429GlufsTer120

p.D429Efs*120

P04424

protein_coding

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

ASL

insertion

In_Frame_Ins

novel

c.1287_1288insATAAAGGCCAGTAAAACA

p.Asp429_Tyr430insIleLysAlaSerLysThr

p.D429_Y430insIKASKT

P04424

protein_coding

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

ASL

SNV

Missense_Mutation

novel

c.486N>C

p.Gln162His

p.Q162H

P04424

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ASL

SNV

Missense_Mutation

c.535G>A

p.Ala179Thr

p.A179T

P04424

protein_coding

tolerated(0.13)

possibly_damaging(0.886)

TCGA-AA-3492-01

Colorectum

colon adenocarcinoma

Female

>=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
435	ASL	ENZYME		sodium benzoate / sodium phenylacetate

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