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: TNFSF10

Gene summary for TNFSF10

Gene summary.

Gene information	Species	Human
	Gene symbol	TNFSF10
	Gene ID	8743
	Gene name	TNF superfamily member 10
	Gene Alias	APO2L
	Cytomap	3q26.31
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P50591

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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
8743	TNFSF10	GSM4909281	Human	Breast	IDC	2.26e-13	-4.63e-01	0.21
8743	TNFSF10	GSM4909285	Human	Breast	IDC	1.95e-14	4.36e-01	0.21
8743	TNFSF10	GSM4909286	Human	Breast	IDC	2.34e-26	-5.30e-01	0.1081
8743	TNFSF10	GSM4909287	Human	Breast	IDC	2.60e-06	-3.07e-01	0.2057
8743	TNFSF10	GSM4909293	Human	Breast	IDC	4.25e-36	8.14e-01	0.1581
8743	TNFSF10	GSM4909295	Human	Breast	IDC	1.90e-03	-3.86e-01	0.0898
8743	TNFSF10	GSM4909296	Human	Breast	IDC	6.97e-07	-2.95e-01	0.1524
8743	TNFSF10	GSM4909297	Human	Breast	IDC	4.65e-12	-3.06e-01	0.1517
8743	TNFSF10	GSM4909298	Human	Breast	IDC	1.10e-03	-3.20e-01	0.1551
8743	TNFSF10	GSM4909299	Human	Breast	IDC	4.91e-02	2.75e-01	0.035
8743	TNFSF10	GSM4909302	Human	Breast	IDC	3.36e-08	-3.37e-01	0.1545
8743	TNFSF10	GSM4909304	Human	Breast	IDC	9.66e-27	-5.23e-01	0.1636
8743	TNFSF10	GSM4909305	Human	Breast	IDC	1.85e-02	4.17e-01	0.0436
8743	TNFSF10	GSM4909309	Human	Breast	IDC	1.74e-04	3.67e-01	0.0483
8743	TNFSF10	GSM4909311	Human	Breast	IDC	6.51e-13	-2.25e-01	0.1534
8743	TNFSF10	GSM4909315	Human	Breast	IDC	2.33e-05	-2.80e-01	0.21
8743	TNFSF10	GSM4909316	Human	Breast	IDC	2.40e-02	-4.04e-01	0.21
8743	TNFSF10	GSM4909318	Human	Breast	IDC	1.97e-04	-5.31e-01	0.2031
8743	TNFSF10	GSM4909319	Human	Breast	IDC	1.37e-21	-4.41e-01	0.1563
8743	TNFSF10	GSM4909320	Human	Breast	IDC	6.38e-08	-4.53e-01	0.1575

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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
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
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:20012339	Breast	Precancer	regulation of apoptotic signaling pathway	65/1080	356/18723	7.70e-17	3.17e-14	65
GO:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:20001169	Breast	Precancer	regulation of cysteine-type endopeptidase activity	43/1080	235/18723	1.30e-11	1.83e-09	43
GO:00432819	Breast	Precancer	regulation of cysteine-type endopeptidase activity involved in apoptotic process	40/1080	209/18723	1.59e-11	2.07e-09	40
GO:00458629	Breast	Precancer	positive regulation of proteolysis	51/1080	372/18723	7.77e-09	5.70e-07	51
GO:00109529	Breast	Precancer	positive regulation of peptidase activity	33/1080	197/18723	3.01e-08	1.89e-06	33
GO:00086378	Breast	Precancer	apoptotic mitochondrial changes	23/1080	107/18723	3.44e-08	2.12e-06	23
GO:20012356	Breast	Precancer	positive regulation of apoptotic signaling pathway	24/1080	126/18723	1.98e-07	1.01e-05	24
GO:00432808	Breast	Precancer	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	24/1080	129/18723	3.13e-07	1.50e-05	24
GO:00109509	Breast	Precancer	positive regulation of endopeptidase activity	29/1080	179/18723	4.23e-07	1.90e-05	29
GO:20010568	Breast	Precancer	positive regulation of cysteine-type endopeptidase activity	25/1080	148/18723	1.19e-06	4.60e-05	25
GO:00018367	Breast	Precancer	release of cytochrome c from mitochondria	14/1080	59/18723	4.80e-06	1.47e-04	14
GO:20012369	Breast	Precancer	regulation of extrinsic apoptotic signaling pathway	24/1080	151/18723	5.78e-06	1.70e-04	24
GO:00971919	Breast	Precancer	extrinsic apoptotic signaling pathway	30/1080	219/18723	9.42e-06	2.50e-04	30
GO:00486087	Breast	Precancer	reproductive structure development	43/1080	424/18723	2.36e-04	3.56e-03	43
GO:00614587	Breast	Precancer	reproductive system development	43/1080	427/18723	2.75e-04	4.00e-03	43
GO:00901996	Breast	Precancer	regulation of release of cytochrome c from mitochondria	10/1080	48/18723	3.43e-04	4.81e-03	10
GO:00108217	Breast	Precancer	regulation of mitochondrion organization	19/1080	144/18723	6.26e-04	7.78e-03	19
GO:0046661	Breast	Precancer	male sex differentiation	19/1080	165/18723	3.14e-03	2.65e-02	19

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0513218	Breast	Precancer	Salmonella infection	49/684	249/8465	2.92e-09	6.15e-08	4.71e-08	49
hsa0513018	Breast	Precancer	Pathogenic Escherichia coli infection	38/684	197/8465	3.12e-07	5.81e-06	4.45e-06	38
hsa0541718	Breast	Precancer	Lipid and atherosclerosis	37/684	215/8465	7.64e-06	9.29e-05	7.12e-05	37
hsa042108	Breast	Precancer	Apoptosis	25/684	136/8465	7.61e-05	6.87e-04	5.26e-04	25
hsa0513219	Breast	Precancer	Salmonella infection	49/684	249/8465	2.92e-09	6.15e-08	4.71e-08	49
hsa0513019	Breast	Precancer	Pathogenic Escherichia coli infection	38/684	197/8465	3.12e-07	5.81e-06	4.45e-06	38
hsa0541719	Breast	Precancer	Lipid and atherosclerosis	37/684	215/8465	7.64e-06	9.29e-05	7.12e-05	37
hsa0421013	Breast	Precancer	Apoptosis	25/684	136/8465	7.61e-05	6.87e-04	5.26e-04	25
hsa0513224	Breast	IDC	Salmonella infection	55/867	249/8465	2.07e-08	4.49e-07	3.36e-07	55
hsa0513024	Breast	IDC	Pathogenic Escherichia coli infection	42/867	197/8465	2.66e-06	3.92e-05	2.94e-05	42
hsa0421022	Breast	IDC	Apoptosis	31/867	136/8465	1.34e-05	1.61e-04	1.20e-04	31
hsa0541724	Breast	IDC	Lipid and atherosclerosis	35/867	215/8465	3.67e-03	2.29e-02	1.71e-02	35
hsa0513234	Breast	IDC	Salmonella infection	55/867	249/8465	2.07e-08	4.49e-07	3.36e-07	55
hsa0513034	Breast	IDC	Pathogenic Escherichia coli infection	42/867	197/8465	2.66e-06	3.92e-05	2.94e-05	42
hsa0421032	Breast	IDC	Apoptosis	31/867	136/8465	1.34e-05	1.61e-04	1.20e-04	31
hsa0541734	Breast	IDC	Lipid and atherosclerosis	35/867	215/8465	3.67e-03	2.29e-02	1.71e-02	35
hsa0513243	Breast	DCIS	Salmonella infection	55/846	249/8465	8.71e-09	1.87e-07	1.38e-07	55
hsa0513043	Breast	DCIS	Pathogenic Escherichia coli infection	42/846	197/8465	1.40e-06	2.15e-05	1.59e-05	42
hsa0421041	Breast	DCIS	Apoptosis	29/846	136/8465	5.92e-05	5.97e-04	4.40e-04	29
hsa0541744	Breast	DCIS	Lipid and atherosclerosis	34/846	215/8465	4.50e-03	2.46e-02	1.82e-02	34

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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
TNFSF10	TNFRSF10A	TNFSF10_TNFRSF10B	TRAIL	Cervix	CC
TNFSF10	TNFRSF10A	TNFSF10_TNFRSF10B	TRAIL	CRC	MSI-H
TNFSF10	TNFRSF10A	TNFSF10_TNFRSF10B	TRAIL	CRC	MSS
TNFSF10	TNFRSF10A	TNFSF10_TNFRSF10B	TRAIL	Lung	AAH

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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

TNFSF10

SNV

Missense_Mutation

rs758693727

c.708N>C

p.Glu236Asp

p.E236D

P50591

protein_coding

tolerated(0.09)

benign(0.019)

TCGA-BH-A0C7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

TNFSF10

insertion

Frame_Shift_Ins

novel

c.224_225insGAATTCTTCTGGCCTTCTC

p.Ser75ArgfsTer21

p.S75Rfs*21

P50591

protein_coding

TCGA-A2-A0D1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

TNFSF10

insertion

Frame_Shift_Ins

novel

c.222_223insTTTA

p.Ser75PhefsTer16

p.S75Ffs*16

P50591

protein_coding

TCGA-A2-A0D1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

TNFSF10

SNV

Missense_Mutation

c.279N>C

p.Leu93Phe

p.L93F

P50591

protein_coding

tolerated(0.49)

probably_damaging(0.963)

TCGA-JX-A3Q0-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

TNFSF10

SNV

Missense_Mutation

c.730C>A

p.Gln244Lys

p.Q244K

P50591

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TNFSF10

SNV

Missense_Mutation

c.340N>A

p.Val114Met

p.V114M

P50591

protein_coding

tolerated(0.13)

benign(0.258)

TCGA-AA-3833-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Unknown

TNFSF10

SNV

Missense_Mutation

rs757021342

c.254G>A

p.Arg85His

p.R85H

P50591

protein_coding

tolerated(1)

benign(0)

TCGA-AA-3949-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

TNFSF10

SNV

Missense_Mutation

rs200301971

c.572N>A

p.Arg191Gln

p.R191Q

P50591

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AJ-A3EL-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

TNFSF10

SNV

Missense_Mutation

novel

c.482N>G

p.His161Arg

p.H161R

P50591

protein_coding

tolerated(0.39)

probably_damaging(0.932)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

TNFSF10

SNV

Missense_Mutation

novel

c.158G>A

p.Gly53Asp

p.G53D

P50591

protein_coding

deleterious(0.01)

possibly_damaging(0.536)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

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
8743	TNFSF10	DRUGGABLE GENOME		Ad5-TRAIL
8743	TNFSF10	DRUGGABLE GENOME		DA-3607
8743	TNFSF10	DRUGGABLE GENOME		TRICHOSTATIN A		16096370
8743	TNFSF10	DRUGGABLE GENOME		SODIUM BUTYRATE		16096370

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