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: LTA4H

Gene summary for LTA4H

Gene summary.

Gene information	Species	Human
	Gene symbol	LTA4H
	Gene ID	4048
	Gene name	leukotriene A4 hydrolase
	Gene Alias	LTA4H
	Cytomap	12q23.1
	Gene Type	protein-coding
	GO ID	GO:0006082
	UniProtAcc	A0A140VK27

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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
4048	LTA4H	HTA11_3410_2000001011	Human	Colorectum	AD	1.37e-02	2.21e-01	0.0155
4048	LTA4H	HTA11_1938_2000001011	Human	Colorectum	AD	3.26e-09	6.42e-01	-0.0811
4048	LTA4H	HTA11_78_2000001011	Human	Colorectum	AD	1.48e-14	6.95e-01	-0.1088
4048	LTA4H	HTA11_347_2000001011	Human	Colorectum	AD	4.06e-14	5.47e-01	-0.1954
4048	LTA4H	HTA11_83_2000001011	Human	Colorectum	SER	4.42e-04	5.53e-01	-0.1526
4048	LTA4H	HTA11_1391_2000001011	Human	Colorectum	AD	1.67e-10	6.43e-01	-0.059
4048	LTA4H	HTA11_7862_2000001011	Human	Colorectum	AD	4.72e-05	6.05e-01	-0.0179
4048	LTA4H	HTA11_866_3004761011	Human	Colorectum	AD	2.74e-05	4.25e-01	0.096
4048	LTA4H	HTA11_4255_2000001011	Human	Colorectum	SER	1.05e-02	6.46e-01	0.0446
4048	LTA4H	HTA11_8622_2000001021	Human	Colorectum	SER	4.57e-04	5.12e-01	0.0528
4048	LTA4H	HTA11_7663_2000001011	Human	Colorectum	SER	4.86e-02	5.15e-01	0.0131
4048	LTA4H	HTA11_6801_2000001011	Human	Colorectum	SER	3.55e-02	5.91e-01	0.0171
4048	LTA4H	HTA11_7696_3000711011	Human	Colorectum	AD	5.74e-05	4.67e-01	0.0674
4048	LTA4H	HTA11_99999970781_79442	Human	Colorectum	MSS	1.11e-21	8.15e-01	0.294
4048	LTA4H	HTA11_99999965062_69753	Human	Colorectum	MSI-H	4.99e-07	1.35e+00	0.3487
4048	LTA4H	HTA11_99999965104_69814	Human	Colorectum	MSS	7.28e-13	7.31e-01	0.281
4048	LTA4H	HTA11_99999971662_82457	Human	Colorectum	MSS	8.87e-32	1.06e+00	0.3859
4048	LTA4H	A015-C-203	Human	Colorectum	FAP	1.97e-04	-1.94e-02	-0.1294
4048	LTA4H	A001-C-108	Human	Colorectum	FAP	6.16e-03	-8.31e-02	-0.0272
4048	LTA4H	A002-C-205	Human	Colorectum	FAP	4.44e-02	-1.40e-01	-0.1236

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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
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
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
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:0046394	Colorectum	MSS	carboxylic acid biosynthetic process	76/3467	314/18723	6.71e-03	4.38e-02	76
GO:0016053	Colorectum	MSS	organic acid biosynthetic process	76/3467	316/18723	7.88e-03	4.84e-02	76
GO:00463941	Colorectum	MSI-H	carboxylic acid biosynthetic process	36/1319	314/18723	2.68e-03	3.48e-02	36
GO:00160531	Colorectum	MSI-H	organic acid biosynthetic process	36/1319	316/18723	2.98e-03	3.78e-02	36
GO:00463948	Esophagus	ESCC	carboxylic acid biosynthetic process	175/8552	314/18723	1.98e-04	1.26e-03	175
GO:00160538	Esophagus	ESCC	organic acid biosynthetic process	175/8552	316/18723	3.04e-04	1.82e-03	175
GO:001605312	Liver	Cirrhotic	organic acid biosynthetic process	139/4634	316/18723	4.28e-14	3.83e-12	139
GO:004639412	Liver	Cirrhotic	carboxylic acid biosynthetic process	137/4634	314/18723	1.40e-13	1.14e-11	137
GO:001605321	Liver	HCC	organic acid biosynthetic process	200/7958	316/18723	5.24e-14	3.22e-12	200
GO:004639421	Liver	HCC	carboxylic acid biosynthetic process	198/7958	314/18723	1.19e-13	6.78e-12	198
GO:00160537	Oral cavity	OSCC	organic acid biosynthetic process	155/7305	316/18723	1.64e-04	1.13e-03	155
GO:00463947	Oral cavity	OSCC	carboxylic acid biosynthetic process	154/7305	314/18723	1.73e-04	1.19e-03	154

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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

LTA4H

SNV

Missense_Mutation

c.295N>G

p.Gln99Glu

p.Q99E

P09960

protein_coding

tolerated(0.47)

benign(0.027)

TCGA-A8-A06Q-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

LTA4H

SNV

Missense_Mutation

novel

c.322N>A

p.Glu108Lys

p.E108K

P09960

protein_coding

tolerated(0.1)

benign(0.092)

TCGA-B6-A40B-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LTA4H

SNV

Missense_Mutation

c.670N>C

p.Glu224Gln

p.E224Q

P09960

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

LTA4H

SNV

Missense_Mutation

c.1228N>A

p.Ala410Thr

p.A410T

P09960

protein_coding

tolerated(0.07)

benign(0.194)

TCGA-AU-3779-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

LTA4H

SNV

Missense_Mutation

c.695C>T

p.Ala232Val

p.A232V

P09960

protein_coding

deleterious(0.04)

benign(0.427)

TCGA-A5-A1OF-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

LTA4H

SNV

Missense_Mutation

novel

c.275N>T

p.Pro92Leu

p.P92L

P09960

protein_coding

deleterious(0.04)

possibly_damaging(0.743)

TCGA-AJ-A3EK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

LTA4H

SNV

Missense_Mutation

c.523N>T

p.Arg175Cys

p.R175C

P09960

protein_coding

deleterious(0.01)

possibly_damaging(0.832)

TCGA-AJ-A3EL-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

LTA4H

SNV

Missense_Mutation

novel

c.1195N>A

p.Gly399Arg

p.G399R

P09960

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

LTA4H

SNV

Missense_Mutation

rs776850878

c.1651G>A

p.Ala551Thr

p.A551T

P09960

protein_coding

tolerated(0.3)

possibly_damaging(0.561)

TCGA-AX-A2HC-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

LTA4H

SNV

Missense_Mutation

novel

c.134C>A

p.Ser45Tyr

p.S45Y

P09960

protein_coding

tolerated(0.14)

benign(0.262)

TCGA-AX-A2HC-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

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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
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		ANTIINFLAMMATORY AGENTS		8423594
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		DIPHENYLETHER	DIPHENYLETHER	18952425
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		montelukast	MONTELUKAST
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE	inhibitor	315661176
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE	inhibitor	315661187	CHEMBL119054
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE	inhibitor	178101843
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		4-PHENOXYPHENOL	CHEMBL224318	18952425
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		DG051
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		4-METHOXYPHENOXYBENZENE	CHEMBL398021	18952425
4048	LTA4H	ENZYME, DRUGGABLE GENOME, PROTEASE		OPIOID		1410529

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