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: TNFRSF21

Gene summary for TNFRSF21

Gene summary.

Gene information	Species	Human
	Gene symbol	TNFRSF21
	Gene ID	27242
	Gene name	TNF receptor superfamily member 21
	Gene Alias	BM-018
	Cytomap	6p12.3
	Gene Type	protein-coding
	GO ID	GO:0001775
	UniProtAcc	A0A024RD71

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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
27242	TNFRSF21	HTA11_2487_2000001011	Human	Colorectum	SER	7.43e-03	4.44e-01	-0.1808
27242	TNFRSF21	HTA11_411_2000001011	Human	Colorectum	SER	1.50e-02	1.02e+00	-0.2602
27242	TNFRSF21	HTA11_2112_2000001011	Human	Colorectum	SER	1.75e-03	7.46e-01	-0.2196
27242	TNFRSF21	A015-C-203	Human	Colorectum	FAP	4.11e-06	-1.66e-01	-0.1294
27242	TNFRSF21	A002-C-205	Human	Colorectum	FAP	1.51e-04	-2.02e-01	-0.1236
27242	TNFRSF21	A015-C-006	Human	Colorectum	FAP	1.18e-03	-2.49e-01	-0.0994
27242	TNFRSF21	A002-C-114	Human	Colorectum	FAP	3.46e-02	-1.55e-01	-0.1561
27242	TNFRSF21	A015-C-104	Human	Colorectum	FAP	9.49e-06	-1.27e-01	-0.1899
27242	TNFRSF21	A002-C-016	Human	Colorectum	FAP	1.37e-03	-9.78e-02	0.0521
27242	TNFRSF21	A002-C-116	Human	Colorectum	FAP	3.15e-05	-1.74e-01	-0.0452
27242	TNFRSF21	A018-E-020	Human	Colorectum	FAP	3.91e-03	-1.98e-01	-0.2034
27242	TNFRSF21	F034	Human	Colorectum	FAP	5.21e-04	-1.52e-01	-0.0665
27242	TNFRSF21	F072B	Human	Colorectum	FAP	1.20e-02	-1.57e-01	0.257
27242	TNFRSF21	LZE4T	Human	Esophagus	ESCC	1.07e-10	-4.55e-01	0.0811
27242	TNFRSF21	LZE5T	Human	Esophagus	ESCC	7.06e-06	-1.36e-02	0.0514
27242	TNFRSF21	LZE7T	Human	Esophagus	ESCC	1.31e-03	-2.41e-01	0.0667
27242	TNFRSF21	LZE8T	Human	Esophagus	ESCC	7.45e-04	-8.65e-02	0.067
27242	TNFRSF21	LZE20T	Human	Esophagus	ESCC	3.76e-02	1.96e-01	0.0662
27242	TNFRSF21	LZE24T	Human	Esophagus	ESCC	3.55e-03	4.94e-01	0.0596
27242	TNFRSF21	P2T-E	Human	Esophagus	ESCC	2.74e-15	-3.62e-01	0.1177

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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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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

∗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:000268317	Skin	AK	negative regulation of immune system process	67/1910	434/18723	3.74e-04	3.63e-03	67
GO:00425525	Skin	AK	myelination	27/1910	134/18723	4.20e-04	4.00e-03	27
GO:007135624	Skin	AK	cellular response to tumor necrosis factor	40/1910	229/18723	4.98e-04	4.58e-03	40
GO:00072725	Skin	AK	ensheathment of neurons	27/1910	136/18723	5.36e-04	4.85e-03	27
GO:00083665	Skin	AK	axon ensheathment	27/1910	136/18723	5.36e-04	4.85e-03	27
GO:00508529	Skin	AK	T cell receptor signaling pathway	25/1910	123/18723	5.89e-04	5.21e-03	25
GO:003461225	Skin	AK	response to tumor necrosis factor	41/1910	253/18723	1.92e-03	1.31e-02	41
GO:0008038	Skin	AK	neuron recognition	12/1910	49/18723	3.13e-03	1.94e-02	12
GO:005140220	Skin	AK	neuron apoptotic process	39/1910	246/18723	3.62e-03	2.17e-02	39
GO:00027647	Skin	AK	immune response-regulating signaling pathway	66/1910	468/18723	4.18e-03	2.45e-02	66
GO:00224087	Skin	AK	negative regulation of cell-cell adhesion	32/1910	196/18723	5.06e-03	2.84e-02	32
GO:00022535	Skin	AK	activation of immune response	54/1910	375/18723	5.90e-03	3.20e-02	54
GO:00316411	Skin	AK	regulation of myelination	11/1910	47/18723	6.62e-03	3.50e-02	11
GO:0022407110	Skin	SCCIS	regulation of cell-cell adhesion	53/919	448/18723	2.75e-09	1.45e-06	53
GO:0042110110	Skin	SCCIS	T cell activation	53/919	487/18723	4.77e-08	8.19e-06	53
GO:000268318	Skin	SCCIS	negative regulation of immune system process	49/919	434/18723	4.92e-08	8.19e-06	49
GO:0007159110	Skin	SCCIS	leukocyte cell-cell adhesion	44/919	371/18723	5.77e-08	9.01e-06	44
GO:190303719	Skin	SCCIS	regulation of leukocyte cell-cell adhesion	40/919	336/18723	2.09e-07	2.17e-05	40
GO:005086318	Skin	SCCIS	regulation of T cell activation	39/919	329/18723	3.30e-07	3.03e-05	39
GO:006156417	Skin	SCCIS	axon development	49/919	467/18723	4.63e-07	3.77e-05	49

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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

TNFRSF21

SNV

Missense_Mutation

c.1600N>A

p.Ala534Thr

p.A534T

O75509

protein_coding

tolerated(1)

benign(0)

TCGA-A8-A097-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

TNFRSF21

insertion

In_Frame_Ins

novel

c.420_421insTATACCAAAGATGTTTTCTCCATTTCGTGTATTCCAAAG

p.Ser140_Asn141insTyrThrLysAspValPheSerIleSerCysIleProLys

p.S140_N141insYTKDVFSISCIPK

O75509

protein_coding

TCGA-A8-A09M-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

paclitaxel

TNFRSF21

insertion

Frame_Shift_Ins

novel

c.1319_1320insACACACACACACACGCATACGCCTGCACA

p.Ser441HisfsTer48

p.S441Hfs*48

O75509

protein_coding

TCGA-AQ-A04J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

TNFRSF21

SNV

Missense_Mutation

rs781439087

c.1414G>A

p.Glu472Lys

p.E472K

O75509

protein_coding

deleterious(0.01)

benign(0.266)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TNFRSF21

SNV

Missense_Mutation

c.1224N>G

p.Ile408Met

p.I408M

O75509

protein_coding

deleterious(0.04)

possibly_damaging(0.779)

TCGA-EK-A2PL-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

TNFRSF21

SNV

Missense_Mutation

c.1036N>G

p.Ile346Val

p.I346V

O75509

protein_coding

deleterious(0)

probably_damaging(0.991)

TCGA-EK-A2RE-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

TNFRSF21

SNV

Missense_Mutation

rs778427574

c.1769N>A

p.Arg590His

p.R590H

O75509

protein_coding

deleterious(0)

probably_damaging(0.981)

TCGA-AA-3672-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

TNFRSF21

SNV

Missense_Mutation

c.1376N>T

p.Ala459Val

p.A459V

O75509

protein_coding

deleterious(0)

possibly_damaging(0.64)

TCGA-AA-3854-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

TNFRSF21

SNV

Missense_Mutation

rs867596127

c.1483N>T

p.Arg495Cys

p.R495C

O75509

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

TNFRSF21

SNV

Missense_Mutation

c.1363G>A

p.Asp455Asn

p.D455N

O75509

protein_coding

deleterious(0.01)

probably_damaging(0.976)

TCGA-CK-5913-01

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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