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: THSD4

Gene summary for THSD4

Gene summary.

Gene information	Species	Human
	Gene symbol	THSD4
	Gene ID	79875
	Gene name	thrombospondin type 1 domain containing 4
	Gene Alias	ADAMTSL-6
	Cytomap	15q23
	Gene Type	protein-coding
	GO ID	GO:0008150
	UniProtAcc	Q6ZMP0

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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
79875	THSD4	GSM4909286	Human	Breast	IDC	7.43e-04	-1.51e-01	0.1081
79875	THSD4	GSM4909293	Human	Breast	IDC	6.64e-03	1.44e-01	0.1581
79875	THSD4	GSM4909298	Human	Breast	IDC	6.46e-15	3.67e-01	0.1551
79875	THSD4	GSM4909301	Human	Breast	IDC	1.93e-23	7.06e-01	0.1577
79875	THSD4	GSM4909302	Human	Breast	IDC	2.83e-08	4.18e-01	0.1545
79875	THSD4	GSM4909307	Human	Breast	IDC	8.14e-05	2.98e-01	0.1569
79875	THSD4	GSM4909308	Human	Breast	IDC	8.77e-21	5.05e-01	0.158
79875	THSD4	GSM4909311	Human	Breast	IDC	2.00e-02	-3.50e-02	0.1534
79875	THSD4	GSM4909319	Human	Breast	IDC	1.57e-03	-6.58e-02	0.1563
79875	THSD4	GSM4909321	Human	Breast	IDC	5.96e-03	2.02e-01	0.1559
79875	THSD4	M1	Human	Breast	IDC	7.19e-08	4.23e-01	0.1577
79875	THSD4	DCIS2	Human	Breast	DCIS	6.44e-03	-8.75e-02	0.0085
79875	THSD4	CA_HPV_1	Human	Cervix	CC	9.18e-29	-7.92e-01	0.0264
79875	THSD4	CA_HPV_2	Human	Cervix	CC	2.01e-21	-7.07e-01	0.0391
79875	THSD4	CA_HPV_3	Human	Cervix	CC	4.67e-11	2.23e-01	0.0414
79875	THSD4	HSIL_HPV_1	Human	Cervix	HSIL_HPV	1.02e-08	-5.27e-01	0.0116
79875	THSD4	HSIL_HPV_2	Human	Cervix	HSIL_HPV	3.16e-07	-5.45e-01	0.0208
79875	THSD4	N_HPV_1	Human	Cervix	N_HPV	2.67e-08	-5.60e-01	0.0079
79875	THSD4	N_HPV_2	Human	Cervix	N_HPV	2.93e-06	-2.07e-01	-0.0131
79875	THSD4	CCII_1	Human	Cervix	CC	3.71e-10	-5.96e-01	0.3249

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
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
Prostate		BPH: Benign Prostatic Hyperplasia
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:0030198	Cervix	CC	extracellular matrix organization	52/2311	301/18723	7.43e-03	3.98e-02	52
GO:0043062	Cervix	CC	extracellular structure organization	52/2311	302/18723	7.92e-03	4.17e-02	52
GO:0045229	Cervix	CC	external encapsulating structure organization	52/2311	304/18723	9.00e-03	4.57e-02	52
GO:00301984	Esophagus	ESCC	extracellular matrix organization	171/8552	301/18723	6.08e-05	4.67e-04	171
GO:00430624	Esophagus	ESCC	extracellular structure organization	171/8552	302/18723	7.73e-05	5.76e-04	171
GO:00452294	Esophagus	ESCC	external encapsulating structure organization	172/8552	304/18723	7.80e-05	5.80e-04	172
GO:00850292	Esophagus	ESCC	extracellular matrix assembly	29/8552	45/18723	8.63e-03	3.04e-02	29
GO:00301983	Oral cavity	OSCC	extracellular matrix organization	146/7305	301/18723	4.67e-04	2.77e-03	146
GO:0085029	Oral cavity	OSCC	extracellular matrix assembly	29/7305	45/18723	4.85e-04	2.86e-03	29
GO:00452293	Oral cavity	OSCC	external encapsulating structure organization	147/7305	304/18723	5.30e-04	3.08e-03	147
GO:00430623	Oral cavity	OSCC	extracellular structure organization	146/7305	302/18723	5.59e-04	3.23e-03	146
GO:0048251	Oral cavity	OSCC	elastic fiber assembly	8/7305	10/18723	1.03e-02	3.53e-02	8
GO:00430621	Prostate	BPH	extracellular structure organization	67/3107	302/18723	6.67e-03	3.00e-02	67
GO:00301981	Prostate	BPH	extracellular matrix organization	66/3107	301/18723	9.20e-03	3.92e-02	66
GO:00452291	Prostate	BPH	external encapsulating structure organization	66/3107	304/18723	1.15e-02	4.66e-02	66
GO:00301986	Thyroid	PTC	extracellular matrix organization	124/5968	301/18723	3.75e-04	2.53e-03	124
GO:00430626	Thyroid	PTC	extracellular structure organization	124/5968	302/18723	4.38e-04	2.92e-03	124
GO:00452296	Thyroid	PTC	external encapsulating structure organization	124/5968	304/18723	5.96e-04	3.79e-03	124
GO:00850293	Thyroid	PTC	extracellular matrix assembly	23/5968	45/18723	5.62e-03	2.55e-02	23
GO:003019812	Thyroid	ATC	extracellular matrix organization	152/6293	301/18723	8.63e-10	2.24e-08	152

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04350	Colorectum	SER	TGF-beta signaling pathway	31/1580	108/8465	7.00e-03	3.77e-02	2.74e-02	31
hsa043501	Colorectum	SER	TGF-beta signaling pathway	31/1580	108/8465	7.00e-03	3.77e-02	2.74e-02	31
hsa043504	Endometrium	AEH	TGF-beta signaling pathway	26/1197	108/8465	3.82e-03	2.18e-02	1.59e-02	26
hsa0435011	Endometrium	AEH	TGF-beta signaling pathway	26/1197	108/8465	3.82e-03	2.18e-02	1.59e-02	26
hsa043502	Endometrium	EEC	TGF-beta signaling pathway	26/1237	108/8465	5.95e-03	3.12e-02	2.33e-02	26
hsa043503	Endometrium	EEC	TGF-beta signaling pathway	26/1237	108/8465	5.95e-03	3.12e-02	2.33e-02	26
hsa043507	Esophagus	ESCC	TGF-beta signaling pathway	69/4205	108/8465	1.92e-03	5.54e-03	2.84e-03	69
hsa0435014	Esophagus	ESCC	TGF-beta signaling pathway	69/4205	108/8465	1.92e-03	5.54e-03	2.84e-03	69
hsa043506	Oral cavity	OSCC	TGF-beta signaling pathway	60/3704	108/8465	8.66e-03	1.97e-02	1.00e-02	60
hsa0435013	Oral cavity	OSCC	TGF-beta signaling pathway	60/3704	108/8465	8.66e-03	1.97e-02	1.00e-02	60
hsa043505	Prostate	BPH	TGF-beta signaling pathway	35/1718	108/8465	1.98e-03	7.92e-03	4.90e-03	35
hsa0435012	Prostate	BPH	TGF-beta signaling pathway	35/1718	108/8465	1.98e-03	7.92e-03	4.90e-03	35
hsa0435021	Prostate	Tumor	TGF-beta signaling pathway	39/1791	108/8465	2.33e-04	1.35e-03	8.39e-04	39
hsa0435031	Prostate	Tumor	TGF-beta signaling pathway	39/1791	108/8465	2.33e-04	1.35e-03	8.39e-04	39

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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

THSD4

SNV

Missense_Mutation

novel

c.2197N>G

p.Leu733Val

p.L733V

Q6ZMP0

protein_coding

deleterious(0.04)

probably_damaging(0.957)

TCGA-3C-AAAU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

zoladex

THSD4

SNV

Missense_Mutation

rs759524945

c.2575G>T

p.Gly859Trp

p.G859W

Q6ZMP0

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A7-A0DB-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

THSD4

SNV

Missense_Mutation

novel

c.1786N>G

p.Arg596Gly

p.R596G

Q6ZMP0

protein_coding

tolerated(0.32)

benign(0.001)

TCGA-A7-A6VY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

THSD4

SNV

Missense_Mutation

novel

c.1750G>A

p.Glu584Lys

p.E584K

Q6ZMP0

protein_coding

tolerated(0.42)

benign(0.003)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

THSD4

SNV

Missense_Mutation

rs757005156

c.1219G>A

p.Asp407Asn

p.D407N

Q6ZMP0

protein_coding

tolerated(0.06)

benign(0.069)

TCGA-AC-A5XS-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

femara

THSD4

SNV

Missense_Mutation

c.2854N>T

p.Pro952Ser

p.P952S

Q6ZMP0

protein_coding

tolerated(0.33)

benign(0.308)

TCGA-AC-A6IW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

THSD4

SNV

Missense_Mutation

rs749243314

c.940N>T

p.Arg314Trp

p.R314W

Q6ZMP0

protein_coding

deleterious(0.02)

benign(0.001)

TCGA-AC-A8OQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

THSD4

SNV

Missense_Mutation

c.920C>T

p.Pro307Leu

p.P307L

Q6ZMP0

protein_coding

deleterious(0.01)

probably_damaging(0.996)

TCGA-C8-A12T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

THSD4

SNV

Missense_Mutation

novel

c.2719N>A

p.Cys907Ser

p.C907S

Q6ZMP0

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-OL-A5RZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

THSD4

insertion

Nonsense_Mutation

novel

c.1979_1980insTGCCTTTGAGCATATTTAGACCGTGTCCA

p.Ser661AlafsTer6

p.S661Afs*6

Q6ZMP0

protein_coding

TCGA-A2-A04X-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

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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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