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: HTRA3

Gene summary for HTRA3

Gene summary.

Gene information	Species	Human
	Gene symbol	HTRA3
	Gene ID	94031
	Gene name	HtrA serine peptidase 3
	Gene Alias	Prsp
	Cytomap	4p16.1
	Gene Type	protein-coding
	GO ID	GO:0006508
	UniProtAcc	P83110

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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
94031	HTRA3	C04	Human	Oral cavity	OSCC	1.13e-04	2.97e-01	0.2633
94031	HTRA3	C30	Human	Oral cavity	OSCC	1.81e-19	9.81e-01	0.3055
94031	HTRA3	C06	Human	Oral cavity	OSCC	1.57e-11	1.66e+00	0.2699
94031	HTRA3	NEOLP-1	Human	Oral cavity	NEOLP	1.14e-02	1.48e-01	-0.0194
94031	HTRA3	male-WTA	Human	Thyroid	PTC	2.64e-07	1.00e-01	0.1037
94031	HTRA3	ATC12	Human	Thyroid	ATC	5.65e-43	1.14e+00	0.34
94031	HTRA3	ATC13	Human	Thyroid	ATC	3.80e-27	7.62e-01	0.34
94031	HTRA3	ATC4	Human	Thyroid	ATC	3.24e-52	1.34e+00	0.34
94031	HTRA3	ATC5	Human	Thyroid	ATC	3.60e-33	8.38e-01	0.34

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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
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:00715598	Oral cavity	OSCC	response to transforming growth factor beta	140/7305	256/18723	2.34e-07	3.70e-06	140
GO:00715608	Oral cavity	OSCC	cellular response to transforming growth factor beta stimulus	137/7305	250/18723	2.68e-07	4.15e-06	137
GO:00071798	Oral cavity	OSCC	transforming growth factor beta receptor signaling pathway	109/7305	198/18723	3.21e-06	3.86e-05	109
GO:00170155	Oral cavity	OSCC	regulation of transforming growth factor beta receptor signaling pathway	71/7305	128/18723	1.14e-04	8.34e-04	71
GO:19038446	Oral cavity	OSCC	regulation of cellular response to transforming growth factor beta stimulus	72/7305	131/18723	1.51e-04	1.06e-03	72
GO:00071789	Oral cavity	OSCC	transmembrane receptor protein serine/threonine kinase signaling pathway	165/7305	355/18723	2.31e-03	1.02e-02	165
GO:007155924	Oral cavity	NEOLP	response to transforming growth factor beta	59/2005	256/18723	8.84e-09	4.49e-07	59
GO:007156024	Oral cavity	NEOLP	cellular response to transforming growth factor beta stimulus	58/2005	250/18723	9.13e-09	4.56e-07	58
GO:000717923	Oral cavity	NEOLP	transforming growth factor beta receptor signaling pathway	48/2005	198/18723	4.01e-08	1.66e-06	48
GO:000717822	Oral cavity	NEOLP	transmembrane receptor protein serine/threonine kinase signaling pathway	70/2005	355/18723	3.04e-07	9.62e-06	70
GO:001701521	Oral cavity	NEOLP	regulation of transforming growth factor beta receptor signaling pathway	33/2005	128/18723	1.18e-06	3.08e-05	33
GO:190384421	Oral cavity	NEOLP	regulation of cellular response to transforming growth factor beta stimulus	33/2005	131/18723	2.05e-06	4.86e-05	33
GO:003051211	Oral cavity	NEOLP	negative regulation of transforming growth factor beta receptor signaling pathway	24/2005	81/18723	2.40e-06	5.53e-05	24
GO:00901011	Oral cavity	NEOLP	negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	32/2005	131/18723	5.88e-06	1.19e-04	32
GO:009028711	Oral cavity	NEOLP	regulation of cellular response to growth factor stimulus	56/2005	304/18723	3.55e-05	5.20e-04	56
GO:009009213	Oral cavity	NEOLP	regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	49/2005	256/18723	3.90e-05	5.62e-04	49
GO:00305101	Oral cavity	NEOLP	regulation of BMP signaling pathway	20/2005	96/18723	2.60e-03	1.63e-02	20
GO:007177212	Oral cavity	NEOLP	response to BMP	29/2005	165/18723	5.04e-03	2.73e-02	29
GO:007177312	Oral cavity	NEOLP	cellular response to BMP stimulus	29/2005	165/18723	5.04e-03	2.73e-02	29
GO:003050912	Oral cavity	NEOLP	BMP signaling pathway	27/2005	152/18723	5.75e-03	3.04e-02	27

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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

HTRA3

insertion

Nonsense_Mutation

novel

c.658_659insCCGGGGGCTCGGGAGGCCTCACAAGCTAAGCCTG

p.Lys220ThrfsTer10

p.K220Tfs*10

P83110

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

HTRA3

insertion

Nonsense_Mutation

novel

c.838_839insCATCCTGGTCTGTCTGGCTCCGTGCTCCGT

p.Glu280delinsAlaSerTrpSerValTrpLeuArgAlaProTer

p.E280delinsASWSVWLRAP*

P83110

protein_coding

TCGA-BH-A0HK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

HTRA3

insertion

Frame_Shift_Ins

novel

c.840_841insTCAAGAT

p.Gly281SerfsTer93

p.G281Sfs*93

P83110

protein_coding

TCGA-BH-A0HK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

HTRA3

deletion

Frame_Shift_Del

novel

c.511delN

p.Leu172CysfsTer14

p.L172Cfs*14

P83110

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

HTRA3

SNV

Missense_Mutation

rs776517422

c.676T>G

p.Ser226Ala

p.S226A

P83110

protein_coding

tolerated(1)

benign(0.006)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HTRA3

SNV

Missense_Mutation

novel

c.1001C>T

p.Ser334Leu

p.S334L

P83110

protein_coding

deleterious(0.03)

probably_damaging(0.914)

TCGA-LP-A4AV-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HTRA3

SNV

Missense_Mutation

c.887C>T

p.Thr296Met

p.T296M

P83110

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-5M-AAT6-01

Colorectum

colon adenocarcinoma

Female

<65

III/IV

Unknown

HTRA3

SNV

Missense_Mutation

c.1276G>A

p.Val426Met

p.V426M

P83110

protein_coding

deleterious(0)

possibly_damaging(0.875)

TCGA-AD-6889-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Chemotherapy

xeloda

HTRA3

SNV

Missense_Mutation

c.1013N>G

p.Thr338Arg

p.T338R

P83110

protein_coding

tolerated(1)

benign(0.001)

TCGA-CK-4951-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HTRA3

SNV

Missense_Mutation

rs137866031

c.1312N>T

p.Arg438Trp

p.R438W

P83110

protein_coding

deleterious(0.02)

probably_damaging(0.957)

TCGA-CK-5916-01

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

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