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:007265918	Oral cavity	OSCC	protein localization to plasma membrane	169/7305	284/18723	1.69e-12	7.21e-11	169
GO:00709369	Oral cavity	OSCC	protein K48-linked ubiquitination	53/7305	65/18723	2.47e-12	1.02e-10	53
GO:007149620	Oral cavity	OSCC	cellular response to external stimulus	186/7305	320/18723	2.56e-12	1.05e-10	186
GO:001082117	Oral cavity	OSCC	regulation of mitochondrion organization	97/7305	144/18723	4.78e-12	1.83e-10	97
GO:000863018	Oral cavity	OSCC	intrinsic apoptotic signaling pathway in response to DNA damage	72/7305	99/18723	9.50e-12	3.50e-10	72
GO:200123620	Oral cavity	OSCC	regulation of extrinsic apoptotic signaling pathway	100/7305	151/18723	1.07e-11	3.90e-10	100
GO:003009920	Oral cavity	OSCC	myeloid cell differentiation	213/7305	381/18723	1.24e-11	4.42e-10	213
GO:199077816	Oral cavity	OSCC	protein localization to cell periphery	190/7305	333/18723	1.46e-11	5.13e-10	190
GO:001095220	Oral cavity	OSCC	positive regulation of peptidase activity	123/7305	197/18723	2.12e-11	7.21e-10	123
GO:004232619	Oral cavity	OSCC	negative regulation of phosphorylation	214/7305	385/18723	2.30e-11	7.74e-10	214
GO:200011718	Oral cavity	OSCC	negative regulation of cysteine-type endopeptidase activity	64/7305	86/18723	2.53e-11	8.44e-10	64
GO:003298410	Oral cavity	OSCC	protein-containing complex disassembly	136/7305	224/18723	3.42e-11	1.13e-09	136
GO:007099720	Oral cavity	OSCC	neuron death	202/7305	361/18723	3.75e-11	1.23e-09	202
GO:007190010	Oral cavity	OSCC	regulation of protein serine/threonine kinase activity	201/7305	359/18723	3.90e-11	1.27e-09	201
GO:005254820	Oral cavity	OSCC	regulation of endopeptidase activity	235/7305	432/18723	4.35e-11	1.40e-09	235
GO:004315417	Oral cavity	OSCC	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process	59/7305	78/18723	4.86e-11	1.53e-09	59
GO:190390020	Oral cavity	OSCC	regulation of viral life cycle	97/7305	148/18723	5.34e-11	1.67e-09	97
GO:005170120	Oral cavity	OSCC	biological process involved in interaction with host	125/7305	203/18723	5.60e-11	1.74e-09	125
GO:007121416	Oral cavity	OSCC	cellular response to abiotic stimulus	186/7305	331/18723	1.38e-10	4.10e-09	186
GO:010400416	Oral cavity	OSCC	cellular response to environmental stimulus	186/7305	331/18723	1.38e-10	4.10e-09	186

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05014210	Esophagus	ESCC	Amyotrophic lateral sclerosis	266/4205	364/8465	1.31e-20	2.20e-18	1.13e-18	266
hsa05132211	Esophagus	ESCC	Salmonella infection	191/4205	249/8465	6.51e-19	5.45e-17	2.79e-17	191
hsa05022210	Esophagus	ESCC	Pathways of neurodegeneration - multiple diseases	318/4205	476/8465	6.10e-15	2.04e-13	1.05e-13	318
hsa05010210	Esophagus	ESCC	Alzheimer disease	263/4205	384/8465	1.80e-14	5.47e-13	2.80e-13	263
hsa04932210	Esophagus	ESCC	Non-alcoholic fatty liver disease	122/4205	155/8465	5.69e-14	1.59e-12	8.14e-13	122
hsa05166211	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa05169210	Esophagus	ESCC	Epstein-Barr virus infection	151/4205	202/8465	1.55e-13	3.45e-12	1.77e-12	151
hsa05020210	Esophagus	ESCC	Prion disease	193/4205	273/8465	6.42e-13	1.34e-11	6.89e-12	193
hsa05418211	Esophagus	ESCC	Fluid shear stress and atherosclerosis	109/4205	139/8465	2.00e-12	3.72e-11	1.90e-11	109
hsa05131211	Esophagus	ESCC	Shigellosis	176/4205	247/8465	2.27e-12	4.01e-11	2.05e-11	176
hsa05130211	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142
hsa0466810	Esophagus	ESCC	TNF signaling pathway	89/4205	114/8465	3.36e-10	4.01e-09	2.06e-09	89
hsa0421027	Esophagus	ESCC	Apoptosis	102/4205	136/8465	1.05e-09	1.21e-08	6.21e-09	102
hsa05170210	Esophagus	ESCC	Human immunodeficiency virus 1 infection	147/4205	212/8465	3.37e-09	3.53e-08	1.81e-08	147
hsa0516425	Esophagus	ESCC	Influenza A	122/4205	171/8465	5.01e-09	4.79e-08	2.45e-08	122
hsa0516510	Esophagus	ESCC	Human papillomavirus infection	215/4205	331/8465	7.86e-09	7.12e-08	3.65e-08	215
hsa0513526	Esophagus	ESCC	Yersinia infection	100/4205	137/8465	1.80e-08	1.59e-07	8.12e-08	100
hsa05171211	Esophagus	ESCC	Coronavirus disease - COVID-19	156/4205	232/8465	3.18e-08	2.68e-07	1.37e-07	156
hsa0520529	Esophagus	ESCC	Proteoglycans in cancer	138/4205	205/8465	1.79e-07	1.40e-06	7.15e-07	138
hsa05417211	Esophagus	ESCC	Lipid and atherosclerosis	143/4205	215/8465	3.30e-07	2.45e-06	1.26e-06	143

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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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