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: CASP8AP2

Gene summary for CASP8AP2

Gene summary.

Gene information	Species	Human
	Gene symbol	CASP8AP2
	Gene ID	9994
	Gene name	caspase 8 associated protein 2
	Gene Alias	CED-4
	Cytomap	6q15
	Gene Type	protein-coding
	GO ID	GO:0006139
	UniProtAcc	Q9UKL3

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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
9994	CASP8AP2	LZE4T	Human	Esophagus	ESCC	4.77e-11	3.63e-01	0.0811
9994	CASP8AP2	LZE7T	Human	Esophagus	ESCC	3.56e-07	5.43e-01	0.0667
9994	CASP8AP2	LZE24T	Human	Esophagus	ESCC	1.23e-03	1.97e-01	0.0596
9994	CASP8AP2	P1T-E	Human	Esophagus	ESCC	4.85e-06	2.60e-01	0.0875
9994	CASP8AP2	P2T-E	Human	Esophagus	ESCC	2.58e-24	5.21e-01	0.1177
9994	CASP8AP2	P4T-E	Human	Esophagus	ESCC	6.06e-12	3.97e-01	0.1323
9994	CASP8AP2	P5T-E	Human	Esophagus	ESCC	1.23e-17	3.16e-01	0.1327
9994	CASP8AP2	P8T-E	Human	Esophagus	ESCC	2.46e-17	3.26e-01	0.0889
9994	CASP8AP2	P9T-E	Human	Esophagus	ESCC	8.82e-04	1.14e-01	0.1131
9994	CASP8AP2	P10T-E	Human	Esophagus	ESCC	3.42e-13	3.01e-01	0.116
9994	CASP8AP2	P11T-E	Human	Esophagus	ESCC	3.72e-10	5.15e-01	0.1426
9994	CASP8AP2	P12T-E	Human	Esophagus	ESCC	8.82e-18	3.39e-01	0.1122
9994	CASP8AP2	P15T-E	Human	Esophagus	ESCC	3.34e-07	2.75e-01	0.1149
9994	CASP8AP2	P16T-E	Human	Esophagus	ESCC	1.88e-23	5.25e-01	0.1153
9994	CASP8AP2	P20T-E	Human	Esophagus	ESCC	3.66e-07	2.21e-01	0.1124
9994	CASP8AP2	P21T-E	Human	Esophagus	ESCC	6.96e-19	4.50e-01	0.1617
9994	CASP8AP2	P22T-E	Human	Esophagus	ESCC	3.29e-21	2.33e-01	0.1236
9994	CASP8AP2	P23T-E	Human	Esophagus	ESCC	5.01e-07	2.55e-01	0.108
9994	CASP8AP2	P24T-E	Human	Esophagus	ESCC	1.02e-12	2.71e-01	0.1287
9994	CASP8AP2	P26T-E	Human	Esophagus	ESCC	3.22e-08	2.43e-01	0.1276

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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
Prostate		BPH: Benign Prostatic Hyperplasia
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: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:0071496111	Esophagus	ESCC	cellular response to external stimulus	215/8552	320/18723	4.29e-15	2.43e-13	215
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: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:0052548111	Esophagus	ESCC	regulation of endopeptidase activity	253/8552	432/18723	3.68e-08	6.78e-07	253
GO:0010950111	Esophagus	ESCC	positive regulation of endopeptidase activity	116/8552	179/18723	1.77e-07	2.79e-06	116
GO:000862519	Esophagus	ESCC	extrinsic apoptotic signaling pathway via death domain receptors	59/8552	82/18723	1.23e-06	1.52e-05	59
GO:0043280110	Esophagus	ESCC	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	84/8552	129/18723	6.38e-06	6.55e-05	84
GO:2001056110	Esophagus	ESCC	positive regulation of cysteine-type endopeptidase activity	94/8552	148/18723	8.87e-06	8.59e-05	94
GO:000691915	Esophagus	ESCC	activation of cysteine-type endopeptidase activity involved in apoptotic process	54/8552	78/18723	2.17e-05	1.87e-04	54
GO:00712606	Esophagus	ESCC	cellular response to mechanical stimulus	54/8552	81/18723	1.09e-04	7.64e-04	54
GO:000961216	Esophagus	ESCC	response to mechanical stimulus	124/8552	216/18723	3.30e-04	1.94e-03	124
GO:004586220	Oral cavity	OSCC	positive regulation of proteolysis	236/7305	372/18723	6.53e-22	1.38e-19	236
GO:200011620	Oral cavity	OSCC	regulation of cysteine-type endopeptidase activity	152/7305	235/18723	1.14e-15	8.13e-14	152
GO:004328120	Oral cavity	OSCC	regulation of cysteine-type endopeptidase activity involved in apoptotic process	137/7305	209/18723	5.94e-15	3.80e-13	137

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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

CASP8AP2

SNV

Missense_Mutation

novel

c.208N>C

p.Glu70Gln

p.E70Q

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

CASP8AP2

SNV

Missense_Mutation

novel

c.368G>T

p.Arg123Ile

p.R123I

protein_coding

deleterious(0)

probably_damaging(0.979)

TCGA-A2-A4S3-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CASP8AP2

SNV

Missense_Mutation

novel

c.5021N>T

p.Ser1674Phe

p.S1674F

protein_coding

deleterious(0.02)

probably_damaging(0.924)

TCGA-A8-A0A7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CASP8AP2

SNV

Missense_Mutation

novel

c.2392A>C

p.Ser798Arg

p.S798R

protein_coding

tolerated(0.19)

benign(0.029)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8AP2

SNV

Missense_Mutation

rs781619316

c.2890C>T

p.Arg964Trp

p.R964W

protein_coding

deleterious(0)

possibly_damaging(0.84)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8AP2

SNV

Missense_Mutation

novel

c.1201C>T

p.His401Tyr

p.H401Y

protein_coding

tolerated(0.13)

benign(0.018)

TCGA-AC-A8OP-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8AP2

SNV

Missense_Mutation

rs758643574

c.908C>T

p.Ser303Leu

p.S303L

protein_coding

tolerated(0.33)

benign(0.112)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CASP8AP2

SNV

Missense_Mutation

novel

c.380A>C

p.Asn127Thr

p.N127T

protein_coding

deleterious(0)

possibly_damaging(0.844)

TCGA-AR-A24Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CASP8AP2

SNV

Missense_Mutation

novel

c.2545N>T

p.His849Tyr

p.H849Y

protein_coding

deleterious(0)

benign(0.198)

TCGA-AR-A250-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CASP8AP2

SNV

Missense_Mutation

c.5065G>A

p.Asp1689Asn

p.D1689N

protein_coding

deleterious(0.01)

probably_damaging(0.944)

TCGA-C8-A1HF-01

Breast

breast invasive carcinoma

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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