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: SPINK5

Gene summary for SPINK5

Gene summary.

Gene information	Species	Human
	Gene symbol	SPINK5
	Gene ID	11005
	Gene name	serine peptidase inhibitor Kazal type 5
	Gene Alias	LEKTI
	Cytomap	5q32
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	Q9NQ38

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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
11005	SPINK5	HTA11_2487_2000001011	Human	Colorectum	SER	7.07e-03	2.48e-01	-0.1808
11005	SPINK5	HTA11_347_2000001011	Human	Colorectum	AD	5.12e-03	2.15e-01	-0.1954
11005	SPINK5	HTA11_411_2000001011	Human	Colorectum	SER	8.77e-04	9.01e-01	-0.2602
11005	SPINK5	HTA11_2112_2000001011	Human	Colorectum	SER	2.95e-07	1.03e+00	-0.2196
11005	SPINK5	HTA11_696_2000001011	Human	Colorectum	AD	5.72e-03	3.26e-01	-0.1464
11005	SPINK5	HTA11_2992_2000001011	Human	Colorectum	SER	1.94e-04	7.88e-01	-0.1706
11005	SPINK5	HTA11_5212_2000001011	Human	Colorectum	AD	6.75e-13	1.13e+00	-0.2061
11005	SPINK5	A002-C-016	Human	Colorectum	FAP	3.61e-02	-7.30e-02	0.0521
11005	SPINK5	LZE4T	Human	Esophagus	ESCC	6.25e-04	1.04e-01	0.0811
11005	SPINK5	P2T-E	Human	Esophagus	ESCC	8.19e-18	1.07e-01	0.1177
11005	SPINK5	P4T-E	Human	Esophagus	ESCC	1.11e-02	2.51e-02	0.1323
11005	SPINK5	P8T-E	Human	Esophagus	ESCC	7.58e-03	6.02e-02	0.0889
11005	SPINK5	P9T-E	Human	Esophagus	ESCC	1.75e-04	4.59e-02	0.1131
11005	SPINK5	P12T-E	Human	Esophagus	ESCC	1.04e-07	3.19e-01	0.1122
11005	SPINK5	P15T-E	Human	Esophagus	ESCC	6.33e-05	3.89e-02	0.1149
11005	SPINK5	P26T-E	Human	Esophagus	ESCC	9.32e-05	4.63e-02	0.1276
11005	SPINK5	P27T-E	Human	Esophagus	ESCC	1.21e-06	4.48e-02	0.1055
11005	SPINK5	P28T-E	Human	Esophagus	ESCC	1.83e-03	2.62e-01	0.1149
11005	SPINK5	P30T-E	Human	Esophagus	ESCC	7.21e-03	2.33e-01	0.137
11005	SPINK5	P48T-E	Human	Esophagus	ESCC	9.49e-07	5.92e-02	0.0959

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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:001095121	Liver	HCC	negative regulation of endopeptidase activity	129/7958	252/18723	3.17e-03	1.47e-02	129
GO:0050777	Liver	HCC	negative regulation of immune response	101/7958	194/18723	4.40e-03	1.90e-02	101
GO:001046621	Liver	HCC	negative regulation of peptidase activity	132/7958	262/18723	5.82e-03	2.42e-02	132
GO:005254720	Oral cavity	OSCC	regulation of peptidase activity	255/7305	461/18723	5.78e-13	2.75e-11	255
GO:005254820	Oral cavity	OSCC	regulation of endopeptidase activity	235/7305	432/18723	4.35e-11	1.40e-09	235
GO:00028317	Oral cavity	OSCC	regulation of response to biotic stimulus	177/7305	327/18723	1.73e-08	3.43e-07	177
GO:004211016	Oral cavity	OSCC	T cell activation	245/7305	487/18723	2.00e-07	3.22e-06	245
GO:00435887	Oral cavity	OSCC	skin development	143/7305	263/18723	2.77e-07	4.27e-06	143
GO:00085449	Oral cavity	OSCC	epidermis development	171/7305	324/18723	2.89e-07	4.43e-06	171
GO:004586120	Oral cavity	OSCC	negative regulation of proteolysis	181/7305	351/18723	1.01e-06	1.37e-05	181
GO:00028324	Oral cavity	OSCC	negative regulation of response to biotic stimulus	65/7305	108/18723	6.62e-06	7.29e-05	65
GO:19031316	Oral cavity	OSCC	mononuclear cell differentiation	210/7305	426/18723	8.44e-06	9.02e-05	210
GO:00099139	Oral cavity	OSCC	epidermal cell differentiation	109/7305	202/18723	1.08e-05	1.14e-04	109
GO:190370618	Oral cavity	OSCC	regulation of hemopoiesis	180/7305	367/18723	5.16e-05	4.30e-04	180
GO:005086315	Oral cavity	OSCC	regulation of T cell activation	161/7305	329/18723	1.44e-04	1.02e-03	161
GO:005134618	Oral cavity	OSCC	negative regulation of hydrolase activity	182/7305	379/18723	1.98e-04	1.32e-03	182
GO:001095117	Oral cavity	OSCC	negative regulation of endopeptidase activity	126/7305	252/18723	2.37e-04	1.54e-03	126
GO:00300983	Oral cavity	OSCC	lymphocyte differentiation	179/7305	374/18723	2.74e-04	1.74e-03	179
GO:001046618	Oral cavity	OSCC	negative regulation of peptidase activity	130/7305	262/18723	2.89e-04	1.82e-03	130
GO:000268310	Oral cavity	OSCC	negative regulation of immune system process	204/7305	434/18723	3.72e-04	2.27e-03	204

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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

SPINK5

SNV

Missense_Mutation

rs371134163

c.2849G>A

p.Arg950Gln

p.R950Q

Q9NQ38

protein_coding

tolerated(0.25)

possibly_damaging(0.511)

TCGA-A2-A0T1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Targeted Molecular therapy

herceptin

SPINK5

SNV

Missense_Mutation

novel

c.2058N>G

p.Asp686Glu

p.D686E

Q9NQ38

protein_coding

tolerated(0.14)

benign(0.281)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

SPINK5

SNV

Missense_Mutation

novel

c.2687G>C

p.Arg896Thr

p.R896T

Q9NQ38

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AR-A1AJ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SPINK5

SNV

Missense_Mutation

c.2403N>C

p.Lys801Asn

p.K801N

Q9NQ38

protein_coding

deleterious(0)

probably_damaging(0.931)

TCGA-BH-A0B5-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

SPINK5

SNV

Missense_Mutation

novel

c.1436N>T

p.Gln479Leu

p.Q479L

Q9NQ38

protein_coding

tolerated(0.22)

possibly_damaging(0.661)

TCGA-BH-A0BO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SPINK5

SNV

Missense_Mutation

novel

c.1890N>T

p.Glu630Asp

p.E630D

Q9NQ38

protein_coding

tolerated(1)

benign(0)

TCGA-C8-A1HM-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

SPINK5

SNV

Missense_Mutation

c.538N>C

p.Asp180His

p.D180H

Q9NQ38

protein_coding

tolerated(0.08)

probably_damaging(0.969)

TCGA-E2-A1LH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

SPINK5

SNV

Missense_Mutation

c.901N>G

p.Gln301Glu

p.Q301E

Q9NQ38

protein_coding

tolerated(0.56)

benign(0.205)

TCGA-GM-A2DF-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxol

SPINK5

insertion

Nonsense_Mutation

novel

c.1874_1875insCTATATATTAACATAAACATTATATGATACAAATAATATCATAT

p.Arg625SerfsTer6

p.R625Sfs*6

Q9NQ38

protein_coding

TCGA-A2-A0CP-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

SPINK5

insertion

Frame_Shift_Ins

novel

c.1956_1957insAGCAAGTGGTGGTTTTCTTGCACCCAATTAAGATTATTAA

p.Val653SerfsTer30

p.V653Sfs*30

Q9NQ38

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

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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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