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: TNFAIP3

Gene summary for TNFAIP3

Gene summary.

Gene information	Species	Human
	Gene symbol	TNFAIP3
	Gene ID	7128
	Gene name	TNF alpha induced protein 3
	Gene Alias	A20
	Cytomap	6q23.3
	Gene Type	protein-coding
	GO ID	GO:0000079
	UniProtAcc	P21580

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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
7128	TNFAIP3	CA_HPV_3	Human	Cervix	CC	4.29e-05	-3.50e-01	0.0414
7128	TNFAIP3	HSIL_HPV_1	Human	Cervix	HSIL_HPV	2.25e-05	-5.14e-01	0.0116
7128	TNFAIP3	HSIL_HPV_2	Human	Cervix	HSIL_HPV	1.42e-14	-5.80e-01	0.0208
7128	TNFAIP3	N_HPV_2	Human	Cervix	N_HPV	1.38e-03	3.37e-01	-0.0131
7128	TNFAIP3	CCI_3	Human	Cervix	CC	1.02e-02	-6.00e-01	0.516
7128	TNFAIP3	CCII_1	Human	Cervix	CC	1.24e-07	-7.05e-01	0.3249
7128	TNFAIP3	Tumor	Human	Cervix	CC	7.02e-16	-4.63e-01	0.1241
7128	TNFAIP3	sample3	Human	Cervix	CC	5.99e-09	-3.58e-01	0.1387
7128	TNFAIP3	H2	Human	Cervix	HSIL_HPV	1.70e-05	-4.43e-01	0.0632
7128	TNFAIP3	T1	Human	Cervix	CC	3.92e-05	2.14e-01	0.0918
7128	TNFAIP3	T3	Human	Cervix	CC	3.73e-10	-3.45e-01	0.1389
7128	TNFAIP3	AEH-subject1	Human	Endometrium	AEH	1.78e-14	5.96e-01	-0.3059
7128	TNFAIP3	AEH-subject2	Human	Endometrium	AEH	3.95e-02	2.91e-01	-0.2525
7128	TNFAIP3	AEH-subject3	Human	Endometrium	AEH	1.05e-02	2.51e-01	-0.2576
7128	TNFAIP3	AEH-subject4	Human	Endometrium	AEH	3.86e-27	9.07e-01	-0.2657
7128	TNFAIP3	AEH-subject5	Human	Endometrium	AEH	1.40e-32	8.87e-01	-0.2953
7128	TNFAIP3	EEC-subject1	Human	Endometrium	EEC	3.69e-10	4.81e-01	-0.2682
7128	TNFAIP3	EEC-subject2	Human	Endometrium	EEC	8.81e-12	4.29e-01	-0.2607
7128	TNFAIP3	EEC-subject3	Human	Endometrium	EEC	5.40e-23	7.03e-01	-0.2525
7128	TNFAIP3	EEC-subject4	Human	Endometrium	EEC	1.60e-32	8.79e-01	-0.2571

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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:000007921	Thyroid	ATC	regulation of cyclin-dependent protein serine/threonine kinase activity	51/6293	94/18723	2.97e-05	2.48e-04	51
GO:003461228	Thyroid	ATC	response to tumor necrosis factor	116/6293	253/18723	3.22e-05	2.68e-04	116
GO:000283123	Thyroid	ATC	regulation of response to biotic stimulus	144/6293	327/18723	4.94e-05	3.91e-04	144
GO:000275315	Thyroid	ATC	cytoplasmic pattern recognition receptor signaling pathway	35/6293	60/18723	7.31e-05	5.56e-04	35
GO:007266523	Thyroid	ATC	protein localization to vacuole	38/6293	67/18723	8.48e-05	6.33e-04	38
GO:007266614	Thyroid	ATC	establishment of protein localization to vacuole	29/6293	49/18723	2.11e-04	1.39e-03	29
GO:000222114	Thyroid	ATC	pattern recognition receptor signaling pathway	80/6293	172/18723	2.89e-04	1.84e-03	80
GO:006075912	Thyroid	ATC	regulation of response to cytokine stimulus	76/6293	162/18723	2.92e-04	1.85e-03	76
GO:007190122	Thyroid	ATC	negative regulation of protein serine/threonine kinase activity	59/6293	120/18723	2.95e-04	1.87e-03	59
GO:000195912	Thyroid	ATC	regulation of cytokine-mediated signaling pathway	71/6293	150/18723	3.28e-04	2.04e-03	71
GO:007135627	Thyroid	ATC	cellular response to tumor necrosis factor	102/6293	229/18723	3.52e-04	2.18e-03	102
GO:005160712	Thyroid	ATC	defense response to virus	115/6293	265/18723	5.31e-04	3.09e-03	115
GO:014054612	Thyroid	ATC	defense response to symbiont	115/6293	265/18723	5.31e-04	3.09e-03	115
GO:190401921	Thyroid	ATC	epithelial cell apoptotic process	58/6293	121/18723	7.47e-04	4.14e-03	58
GO:003300214	Thyroid	ATC	muscle cell proliferation	107/6293	248/18723	1.03e-03	5.47e-03	107
GO:190204212	Thyroid	ATC	negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	19/6293	31/18723	1.45e-03	7.47e-03	19
GO:003320917	Thyroid	ATC	tumor necrosis factor-mediated signaling pathway	48/6293	99/18723	1.51e-03	7.70e-03	48
GO:007064613	Thyroid	ATC	protein modification by small protein removal	71/6293	157/18723	1.59e-03	7.99e-03	71
GO:00487715	Thyroid	ATC	tissue remodeling	78/6293	175/18723	1.60e-03	8.04e-03	78
GO:00457657	Thyroid	ATC	regulation of angiogenesis	141/6293	342/18723	1.80e-03	8.85e-03	141

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0516920	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0465718	Cervix	CC	IL-17 signaling pathway	31/1267	94/8465	8.71e-06	7.43e-05	4.39e-05	31
hsa046686	Cervix	CC	TNF signaling pathway	28/1267	114/8465	4.60e-03	1.62e-02	9.59e-03	28
hsa046213	Cervix	CC	NOD-like receptor signaling pathway	41/1267	186/8465	5.90e-03	1.95e-02	1.15e-02	41
hsa05169110	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0465719	Cervix	CC	IL-17 signaling pathway	31/1267	94/8465	8.71e-06	7.43e-05	4.39e-05	31
hsa0466813	Cervix	CC	TNF signaling pathway	28/1267	114/8465	4.60e-03	1.62e-02	9.59e-03	28
hsa0462112	Cervix	CC	NOD-like receptor signaling pathway	41/1267	186/8465	5.90e-03	1.95e-02	1.15e-02	41
hsa0465722	Cervix	HSIL_HPV	IL-17 signaling pathway	15/459	94/8465	1.45e-04	1.74e-03	1.40e-03	15
hsa0516923	Cervix	HSIL_HPV	Epstein-Barr virus infection	22/459	202/8465	1.35e-03	9.68e-03	7.82e-03	22
hsa0465732	Cervix	HSIL_HPV	IL-17 signaling pathway	15/459	94/8465	1.45e-04	1.74e-03	1.40e-03	15
hsa0516933	Cervix	HSIL_HPV	Epstein-Barr virus infection	22/459	202/8465	1.35e-03	9.68e-03	7.82e-03	22
hsa0516942	Cervix	N_HPV	Epstein-Barr virus infection	19/349	202/8465	6.54e-04	4.94e-03	3.86e-03	19
hsa0516952	Cervix	N_HPV	Epstein-Barr virus infection	19/349	202/8465	6.54e-04	4.94e-03	3.86e-03	19
hsa0516924	Endometrium	AEH	Epstein-Barr virus infection	42/1197	202/8465	5.72e-03	3.05e-02	2.23e-02	42
hsa05169111	Endometrium	AEH	Epstein-Barr virus infection	42/1197	202/8465	5.72e-03	3.05e-02	2.23e-02	42
hsa0516925	Endometrium	EEC	Epstein-Barr virus infection	47/1237	202/8465	6.17e-04	4.41e-03	3.29e-03	47
hsa046687	Endometrium	EEC	TNF signaling pathway	27/1237	114/8465	6.47e-03	3.22e-02	2.40e-02	27
hsa0465720	Endometrium	EEC	IL-17 signaling pathway	23/1237	94/8465	7.61e-03	3.63e-02	2.71e-02	23
hsa0516934	Endometrium	EEC	Epstein-Barr virus infection	47/1237	202/8465	6.17e-04	4.41e-03	3.29e-03	47

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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

TNFAIP3

SNV

Missense_Mutation

c.36N>C

p.Leu12Phe

p.L12F

P21580

protein_coding

tolerated(0.29)

benign(0.2)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

TNFAIP3

SNV

Missense_Mutation

c.1439N>A

p.Ser480Asn

p.S480N

P21580

protein_coding

deleterious(0.01)

benign(0.003)

TCGA-A2-A04P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxol

TNFAIP3

SNV

Missense_Mutation

c.979N>T

p.Ala327Ser

p.A327S

P21580

protein_coding

tolerated(0.07)

benign(0.305)

TCGA-A2-A0YG-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

TNFAIP3

SNV

Missense_Mutation

c.650N>C

p.Ser217Thr

p.S217T

P21580

protein_coding

deleterious(0.01)

possibly_damaging(0.79)

TCGA-AO-A1KR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

TNFAIP3

SNV

Missense_Mutation

c.1711N>A

p.Val571Ile

p.V571I

P21580

protein_coding

tolerated(0.48)

benign(0)

TCGA-BH-A0H6-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TNFAIP3

deletion

Frame_Shift_Del

novel

c.285_294delNNNNNNNNNN

p.Lys96ValfsTer24

p.K96Vfs*24

P21580

protein_coding

TCGA-A2-A25B-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

TNFAIP3

insertion

Frame_Shift_Ins

novel

c.2184_2185insACATTAGT

p.Ser729ThrfsTer90

p.S729Tfs*90

P21580

protein_coding

TCGA-AR-A0TW-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

TNFAIP3

SNV

Missense_Mutation

rs775850329

c.259N>G

p.Arg87Gly

p.R87G

P21580

protein_coding

deleterious(0.03)

benign(0.009)

TCGA-C5-A2M2-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

TNFAIP3

SNV

Missense_Mutation

c.2193N>T

p.Glu731Asp

p.E731D

P21580

protein_coding

tolerated(0.67)

benign(0.031)

TCGA-DS-A7WF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TNFAIP3

SNV

Missense_Mutation

novel

c.217N>G

p.Ile73Val

p.I73V

P21580

protein_coding

tolerated(1)

benign(0)

TCGA-5M-AAT4-01

Colorectum

colon adenocarcinoma

Male

>=65

III/IV

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
7128	TNFAIP3	PROTEASE, ENZYME, CLINICALLY ACTIONABLE, KINASE		Tumor necrosis factor alpha (TNF-alpha) inhibitors		24776844,30653751
7128	TNFAIP3	PROTEASE, ENZYME, CLINICALLY ACTIONABLE, KINASE		ustekinumab	USTEKINUMAB	27564082,23521149
7128	TNFAIP3	PROTEASE, ENZYME, CLINICALLY ACTIONABLE, KINASE		methotrexate	METHOTREXATE	20921970

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