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: SPHK1

Gene summary for SPHK1

Gene summary.

Gene information	Species	Human
	Gene symbol	SPHK1
	Gene ID	8877
	Gene name	sphingosine kinase 1
	Gene Alias	SPHK
	Cytomap	17q25.1
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q53ZR5

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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
8877	SPHK1	P22T-E	Human	Esophagus	ESCC	1.51e-18	5.48e-01	0.1236
8877	SPHK1	P23T-E	Human	Esophagus	ESCC	2.82e-17	6.64e-01	0.108
8877	SPHK1	P24T-E	Human	Esophagus	ESCC	9.18e-51	1.54e+00	0.1287
8877	SPHK1	P26T-E	Human	Esophagus	ESCC	2.02e-07	3.14e-01	0.1276
8877	SPHK1	P27T-E	Human	Esophagus	ESCC	2.08e-19	5.45e-01	0.1055
8877	SPHK1	P28T-E	Human	Esophagus	ESCC	2.19e-21	5.11e-01	0.1149
8877	SPHK1	P30T-E	Human	Esophagus	ESCC	9.83e-13	6.83e-01	0.137
8877	SPHK1	P31T-E	Human	Esophagus	ESCC	1.45e-71	1.43e+00	0.1251
8877	SPHK1	P32T-E	Human	Esophagus	ESCC	1.40e-72	2.22e+00	0.1666
8877	SPHK1	P36T-E	Human	Esophagus	ESCC	1.14e-19	1.00e+00	0.1187
8877	SPHK1	P37T-E	Human	Esophagus	ESCC	2.42e-38	1.15e+00	0.1371
8877	SPHK1	P38T-E	Human	Esophagus	ESCC	3.94e-12	4.53e-01	0.127
8877	SPHK1	P39T-E	Human	Esophagus	ESCC	1.97e-16	4.96e-01	0.0894
8877	SPHK1	P40T-E	Human	Esophagus	ESCC	2.83e-09	4.62e-01	0.109
8877	SPHK1	P42T-E	Human	Esophagus	ESCC	7.04e-20	8.22e-01	0.1175
8877	SPHK1	P44T-E	Human	Esophagus	ESCC	4.70e-11	7.25e-01	0.1096
8877	SPHK1	P47T-E	Human	Esophagus	ESCC	1.15e-10	5.82e-01	0.1067
8877	SPHK1	P48T-E	Human	Esophagus	ESCC	3.80e-10	3.02e-01	0.0959
8877	SPHK1	P49T-E	Human	Esophagus	ESCC	6.73e-14	1.73e+00	0.1768
8877	SPHK1	P52T-E	Human	Esophagus	ESCC	6.91e-66	1.63e+00	0.1555

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
Prostate		BPH: Benign Prostatic Hyperplasia
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
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:190332017	Endometrium	EEC	regulation of protein modification by small protein conjugation or removal	72/2168	242/18723	1.45e-14	4.36e-12	72
GO:003139617	Endometrium	EEC	regulation of protein ubiquitination	62/2168	210/18723	1.42e-12	2.76e-10	62
GO:000697917	Endometrium	EEC	response to oxidative stress	99/2168	446/18723	9.02e-11	1.13e-08	99
GO:006219717	Endometrium	EEC	cellular response to chemical stress	77/2168	337/18723	2.87e-09	2.10e-07	77
GO:000030217	Endometrium	EEC	response to reactive oxygen species	57/2168	222/18723	4.04e-09	2.82e-07	57
GO:004254216	Endometrium	EEC	response to hydrogen peroxide	41/2168	146/18723	4.12e-08	2.29e-06	41
GO:001604915	Endometrium	EEC	cell growth	95/2168	482/18723	1.16e-07	5.54e-06	95
GO:003806612	Endometrium	EEC	p38MAPK cascade	21/2168	55/18723	3.30e-07	1.33e-05	21
GO:005140314	Endometrium	EEC	stress-activated MAPK cascade	55/2168	239/18723	3.98e-07	1.56e-05	55
GO:003459917	Endometrium	EEC	cellular response to oxidative stress	63/2168	288/18723	4.05e-07	1.58e-05	63
GO:003109814	Endometrium	EEC	stress-activated protein kinase signaling cascade	56/2168	247/18723	5.25e-07	2.00e-05	56
GO:003287214	Endometrium	EEC	regulation of stress-activated MAPK cascade	46/2168	192/18723	1.06e-06	3.56e-05	46
GO:007030214	Endometrium	EEC	regulation of stress-activated protein kinase signaling cascade	46/2168	195/18723	1.67e-06	5.12e-05	46
GO:190074411	Endometrium	EEC	regulation of p38MAPK cascade	18/2168	47/18723	2.16e-06	6.41e-05	18
GO:004341011	Endometrium	EEC	positive regulation of MAPK cascade	89/2168	480/18723	4.21e-06	1.08e-04	89
GO:003461416	Endometrium	EEC	cellular response to reactive oxygen species	37/2168	155/18723	1.26e-05	2.55e-04	37
GO:000155814	Endometrium	EEC	regulation of cell growth	77/2168	414/18723	1.64e-05	3.16e-04	77
GO:003010014	Endometrium	EEC	regulation of endocytosis	45/2168	211/18723	3.40e-05	5.78e-04	45
GO:190332213	Endometrium	EEC	positive regulation of protein modification by small protein conjugation or removal	33/2168	138/18723	3.49e-05	5.90e-04	33
GO:003139813	Endometrium	EEC	positive regulation of protein ubiquitination	29/2168	119/18723	7.05e-05	1.04e-03	29

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0407116	Esophagus	ESCC	Sphingolipid signaling pathway	85/4205	121/8465	3.04e-06	1.73e-05	8.84e-06	85
hsa051527	Esophagus	ESCC	Tuberculosis	111/4205	180/8465	7.14e-04	2.32e-03	1.19e-03	111
hsa0466620	Esophagus	ESCC	Fc gamma R-mediated phagocytosis	63/4205	97/8465	1.63e-03	4.89e-03	2.50e-03	63
hsa006003	Esophagus	ESCC	Sphingolipid metabolism	36/4205	53/8465	5.41e-03	1.36e-02	6.99e-03	36
hsa0407117	Esophagus	ESCC	Sphingolipid signaling pathway	85/4205	121/8465	3.04e-06	1.73e-05	8.84e-06	85
hsa0515212	Esophagus	ESCC	Tuberculosis	111/4205	180/8465	7.14e-04	2.32e-03	1.19e-03	111
hsa04666110	Esophagus	ESCC	Fc gamma R-mediated phagocytosis	63/4205	97/8465	1.63e-03	4.89e-03	2.50e-03	63
hsa0060012	Esophagus	ESCC	Sphingolipid metabolism	36/4205	53/8465	5.41e-03	1.36e-02	6.99e-03	36
hsa040718	Liver	HCC	Sphingolipid signaling pathway	72/4020	121/8465	5.01e-03	1.47e-02	8.18e-03	72
hsa0466610	Liver	HCC	Fc gamma R-mediated phagocytosis	58/4020	97/8465	9.65e-03	2.52e-02	1.40e-02	58
hsa00600	Liver	HCC	Sphingolipid metabolism	34/4020	53/8465	1.06e-02	2.71e-02	1.51e-02	34
hsa0407111	Liver	HCC	Sphingolipid signaling pathway	72/4020	121/8465	5.01e-03	1.47e-02	8.18e-03	72
hsa0466611	Liver	HCC	Fc gamma R-mediated phagocytosis	58/4020	97/8465	9.65e-03	2.52e-02	1.40e-02	58
hsa006001	Liver	HCC	Sphingolipid metabolism	34/4020	53/8465	1.06e-02	2.71e-02	1.51e-02	34
hsa0407114	Oral cavity	OSCC	Sphingolipid signaling pathway	82/3704	121/8465	6.97e-08	5.08e-07	2.58e-07	82
hsa051526	Oral cavity	OSCC	Tuberculosis	105/3704	180/8465	5.00e-05	2.04e-04	1.04e-04	105
hsa0466618	Oral cavity	OSCC	Fc gamma R-mediated phagocytosis	60/3704	97/8465	2.35e-04	7.72e-04	3.93e-04	60
hsa04370	Oral cavity	OSCC	VEGF signaling pathway	37/3704	59/8465	2.53e-03	6.62e-03	3.37e-03	37
hsa006002	Oral cavity	OSCC	Sphingolipid metabolism	33/3704	53/8465	5.00e-03	1.20e-02	6.13e-03	33
hsa0407115	Oral cavity	OSCC	Sphingolipid signaling pathway	82/3704	121/8465	6.97e-08	5.08e-07	2.58e-07	82

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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

SPHK1

SNV

Missense_Mutation

rs149492135

c.1055N>T

p.Ser352Leu

p.S352L

Q9NYA1

protein_coding

deleterious(0)

possibly_damaging(0.755)

TCGA-A7-A26E-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

cytoxan

SPHK1

deletion

Frame_Shift_Del

c.290_303delTCCCGCGGCCCTGC

p.Leu97ProfsTer29

p.L97Pfs*29

Q9NYA1

protein_coding

TCGA-D8-A1JG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

SPHK1

SNV

Missense_Mutation

rs866618568

c.812N>A

p.Arg271Gln

p.R271Q

Q9NYA1

protein_coding

deleterious(0)

probably_damaging(0.985)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SPHK1

SNV

Missense_Mutation

c.961G>C

p.Asp321His

p.D321H

Q9NYA1

protein_coding

deleterious(0.03)

possibly_damaging(0.847)

TCGA-DS-A0VN-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SPHK1

SNV

Missense_Mutation

novel

c.510G>A

p.Met170Ile

p.M170I

Q9NYA1

protein_coding

tolerated(0.24)

benign(0.003)

TCGA-CK-4951-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

SPHK1

deletion

Frame_Shift_Del

c.1160delG

p.Arg387ProfsTer44

p.R387Pfs*44

Q9NYA1

protein_coding

TCGA-AA-3663-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

SPHK1

SNV

Missense_Mutation

rs773839692

c.1133N>T

p.Ala378Val

p.A378V

Q9NYA1

protein_coding

deleterious(0)

benign(0.325)

TCGA-A5-A0VP-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

SPHK1

SNV

Missense_Mutation

rs775563147

c.255N>T

p.Glu85Asp

p.E85D

Q9NYA1

protein_coding

tolerated(0.08)

benign(0.06)

TCGA-AJ-A3EL-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

SPHK1

SNV

Missense_Mutation

novel

c.713N>C

p.Leu238Pro

p.L238P

Q9NYA1

protein_coding

deleterious(0)

possibly_damaging(0.637)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

SPHK1

SNV

Missense_Mutation

novel

c.1220N>G

p.Tyr407Cys

p.Y407C

Q9NYA1

protein_coding

tolerated(0.1)

benign(0.047)

TCGA-AX-A1CE-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unspecific

Paclitaxel

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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
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		PMID27539678-Compound-11
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		ABC294640
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME	inhibitor	404859088
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		PMID27539678-Compound-13
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		GSK618334
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME	inhibitor	178103235
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		PMID27539678-Compound-16
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		PMID27539678-Compound-7
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME	inhibitor	381744899
8877	SPHK1	ENZYME, KINASE, LIPID KINASE, DRUGGABLE GENOME		Methylbenzenesulfonamide derivative 1

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