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: CASP8

Gene summary for CASP8

Gene summary.

Gene information	Species	Human
	Gene symbol	CASP8
	Gene ID	841
	Gene name	caspase 8
	Gene Alias	ALPS2B
	Cytomap	2q33.1
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A024R3Z8

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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
841	CASP8	LZE2T	Human	Esophagus	ESCC	9.81e-04	4.70e-01	0.082
841	CASP8	LZE4T	Human	Esophagus	ESCC	1.86e-06	2.45e-01	0.0811
841	CASP8	LZE7T	Human	Esophagus	ESCC	5.00e-04	2.57e-01	0.0667
841	CASP8	LZE20T	Human	Esophagus	ESCC	2.20e-05	1.53e-01	0.0662
841	CASP8	LZE24T	Human	Esophagus	ESCC	2.93e-19	5.33e-01	0.0596
841	CASP8	LZE21T	Human	Esophagus	ESCC	5.29e-04	1.62e-01	0.0655
841	CASP8	LZE6T	Human	Esophagus	ESCC	6.15e-10	4.46e-01	0.0845
841	CASP8	P1T-E	Human	Esophagus	ESCC	2.07e-07	2.33e-01	0.0875
841	CASP8	P2T-E	Human	Esophagus	ESCC	7.94e-31	4.51e-01	0.1177
841	CASP8	P4T-E	Human	Esophagus	ESCC	1.14e-31	7.80e-01	0.1323
841	CASP8	P5T-E	Human	Esophagus	ESCC	4.27e-17	2.08e-01	0.1327
841	CASP8	P8T-E	Human	Esophagus	ESCC	3.04e-17	2.96e-01	0.0889
841	CASP8	P9T-E	Human	Esophagus	ESCC	1.53e-20	3.80e-01	0.1131
841	CASP8	P10T-E	Human	Esophagus	ESCC	7.46e-21	2.79e-01	0.116
841	CASP8	P11T-E	Human	Esophagus	ESCC	7.86e-06	3.58e-01	0.1426
841	CASP8	P12T-E	Human	Esophagus	ESCC	2.94e-18	2.35e-01	0.1122
841	CASP8	P15T-E	Human	Esophagus	ESCC	7.29e-23	3.56e-01	0.1149
841	CASP8	P16T-E	Human	Esophagus	ESCC	3.46e-14	2.03e-01	0.1153
841	CASP8	P17T-E	Human	Esophagus	ESCC	2.49e-06	4.25e-01	0.1278
841	CASP8	P20T-E	Human	Esophagus	ESCC	1.37e-23	5.50e-01	0.1124

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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:0045862111	Esophagus	ESCC	positive regulation of proteolysis	256/8552	372/18723	7.88e-20	9.43e-18	256
GO:0097191111	Esophagus	ESCC	extrinsic apoptotic signaling pathway	159/8552	219/18723	4.12e-16	2.94e-14	159
GO:000170119	Esophagus	ESCC	in utero embryonic development	243/8552	367/18723	1.00e-15	6.86e-14	243
GO:0071496111	Esophagus	ESCC	cellular response to external stimulus	215/8552	320/18723	4.29e-15	2.43e-13	215
GO:004312318	Esophagus	ESCC	positive regulation of I-kappaB kinase/NF-kappaB signaling	132/8552	186/18723	2.07e-12	8.58e-11	132
GO:0043122110	Esophagus	ESCC	regulation of I-kappaB kinase/NF-kappaB signaling	167/8552	249/18723	6.11e-12	2.32e-10	167
GO:2000116111	Esophagus	ESCC	regulation of cysteine-type endopeptidase activity	158/8552	235/18723	1.67e-11	5.90e-10	158
GO:0043281111	Esophagus	ESCC	regulation of cysteine-type endopeptidase activity involved in apoptotic process	143/8552	209/18723	2.12e-11	7.31e-10	143
GO:000724919	Esophagus	ESCC	I-kappaB kinase/NF-kappaB signaling	183/8552	281/18723	3.02e-11	1.01e-09	183
GO:005160418	Esophagus	ESCC	protein maturation	189/8552	294/18723	7.64e-11	2.39e-09	189
GO:0010952111	Esophagus	ESCC	positive regulation of peptidase activity	133/8552	197/18723	4.31e-10	1.14e-08	133
GO:007121419	Esophagus	ESCC	cellular response to abiotic stimulus	206/8552	331/18723	7.52e-10	1.88e-08	206
GO:010400419	Esophagus	ESCC	cellular response to environmental stimulus	206/8552	331/18723	7.52e-10	1.88e-08	206
GO:0052547111	Esophagus	ESCC	regulation of peptidase activity	275/8552	461/18723	7.54e-10	1.88e-08	275
GO:0030099111	Esophagus	ESCC	myeloid cell differentiation	232/8552	381/18723	1.22e-09	2.90e-08	232
GO:0070997111	Esophagus	ESCC	neuron death	216/8552	361/18723	3.49e-08	6.45e-07	216
GO:0052548111	Esophagus	ESCC	regulation of endopeptidase activity	253/8552	432/18723	3.68e-08	6.78e-07	253
GO:0001890110	Esophagus	ESCC	placenta development	98/8552	144/18723	4.46e-08	8.11e-07	98
GO:0010950111	Esophagus	ESCC	positive regulation of endopeptidase activity	116/8552	179/18723	1.77e-07	2.79e-06	116
GO:0061458110	Esophagus	ESCC	reproductive system development	247/8552	427/18723	2.24e-07	3.42e-06	247

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05132211	Esophagus	ESCC	Salmonella infection	191/4205	249/8465	6.51e-19	5.45e-17	2.79e-17	191
hsa05016210	Esophagus	ESCC	Huntington disease	226/4205	306/8465	1.38e-18	8.72e-17	4.46e-17	226
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
hsa05169210	Esophagus	ESCC	Epstein-Barr virus infection	151/4205	202/8465	1.55e-13	3.45e-12	1.77e-12	151
hsa0411524	Esophagus	ESCC	p53 signaling pathway	65/4205	74/8465	3.88e-12	6.50e-11	3.33e-11	65
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
hsa05167211	Esophagus	ESCC	Kaposi sarcoma-associated herpesvirus infection	136/4205	194/8465	4.28e-09	4.22e-08	2.16e-08	136
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
hsa0520325	Esophagus	ESCC	Viral carcinogenesis	137/4205	204/8465	2.47e-07	1.88e-06	9.62e-07	137
hsa05417211	Esophagus	ESCC	Lipid and atherosclerosis	143/4205	215/8465	3.30e-07	2.45e-06	1.26e-06	143
hsa05163210	Esophagus	ESCC	Human cytomegalovirus infection	148/4205	225/8465	5.73e-07	4.00e-06	2.05e-06	148
hsa051609	Esophagus	ESCC	Hepatitis C	107/4205	157/8465	1.75e-06	1.08e-05	5.55e-06	107
hsa015247	Esophagus	ESCC	Platinum drug resistance	56/4205	73/8465	1.85e-06	1.13e-05	5.78e-06	56
hsa051619	Esophagus	ESCC	Hepatitis B	108/4205	162/8465	7.68e-06	4.15e-05	2.12e-05	108

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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

CASP8

SNV

Missense_Mutation

novel

c.1293G>C

p.Glu431Asp

p.E431D

Q14790

protein_coding

tolerated(0.07)

benign(0.013)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

CASP8

SNV

Missense_Mutation

c.676N>C

p.Ile226Leu

p.I226L

Q14790

protein_coding

tolerated(0.11)

benign(0.01)

TCGA-A2-A0EV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8

SNV

Missense_Mutation

rs17860424

c.919N>T

p.Arg307Trp

p.R307W

Q14790

protein_coding

deleterious(0.02)

probably_damaging(0.993)

TCGA-A7-A6VY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

CASP8

SNV

Missense_Mutation

novel

c.1388N>T

p.Ala463Val

p.A463V

Q14790

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-AC-A6IW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8

SNV

Missense_Mutation

c.628N>G

p.Ile210Val

p.I210V

Q14790

protein_coding

deleterious(0.02)

benign(0.384)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8

SNV

Missense_Mutation

c.1006N>T

p.Leu336Phe

p.L336F

Q14790

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-AR-A24Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CASP8

SNV

Missense_Mutation

c.1415N>A

p.Arg472Gln

p.R472Q

Q14790

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C8-A8HP-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

5-fluorouracil

CASP8

SNV

Missense_Mutation

c.1190N>T

p.Ser397Phe

p.S397F

Q14790

protein_coding

deleterious(0)

probably_damaging(0.968)

TCGA-D8-A1JD-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CASP8

SNV

Missense_Mutation

c.112N>T

p.Asp38Tyr

p.D38Y

Q14790

protein_coding

deleterious_low_confidence(0.05)

benign(0.325)

TCGA-D8-A1JH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

nolvadex

CASP8

SNV

Missense_Mutation

c.854N>T

p.Tyr285Phe

p.Y285F

Q14790

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-D8-A1XW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin+cyclophosphamide

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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
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	252166828
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	178101978
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	CHEMBL197672	EMRICASAN
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	CHEMBL2105721	NIVOCASAN
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE		ISOQUINOLINE-1,3(2H,4H)-DIONE	CHEMBL1210769
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE		CONATUMUMAB	CONATUMUMAB	26291055
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE		20(S)-PROTOPANAXADIOL	CHEMBL375563	17261067
841	CASP8	DRUGGABLE GENOME, PROTEASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	178103122	EMRICASAN

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