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: COMT

Gene summary for COMT

Gene summary.

Gene information	Species	Human
	Gene symbol	COMT
	Gene ID	1312
	Gene name	catechol-O-methyltransferase
	Gene Alias	HEL-S-98n
	Cytomap	22q11.21
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A140VJG8

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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
1312	COMT	HTA11_3410_2000001011	Human	Colorectum	AD	4.24e-16	4.19e-01	0.0155
1312	COMT	HTA11_2487_2000001011	Human	Colorectum	SER	1.68e-10	5.61e-01	-0.1808
1312	COMT	HTA11_2951_2000001011	Human	Colorectum	AD	1.32e-02	2.53e-01	0.0216
1312	COMT	HTA11_1938_2000001011	Human	Colorectum	AD	4.67e-12	7.49e-01	-0.0811
1312	COMT	HTA11_78_2000001011	Human	Colorectum	AD	8.99e-06	3.30e-01	-0.1088
1312	COMT	HTA11_347_2000001011	Human	Colorectum	AD	4.66e-19	5.84e-01	-0.1954
1312	COMT	HTA11_411_2000001011	Human	Colorectum	SER	1.23e-04	8.15e-01	-0.2602
1312	COMT	HTA11_696_2000001011	Human	Colorectum	AD	5.37e-18	6.06e-01	-0.1464
1312	COMT	HTA11_866_2000001011	Human	Colorectum	AD	4.01e-02	3.17e-01	-0.1001
1312	COMT	HTA11_1391_2000001011	Human	Colorectum	AD	2.01e-17	6.75e-01	-0.059
1312	COMT	HTA11_2992_2000001011	Human	Colorectum	SER	7.40e-05	5.34e-01	-0.1706
1312	COMT	HTA11_546_2000001011	Human	Colorectum	AD	3.28e-14	6.68e-01	-0.0842
1312	COMT	HTA11_7862_2000001011	Human	Colorectum	AD	5.97e-03	2.74e-01	-0.0179
1312	COMT	HTA11_866_3004761011	Human	Colorectum	AD	2.76e-30	8.09e-01	0.096
1312	COMT	HTA11_4255_2000001011	Human	Colorectum	SER	4.88e-04	5.12e-01	0.0446
1312	COMT	HTA11_9408_2000001011	Human	Colorectum	AD	2.66e-02	5.06e-01	0.0451
1312	COMT	HTA11_8622_2000001021	Human	Colorectum	SER	2.12e-12	8.86e-01	0.0528
1312	COMT	HTA11_7663_2000001011	Human	Colorectum	SER	1.74e-03	5.81e-01	0.0131
1312	COMT	HTA11_10623_2000001011	Human	Colorectum	AD	3.67e-05	4.74e-01	-0.0177
1312	COMT	HTA11_6801_2000001011	Human	Colorectum	SER	1.00e-09	8.75e-01	0.0171

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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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
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:004866013	Endometrium	EEC	regulation of smooth muscle cell proliferation	43/2168	180/18723	2.54e-06	7.35e-05	43
GO:004865913	Endometrium	EEC	smooth muscle cell proliferation	43/2168	184/18723	4.65e-06	1.16e-04	43
GO:000756513	Endometrium	EEC	female pregnancy	43/2168	193/18723	1.66e-05	3.18e-04	43
GO:000223714	Endometrium	EEC	response to molecule of bacterial origin	68/2168	363/18723	3.96e-05	6.64e-04	68
GO:003249614	Endometrium	EEC	response to lipopolysaccharide	65/2168	343/18723	4.04e-05	6.75e-04	65
GO:001943913	Endometrium	EEC	aromatic compound catabolic process	83/2168	467/18723	4.32e-05	7.10e-04	83
GO:007149617	Endometrium	EEC	cellular response to external stimulus	61/2168	320/18723	5.76e-05	8.97e-04	61
GO:00330021	Endometrium	EEC	muscle cell proliferation	50/2168	248/18723	6.08e-05	9.21e-04	50
GO:190136113	Endometrium	EEC	organic cyclic compound catabolic process	86/2168	495/18723	7.31e-05	1.07e-03	86
GO:004470612	Endometrium	EEC	multi-multicellular organism process	45/2168	220/18723	9.73e-05	1.35e-03	45
GO:003166717	Endometrium	EEC	response to nutrient levels	82/2168	474/18723	1.23e-04	1.64e-03	82
GO:005105111	Endometrium	EEC	negative regulation of transport	80/2168	470/18723	2.53e-04	2.93e-03	80
GO:003166916	Endometrium	EEC	cellular response to nutrient levels	41/2168	215/18723	8.72e-04	7.97e-03	41
GO:003166816	Endometrium	EEC	cellular response to extracellular stimulus	45/2168	246/18723	1.24e-03	1.03e-02	45
GO:000926715	Endometrium	EEC	cellular response to starvation	31/2168	156/18723	1.80e-03	1.39e-02	31
GO:000941015	Endometrium	EEC	response to xenobiotic stimulus	73/2168	462/18723	3.55e-03	2.38e-02	73
GO:004259414	Endometrium	EEC	response to starvation	36/2168	197/18723	3.66e-03	2.45e-02	36
GO:00486621	Endometrium	EEC	negative regulation of smooth muscle cell proliferation	17/2168	75/18723	4.71e-03	2.99e-02	17
GO:0071496111	Esophagus	ESCC	cellular response to external stimulus	215/8552	320/18723	4.29e-15	2.43e-13	215
GO:001943918	Esophagus	ESCC	aromatic compound catabolic process	295/8552	467/18723	1.09e-14	5.98e-13	295

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04728	Colorectum	AD	Dopaminergic synapse	46/2092	132/8465	5.55e-03	2.48e-02	1.58e-02	46
hsa047281	Colorectum	AD	Dopaminergic synapse	46/2092	132/8465	5.55e-03	2.48e-02	1.58e-02	46
hsa047282	Colorectum	SER	Dopaminergic synapse	37/1580	132/8465	5.27e-03	3.28e-02	2.38e-02	37
hsa047283	Colorectum	SER	Dopaminergic synapse	37/1580	132/8465	5.27e-03	3.28e-02	2.38e-02	37
hsa047284	Colorectum	MSS	Dopaminergic synapse	45/1875	132/8465	1.02e-03	5.94e-03	3.64e-03	45
hsa047285	Colorectum	MSS	Dopaminergic synapse	45/1875	132/8465	1.02e-03	5.94e-03	3.64e-03	45
hsa0472810	Prostate	BPH	Dopaminergic synapse	38/1718	132/8465	1.19e-02	3.55e-02	2.20e-02	38
hsa0472811	Prostate	BPH	Dopaminergic synapse	38/1718	132/8465	1.19e-02	3.55e-02	2.20e-02	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

COMT

SNV

Missense_Mutation

c.115N>G

p.Asn39Asp

p.N39D

P21964

protein_coding

tolerated(0.07)

benign(0.039)

TCGA-B6-A0WV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

COMT

SNV

Missense_Mutation

c.115N>G

p.Asn39Asp

p.N39D

P21964

protein_coding

tolerated(0.07)

benign(0.039)

TCGA-HN-A2NL-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

COMT

SNV

Missense_Mutation

novel

c.490C>A

p.Leu164Ile

p.L164I

P21964

protein_coding

tolerated(0.52)

benign(0.006)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

COMT

SNV

Missense_Mutation

rs766020740

c.368N>A

p.Ala123Asp

p.A123D

P21964

protein_coding

deleterious(0)

probably_damaging(0.976)

TCGA-A5-A1OF-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

COMT

SNV

Missense_Mutation

rs752035611

c.727C>T

p.His243Tyr

p.H243Y

P21964

protein_coding

tolerated(0.65)

benign(0)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

COMT

SNV

Missense_Mutation

novel

c.595N>T

p.Pro199Ser

p.P199S

P21964

protein_coding

deleterious(0.02)

possibly_damaging(0.876)

TCGA-BG-A222-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

COMT

SNV

Missense_Mutation

c.285G>T

p.Lys95Asn

p.K95N

P21964

protein_coding

tolerated(0.07)

possibly_damaging(0.474)

TCGA-BS-A0UV-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

COMT

SNV

Missense_Mutation

novel

c.275N>G

p.Val92Gly

p.V92G

P21964

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-95-7567-01

Lung

lung adenocarcinoma

Male

<65

I/II

Chemotherapy

cisplatin

COMT

SNV

Missense_Mutation

novel

c.718G>C

p.Glu240Gln

p.E240Q

P21964

protein_coding

tolerated(0.1)

benign(0.019)

TCGA-98-A539-01

Lung

lung squamous cell carcinoma

Male

<65

I/II

Unknown

COMT

SNV

Missense_Mutation

novel

c.428N>T

p.Pro143Leu

p.P143L

P21964

protein_coding

deleterious(0)

possibly_damaging(0.905)

TCGA-CV-A460-01

Oral cavity

head & neck squamous cell carcinoma

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
1312	COMT	DRUGGABLE GENOME, ENZYME		fluvoxamine	FLUVOXAMINE	20619611
1312	COMT	DRUGGABLE GENOME, ENZYME		methylphenidate	METHYLPHENIDATE	29230023,23131881,24763183,18214865,18703939,22149470,24035255,21550019
1312	COMT	DRUGGABLE GENOME, ENZYME		Opicapone	OPICAPONE
1312	COMT	DRUGGABLE GENOME, ENZYME		TOLCAPONE	TOLCAPONE
1312	COMT	DRUGGABLE GENOME, ENZYME		ENTACAPONE	ENTACAPONE
1312	COMT	DRUGGABLE GENOME, ENZYME		Entacapone	ENTACAPONE
1312	COMT	DRUGGABLE GENOME, ENZYME		ENTACAPONE	ENTACAPONE
1312	COMT	DRUGGABLE GENOME, ENZYME		methadone	METHADONE	28006928,32407152,23686330,21398039,23302985,26902643,29474345,23773341,25155931,25185591,19514130,28745577,27027462
1312	COMT	DRUGGABLE GENOME, ENZYME		oxycodone	OXYCODONE	28006928,23686330,21398039,23302985,26902643,29474345,23773341,25155931,25185591,19514130,28745577,27027462
1312	COMT	DRUGGABLE GENOME, ENZYME		Analgesics		25096645

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