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: TNF

Gene summary for TNF

Gene summary.

Gene information	Species	Human
	Gene symbol	TNF
	Gene ID	7124
	Gene name	tumor necrosis factor
	Gene Alias	DIF
	Cytomap	6p21.33
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	P01375

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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
7124	TNF	LZE4T	Human	Esophagus	ESCC	1.70e-04	2.63e-01	0.0811
7124	TNF	LZE7T	Human	Esophagus	ESCC	1.42e-05	7.23e-01	0.0667
7124	TNF	LZE22T	Human	Esophagus	ESCC	1.51e-04	6.04e-01	0.068
7124	TNF	LZE6T	Human	Esophagus	ESCC	3.87e-07	4.90e-01	0.0845
7124	TNF	P1T-E	Human	Esophagus	ESCC	7.25e-06	1.28e+00	0.0875
7124	TNF	P2T-E	Human	Esophagus	ESCC	8.66e-119	3.77e+00	0.1177
7124	TNF	P4T-E	Human	Esophagus	ESCC	1.88e-27	1.24e+00	0.1323
7124	TNF	P5T-E	Human	Esophagus	ESCC	1.35e-10	6.72e-01	0.1327
7124	TNF	P11T-E	Human	Esophagus	ESCC	1.60e-02	8.20e-01	0.1426
7124	TNF	P16T-E	Human	Esophagus	ESCC	7.98e-43	1.39e+00	0.1153
7124	TNF	P20T-E	Human	Esophagus	ESCC	8.32e-11	8.03e-01	0.1124
7124	TNF	P21T-E	Human	Esophagus	ESCC	3.35e-10	8.56e-01	0.1617
7124	TNF	P23T-E	Human	Esophagus	ESCC	8.79e-14	1.73e+00	0.108
7124	TNF	P24T-E	Human	Esophagus	ESCC	1.07e-16	8.13e-01	0.1287
7124	TNF	P27T-E	Human	Esophagus	ESCC	1.48e-05	7.80e-01	0.1055
7124	TNF	P31T-E	Human	Esophagus	ESCC	5.34e-21	1.02e+00	0.1251
7124	TNF	P36T-E	Human	Esophagus	ESCC	1.62e-03	4.05e-01	0.1187
7124	TNF	P37T-E	Human	Esophagus	ESCC	3.18e-35	1.55e+00	0.1371
7124	TNF	P40T-E	Human	Esophagus	ESCC	2.10e-06	4.96e-01	0.109
7124	TNF	P42T-E	Human	Esophagus	ESCC	7.98e-18	1.18e+00	0.1175

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma

∗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:00420609	Breast	Precancer	wound healing	48/1080	422/18723	5.48e-06	1.63e-04	48
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:0050727	Breast	Precancer	regulation of inflammatory response	44/1080	386/18723	1.26e-05	3.22e-04	44
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

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0421036	Oral cavity	LP	Apoptosis	65/2418	136/8465	1.33e-06	1.48e-05	9.53e-06	65
hsa0513038	Oral cavity	LP	Pathogenic Escherichia coli infection	87/2418	197/8465	1.71e-06	1.78e-05	1.15e-05	87
hsa0517037	Oral cavity	LP	Human immunodeficiency virus 1 infection	92/2418	212/8465	2.18e-06	2.20e-05	1.42e-05	92
hsa0513435	Oral cavity	LP	Legionellosis	33/2418	57/8465	3.29e-06	3.23e-05	2.08e-05	33
hsa0541838	Oral cavity	LP	Fluid shear stress and atherosclerosis	65/2418	139/8465	3.42e-06	3.26e-05	2.10e-05	65
hsa0513138	Oral cavity	LP	Shigellosis	103/2418	247/8465	4.98e-06	4.14e-05	2.67e-05	103
hsa0465733	Oral cavity	LP	IL-17 signaling pathway	47/2418	94/8465	8.45e-06	6.25e-05	4.03e-05	47
hsa0514534	Oral cavity	LP	Toxoplasmosis	51/2418	112/8465	8.99e-05	5.54e-04	3.57e-04	51
hsa0513535	Oral cavity	LP	Yersinia infection	59/2418	137/8465	1.81e-04	1.04e-03	6.71e-04	59
hsa0461237	Oral cavity	LP	Antigen processing and presentation	37/2418	78/8465	2.98e-04	1.60e-03	1.03e-03	37
hsa0541738	Oral cavity	LP	Lipid and atherosclerosis	84/2418	215/8465	5.02e-04	2.61e-03	1.68e-03	84
hsa0466832	Oral cavity	LP	TNF signaling pathway	49/2418	114/8465	6.51e-04	3.29e-03	2.12e-03	49
hsa0516533	Oral cavity	LP	Human papillomavirus infection	121/2418	331/8465	8.00e-04	3.86e-03	2.49e-03	121
hsa0516131	Oral cavity	LP	Hepatitis B	65/2418	162/8465	9.31e-04	4.43e-03	2.86e-03	65
hsa0462131	Oral cavity	LP	NOD-like receptor signaling pathway	73/2418	186/8465	9.80e-04	4.53e-03	2.92e-03	73
hsa0516337	Oral cavity	LP	Human cytomegalovirus infection	85/2418	225/8465	1.55e-03	6.89e-03	4.45e-03	85
hsa0520536	Oral cavity	LP	Proteoglycans in cancer	77/2418	205/8465	3.01e-03	1.29e-02	8.35e-03	77
hsa0462531	Oral cavity	LP	C-type lectin receptor signaling pathway	43/2418	104/8465	3.33e-03	1.41e-02	9.06e-03	43
hsa0407132	Oral cavity	LP	Sphingolipid signaling pathway	48/2418	121/8465	5.30e-03	2.15e-02	1.39e-02	48
hsa0513332	Oral cavity	LP	Pertussis	32/2418	76/8465	7.65e-03	2.93e-02	1.89e-02	32

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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
TNF	TNFRSF1A	TNF_TNFRSF1A	TNF	Breast	ADJ
TNF	TNFRSF1B	TNF_TNFRSF1B	TNF	Breast	ADJ
TNFSF13B	TNFRSF17	TNFSF13B_TNFRSF17	BAFF	Breast	DCIS
TNFSF13B	TNFRSF13B	TNFSF13B_TNFRSF13B	BAFF	Breast	DCIS
TNFSF13B	TNFRSF13C	TNFSF13B_TNFRSF13C	BAFF	Breast	DCIS
TNF	TNFRSF1A	TNF_TNFRSF1A	TNF	Breast	DCIS
TNF	TNFRSF1B	TNF_TNFRSF1B	TNF	Breast	DCIS
TNFSF14	TNFRSF14	TNFSF14_TNFRSF14	LIGHT	Breast	DCIS
TNFSF12	TNFRSF12A	TNFSF12_TNFRSF12A	TWEAK	Breast	DCIS
TNFSF9	TNFRSF9	TNFSF9_TNFRSF9	CD137	Breast	DCIS
TNF	TNFRSF1A	TNF_TNFRSF1A	TNF	Breast	Healthy
TNF	TNFRSF1B	TNF_TNFRSF1B	TNF	Breast	Healthy
TNFSF12	TNFRSF12A	TNFSF12_TNFRSF12A	TWEAK	Breast	Healthy
TNFSF13B	TNFRSF17	TNFSF13B_TNFRSF17	BAFF	Breast	Healthy
TNFSF13B	TNFRSF13C	TNFSF13B_TNFRSF13C	BAFF	Breast	Healthy
TNFSF9	TNFRSF9	TNFSF9_TNFRSF9	CD137	Breast	Healthy
TNFSF13B	TNFRSF17	TNFSF13B_TNFRSF17	BAFF	Breast	IDC
TNFSF13B	TNFRSF13C	TNFSF13B_TNFRSF13C	BAFF	Breast	IDC
TNFSF12	TNFRSF12A	TNFSF12_TNFRSF12A	TWEAK	Cervix	ADJ
LTA	TNFRSF1A	LTA_TNFRSF1A	LT	Cervix	ADJ

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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

TNF

SNV

Missense_Mutation

rs373646181

c.481N>A

p.Val161Ile

p.V161I

P01375

protein_coding

tolerated(0.2)

benign(0)

TCGA-CM-4752-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

TNF

SNV

Missense_Mutation

novel

c.186N>T

p.Glu62Asp

p.E62D

P01375

protein_coding

tolerated(0.08)

possibly_damaging(0.67)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

TNF

SNV

Missense_Mutation

rs369510319

c.473N>A

p.Arg158His

p.R158H

P01375

protein_coding

deleterious(0.03)

probably_damaging(0.98)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

TNF

SNV

Missense_Mutation

rs373646181

c.481N>A

p.Val161Ile

p.V161I

P01375

protein_coding

tolerated(0.2)

benign(0)

TCGA-EO-A22R-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

TNF

SNV

Missense_Mutation

novel

c.607N>A

p.Glu203Lys

p.E203K

P01375

protein_coding

tolerated(0.13)

benign(0.031)

TCGA-EO-A22T-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

TNF

SNV

Missense_Mutation

novel

c.341N>T

p.Ala114Val

p.A114V

P01375

protein_coding

tolerated(0.16)

benign(0.267)

TCGA-EO-A3B0-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

TNF

SNV

Missense_Mutation

rs777874746

c.169G>A

p.Gly57Ser

p.G57S

P01375

protein_coding

deleterious(0.03)

probably_damaging(0.995)

TCGA-FI-A2D5-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

carboplatinum

TNF

insertion

Frame_Shift_Ins

novel

c.315_316insGGTTTGGGTTTGGGGGT

p.Asn106GlyfsTer20

p.N106Gfs*20

P01375

protein_coding

TCGA-B5-A5OD-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

III/IV

Chemotherapy

carboplatin

TNF

insertion

Frame_Shift_Ins

novel

c.316_317insGGGTTAGT

p.Asn106ArgfsTer17

p.N106Rfs*17

P01375

protein_coding

TCGA-B5-A5OD-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

III/IV

Chemotherapy

carboplatin

TNF

SNV

Missense_Mutation

c.291N>T

p.Gln97His

p.Q97H

P01375

protein_coding

deleterious(0.05)

benign(0.161)

TCGA-ED-A459-01

Liver

liver hepatocellular carcinoma

Male

<65

I/II

Ancillary

alvesin

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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
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		HYDROXYCHLOROQUINE	HYDROXYCHLOROQUINE	9002011
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		MIDAZOLAM	MIDAZOLAM	16406030
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		SODIUM CROMOGLYCATE		7554404
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		CYT-609		20876255
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		ABT-122	REMTOLUMAB
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		rifampin	RIFAMPIN	22151084
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		DLX-105
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		PRAZOSIN HYDROCHLORIDE		11406472
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		CEFOTAXIME	CEFOTAXIME	8354907,10989981
7124	TNF	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE		CPL-7075	LENABASUM

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