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: CASP6

Gene summary for CASP6

Gene summary.

Gene information	Species	Human
	Gene symbol	CASP6
	Gene ID	839
	Gene name	caspase 6
	Gene Alias	MCH2
	Cytomap	4q25
	Gene Type	protein-coding
	GO ID	GO:0006508
	UniProtAcc	P55212

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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
839	CASP6	HTA11_1938_2000001011	Human	Colorectum	AD	8.62e-09	6.35e-01	-0.0811
839	CASP6	HTA11_347_2000001011	Human	Colorectum	AD	3.61e-26	7.52e-01	-0.1954
839	CASP6	HTA11_83_2000001011	Human	Colorectum	SER	4.30e-02	3.68e-01	-0.1526
839	CASP6	HTA11_696_2000001011	Human	Colorectum	AD	8.60e-06	3.71e-01	-0.1464
839	CASP6	HTA11_866_2000001011	Human	Colorectum	AD	3.05e-02	2.25e-01	-0.1001
839	CASP6	HTA11_1391_2000001011	Human	Colorectum	AD	3.84e-05	4.86e-01	-0.059
839	CASP6	HTA11_546_2000001011	Human	Colorectum	AD	2.38e-06	4.51e-01	-0.0842
839	CASP6	HTA11_7696_3000711011	Human	Colorectum	AD	2.44e-12	5.15e-01	0.0674
839	CASP6	HTA11_99999965104_69814	Human	Colorectum	MSS	8.41e-05	4.91e-01	0.281
839	CASP6	HTA11_99999971662_82457	Human	Colorectum	MSS	1.65e-04	3.96e-01	0.3859
839	CASP6	A015-C-203	Human	Colorectum	FAP	3.17e-05	-1.23e-01	-0.1294
839	CASP6	A002-C-201	Human	Colorectum	FAP	1.74e-02	-2.00e-01	0.0324
839	CASP6	A001-C-108	Human	Colorectum	FAP	1.98e-02	-1.80e-01	-0.0272
839	CASP6	A002-C-205	Human	Colorectum	FAP	2.93e-03	-1.12e-01	-0.1236
839	CASP6	A015-C-006	Human	Colorectum	FAP	6.41e-05	-2.96e-01	-0.0994
839	CASP6	A015-C-106	Human	Colorectum	FAP	3.28e-03	-1.69e-01	-0.0511
839	CASP6	A002-C-114	Human	Colorectum	FAP	9.93e-03	-1.18e-01	-0.1561
839	CASP6	A015-C-104	Human	Colorectum	FAP	1.65e-06	-3.86e-02	-0.1899
839	CASP6	A001-C-014	Human	Colorectum	FAP	2.35e-02	-1.99e-01	0.0135
839	CASP6	A002-C-016	Human	Colorectum	FAP	1.55e-05	-1.65e-01	0.0521

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Colorectum (GSE201348)		FAP: Familial adenomatous polyposis
		CRC: Colorectal cancer
Colorectum (HTA11)		AD: Adenomas
		SER: Sessile serrated lesions
		MSI-H: Microsatellite-high colorectal cancer
		MSS: Microsatellite stable colorectal cancer
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
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
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ

∗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:0097194	Liver	HCC	execution phase of apoptosis	48/7958	85/18723	6.47e-03	2.63e-02	48
GO:00432791	Liver	HCC	response to alkaloid	62/7958	115/18723	8.79e-03	3.42e-02	62

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05417	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73
hsa054171	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73
hsa054172	Colorectum	SER	Lipid and atherosclerosis	55/1580	215/8465	6.83e-03	3.77e-02	2.74e-02	55
hsa054173	Colorectum	SER	Lipid and atherosclerosis	55/1580	215/8465	6.83e-03	3.77e-02	2.74e-02	55
hsa054174	Colorectum	MSS	Lipid and atherosclerosis	70/1875	215/8465	2.38e-04	1.81e-03	1.11e-03	70
hsa04210	Colorectum	MSS	Apoptosis	44/1875	136/8465	3.66e-03	1.66e-02	1.01e-02	44
hsa054175	Colorectum	MSS	Lipid and atherosclerosis	70/1875	215/8465	2.38e-04	1.81e-03	1.11e-03	70
hsa042101	Colorectum	MSS	Apoptosis	44/1875	136/8465	3.66e-03	1.66e-02	1.01e-02	44
hsa054176	Colorectum	FAP	Lipid and atherosclerosis	54/1404	215/8465	8.04e-04	5.14e-03	3.13e-03	54
hsa054177	Colorectum	FAP	Lipid and atherosclerosis	54/1404	215/8465	8.04e-04	5.14e-03	3.13e-03	54
hsa054178	Colorectum	CRC	Lipid and atherosclerosis	45/1091	215/8465	5.73e-04	5.48e-03	3.72e-03	45
hsa054179	Colorectum	CRC	Lipid and atherosclerosis	45/1091	215/8465	5.73e-04	5.48e-03	3.72e-03	45
hsa0421027	Esophagus	ESCC	Apoptosis	102/4205	136/8465	1.05e-09	1.21e-08	6.21e-09	102
hsa05417211	Esophagus	ESCC	Lipid and atherosclerosis	143/4205	215/8465	3.30e-07	2.45e-06	1.26e-06	143
hsa0421037	Esophagus	ESCC	Apoptosis	102/4205	136/8465	1.05e-09	1.21e-08	6.21e-09	102
hsa05417310	Esophagus	ESCC	Lipid and atherosclerosis	143/4205	215/8465	3.30e-07	2.45e-06	1.26e-06	143
hsa042102	Liver	HCC	Apoptosis	83/4020	136/8465	9.51e-04	3.58e-03	1.99e-03	83
hsa0541742	Liver	HCC	Lipid and atherosclerosis	118/4020	215/8465	1.66e-02	3.92e-02	2.18e-02	118
hsa042103	Liver	HCC	Apoptosis	83/4020	136/8465	9.51e-04	3.58e-03	1.99e-03	83
hsa0541752	Liver	HCC	Lipid and atherosclerosis	118/4020	215/8465	1.66e-02	3.92e-02	2.18e-02	118

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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

CASP6

SNV

Missense_Mutation

c.826N>T

p.Pro276Ser

p.P276S

P55212

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-E2-A1AZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CASP6

SNV

Missense_Mutation

novel

c.596N>T

p.Thr199Met

p.T199M

P55212

protein_coding

deleterious(0)

probably_damaging(0.982)

TCGA-E9-A6HE-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

CASP6

SNV

Missense_Mutation

c.316N>A

p.Val106Ile

p.V106I

P55212

protein_coding

tolerated(0.08)

benign(0.006)

TCGA-EK-A2PG-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

CASP6

SNV

Missense_Mutation

c.296N>C

p.Lys99Thr

p.K99T

P55212

protein_coding

tolerated(0.41)

benign(0.111)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CASP6

SNV

Missense_Mutation

c.292N>T

p.Leu98Phe

p.L98F

P55212

protein_coding

deleterious(0.05)

benign(0.209)

TCGA-A5-A0GU-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

CASP6

SNV

Missense_Mutation

rs752173591

c.658N>T

p.Arg220Trp

p.R220W

P55212

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

CASP6

SNV

Missense_Mutation

novel

c.166N>C

p.Phe56Leu

p.F56L

P55212

protein_coding

tolerated(0.63)

benign(0.005)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

CASP6

SNV

Missense_Mutation

novel

c.583G>A

p.Ala195Thr

p.A195T

P55212

protein_coding

tolerated(0.12)

benign(0.41)

TCGA-AX-A06F-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

carboplatin

CASP6

SNV

Missense_Mutation

novel

c.875N>A

p.Ser292Tyr

p.S292Y

P55212

protein_coding

deleterious_low_confidence(0)

benign(0.259)

TCGA-AX-A2HC-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

CASP6

SNV

Missense_Mutation

c.775C>T

p.Arg259Cys

p.R259C

P55212

protein_coding

deleterious(0.03)

probably_damaging(0.999)

TCGA-B5-A11E-01

Endometrium

uterine corpus endometrioid 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
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		MYRICETIN	MYRICETIN
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		NSC-92207	CHEMBL139935
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		PAPAVERINE HYDROCHLORIDE	PAPAVERINE HYDROCHLORIDE
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		METHYLTHIONINIUM CHLORIDE	METHYLTHIONINIUM CHLORIDE
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		NSC-37136	CHEMBL1370674
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		THIOMERSAL	THIMEROSAL
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		ROEMERINE	ROEMERINE
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		SJ000113972	CHEMBL591137
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		ISOQUINOLINE-1,3(2H,4H)-DIONE	CHEMBL1210769
839	CASP6	DRUGGABLE GENOME, PROTEASE, ENZYME		STICTIC ACID	STICTIC ACID

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