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: TH

Gene summary for TH

Gene summary.

Gene information	Species	Human
	Gene symbol	TH
	Gene ID	7054
	Gene name	tyrosine hydroxylase
	Gene Alias	DYT14
	Cytomap	11p15.5
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P07101

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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
7054	TH	C04	Human	Oral cavity	OSCC	2.26e-15	7.94e-01	0.2633
7054	TH	C21	Human	Oral cavity	OSCC	3.65e-07	1.94e-01	0.2678
7054	TH	C30	Human	Oral cavity	OSCC	2.87e-17	6.63e-01	0.3055
7054	TH	C51	Human	Oral cavity	OSCC	4.98e-04	2.56e-01	0.2674
7054	TH	SYSMH5	Human	Oral cavity	OSCC	3.73e-03	1.34e-01	0.0647
7054	TH	P4_cSCC	Human	Skin	cSCC	3.76e-02	9.18e-02	-0.00290000000000005

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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

∗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:00512358	Breast	Precancer	maintenance of location	40/1080	327/18723	5.85e-06	1.71e-04	40
GO:00516519	Breast	Precancer	maintenance of location in cell	30/1080	214/18723	5.91e-06	1.71e-04	30
GO:00512383	Breast	Precancer	sequestering of metal ion	7/1080	16/18723	1.50e-05	3.71e-04	7
GO:00550767	Breast	Precancer	transition metal ion homeostasis	20/1080	138/18723	1.28e-04	2.24e-03	20
GO:00469165	Breast	Precancer	cellular transition metal ion homeostasis	17/1080	115/18723	3.15e-04	4.49e-03	17
GO:00481453	Breast	Precancer	regulation of fibroblast proliferation	12/1080	80/18723	2.03e-03	1.94e-02	12
GO:00481443	Breast	Precancer	fibroblast proliferation	12/1080	81/18723	2.26e-03	2.12e-02	12
GO:00550725	Breast	Precancer	iron ion homeostasis	12/1080	85/18723	3.41e-03	2.85e-02	12
GO:00068263	Breast	Precancer	iron ion transport	9/1080	58/18723	5.67e-03	4.08e-02	9
GO:00000412	Breast	Precancer	transition metal ion transport	13/1080	105/18723	7.35e-03	4.89e-02	13
GO:005109814	Breast	IDC	regulation of binding	57/1434	363/18723	1.59e-07	8.76e-06	57
GO:005165114	Breast	IDC	maintenance of location in cell	37/1434	214/18723	2.39e-06	9.35e-05	37
GO:005123513	Breast	IDC	maintenance of location	48/1434	327/18723	9.90e-06	2.77e-04	48
GO:005109914	Breast	IDC	positive regulation of binding	30/1434	173/18723	1.96e-05	4.86e-04	30
GO:000164912	Breast	IDC	osteoblast differentiation	35/1434	229/18723	6.64e-05	1.35e-03	35
GO:005123811	Breast	IDC	sequestering of metal ion	7/1434	16/18723	9.40e-05	1.81e-03	7
GO:006056212	Breast	IDC	epithelial tube morphogenesis	44/1434	325/18723	1.58e-04	2.73e-03	44
GO:005507613	Breast	IDC	transition metal ion homeostasis	23/1434	138/18723	3.20e-04	4.79e-03	23
GO:004691612	Breast	IDC	cellular transition metal ion homeostasis	20/1434	115/18723	4.35e-04	5.90e-03	20
GO:000150311	Breast	IDC	ossification	50/1434	408/18723	6.51e-04	8.04e-03	50

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501230	Oral cavity	OSCC	Parkinson disease	188/3704	266/8465	1.82e-19	1.52e-17	7.75e-18	188
hsa05012113	Oral cavity	OSCC	Parkinson disease	188/3704	266/8465	1.82e-19	1.52e-17	7.75e-18	188

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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

SNV

Missense_Mutation

c.58N>C

p.Glu20Gln

p.E20Q

P07101

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.998)

TCGA-E2-A1LS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Cyclophosphamide

SNV

Missense_Mutation

novel

c.307N>A

p.Ala103Thr

p.A103T

P07101

protein_coding

tolerated(0.31)

benign(0.055)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SNV

Missense_Mutation

rs760640869

c.374N>T

p.Ser125Leu

p.S125L

P07101

protein_coding

deleterious(0.01)

benign(0.058)

TCGA-EA-A3QD-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

SNV

Missense_Mutation

c.235N>A

p.Glu79Lys

p.E79K

P07101

protein_coding

deleterious(0.04)

probably_damaging(0.957)

TCGA-MY-A5BD-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SNV

Missense_Mutation

rs372409517

c.677N>T

p.Ser226Leu

p.S226L

P07101

protein_coding

deleterious(0.01)

possibly_damaging(0.661)

TCGA-A6-6780-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

SNV

Missense_Mutation

novel

c.1201N>C

p.Tyr401His

p.Y401H

P07101

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AA-3663-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

SNV

Missense_Mutation

novel

c.944N>A

p.Gly315Asp

p.G315D

P07101

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

SNV

Missense_Mutation

rs757607038

c.806C>T

p.Thr269Met

p.T269M

P07101

protein_coding

deleterious(0.04)

possibly_damaging(0.904)

TCGA-AA-A022-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

SNV

Missense_Mutation

c.721N>A

p.Ala241Thr

p.A241T

P07101

protein_coding

deleterious(0)

probably_damaging(0.992)

TCGA-F4-6703-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

SNV

Missense_Mutation

rs200751977

c.1492G>A

p.Asp498Asn

p.D498N

P07101

protein_coding

deleterious(0.02)

benign(0.077)

TCGA-EI-6917-01

Colorectum

rectum adenocarcinoma

Male

<65

III/IV

Chemotherapy

5fluorouracil+oxaciplatina+l-folinian

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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
7054	TH	ENZYME, DRUGGABLE GENOME		L-Phenylalanine	PHENYLALANINE
7054	TH	ENZYME, DRUGGABLE GENOME		methylphenidate	METHYLPHENIDATE	26810137
7054	TH	ENZYME, DRUGGABLE GENOME		metyrosine	METYROSINE
7054	TH	ENZYME, DRUGGABLE GENOME		EPO	EPOETIN ALFA	16368081
7054	TH	ENZYME, DRUGGABLE GENOME		TETRAHYDROBIOPTERIN	SAPROPTERIN
7054	TH	ENZYME, DRUGGABLE GENOME		SERTRALINE HYDROCHLORIDE		8629887
7054	TH	ENZYME, DRUGGABLE GENOME		DEHYDROEPIANDROSTERONE	PRASTERONE	8704732
7054	TH	ENZYME, DRUGGABLE GENOME	inhibitor	CHEMBL1200862	METYROSINE
7054	TH	ENZYME, DRUGGABLE GENOME		IFN		8724983
7054	TH	ENZYME, DRUGGABLE GENOME		DOXYCYCLINE	DOXYCYCLINE	15585109

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