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: NPEPPS

Gene summary for NPEPPS

Gene summary.

Gene information	Species	Human
	Gene symbol	NPEPPS
	Gene ID	9520
	Gene name	aminopeptidase puromycin sensitive
	Gene Alias	AAP-S
	Cytomap	17q21.32
	Gene Type	protein-coding
	GO ID	GO:0000209
	UniProtAcc	B7Z899

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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
9520	NPEPPS	P37T-E	Human	Esophagus	ESCC	3.34e-26	4.33e-01	0.1371
9520	NPEPPS	P38T-E	Human	Esophagus	ESCC	3.23e-09	4.26e-01	0.127
9520	NPEPPS	P39T-E	Human	Esophagus	ESCC	7.96e-27	4.77e-01	0.0894
9520	NPEPPS	P40T-E	Human	Esophagus	ESCC	1.82e-15	1.87e-01	0.109
9520	NPEPPS	P42T-E	Human	Esophagus	ESCC	1.38e-21	4.23e-01	0.1175
9520	NPEPPS	P44T-E	Human	Esophagus	ESCC	3.86e-18	4.73e-01	0.1096
9520	NPEPPS	P47T-E	Human	Esophagus	ESCC	2.18e-25	5.95e-01	0.1067
9520	NPEPPS	P48T-E	Human	Esophagus	ESCC	9.62e-25	4.58e-01	0.0959
9520	NPEPPS	P49T-E	Human	Esophagus	ESCC	6.63e-15	1.48e+00	0.1768
9520	NPEPPS	P52T-E	Human	Esophagus	ESCC	1.15e-24	4.98e-01	0.1555
9520	NPEPPS	P54T-E	Human	Esophagus	ESCC	5.87e-19	3.99e-01	0.0975
9520	NPEPPS	P56T-E	Human	Esophagus	ESCC	2.91e-12	1.32e+00	0.1613
9520	NPEPPS	P57T-E	Human	Esophagus	ESCC	3.91e-19	4.76e-01	0.0926
9520	NPEPPS	P61T-E	Human	Esophagus	ESCC	4.36e-27	5.56e-01	0.099
9520	NPEPPS	P62T-E	Human	Esophagus	ESCC	2.70e-43	6.92e-01	0.1302
9520	NPEPPS	P65T-E	Human	Esophagus	ESCC	1.08e-18	3.08e-01	0.0978
9520	NPEPPS	P74T-E	Human	Esophagus	ESCC	2.67e-32	7.88e-01	0.1479
9520	NPEPPS	P75T-E	Human	Esophagus	ESCC	8.25e-38	7.16e-01	0.1125
9520	NPEPPS	P76T-E	Human	Esophagus	ESCC	1.09e-25	4.10e-01	0.1207
9520	NPEPPS	P79T-E	Human	Esophagus	ESCC	1.03e-29	5.22e-01	0.1154

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
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
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:00725949	Cervix	CC	establishment of protein localization to organelle	99/2311	422/18723	1.23e-10	2.11e-08	99
GO:190382910	Cervix	CC	positive regulation of cellular protein localization	72/2311	276/18723	3.20e-10	4.46e-08	72
GO:005122210	Cervix	CC	positive regulation of protein transport	72/2311	303/18723	2.36e-08	1.70e-06	72
GO:190495110	Cervix	CC	positive regulation of establishment of protein localization	73/2311	319/18723	9.69e-08	5.25e-06	73
GO:00002097	Cervix	CC	protein polyubiquitination	58/2311	236/18723	1.57e-07	7.41e-06	58
GO:00068399	Cervix	CC	mitochondrial transport	60/2311	254/18723	4.21e-07	1.67e-05	60
GO:000660510	Cervix	CC	protein targeting	68/2311	314/18723	2.17e-06	6.55e-05	68
GO:00903167	Cervix	CC	positive regulation of intracellular protein transport	41/2311	160/18723	3.24e-06	8.80e-05	41
GO:00323868	Cervix	CC	regulation of intracellular transport	71/2311	337/18723	3.70e-06	9.74e-05	71
GO:00331579	Cervix	CC	regulation of intracellular protein transport	52/2311	229/18723	8.16e-06	1.88e-04	52
GO:00705859	Cervix	CC	protein localization to mitochondrion	33/2311	125/18723	1.46e-05	2.90e-04	33
GO:00323889	Cervix	CC	positive regulation of intracellular transport	46/2311	202/18723	2.45e-05	4.24e-04	46
GO:00726559	Cervix	CC	establishment of protein localization to mitochondrion	31/2311	120/18723	4.13e-05	6.36e-04	31
GO:000166610	Cervix	CC	response to hypoxia	61/2311	307/18723	1.04e-04	1.34e-03	61
GO:007048210	Cervix	CC	response to oxygen levels	67/2311	347/18723	1.21e-04	1.51e-03	67
GO:003629310	Cervix	CC	response to decreased oxygen levels	62/2311	322/18723	2.29e-04	2.57e-03	62
GO:00066269	Cervix	CC	protein targeting to mitochondrion	25/2311	100/18723	3.80e-04	3.89e-03	25
GO:00714539	Cervix	CC	cellular response to oxygen levels	38/2311	177/18723	4.23e-04	4.27e-03	38
GO:00362949	Cervix	CC	cellular response to decreased oxygen levels	35/2311	161/18723	5.49e-04	5.29e-03	35
GO:00714566	Cervix	CC	cellular response to hypoxia	33/2311	151/18723	7.06e-04	6.41e-03	33

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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

NPEPPS

SNV

Missense_Mutation

c.1013C>G

p.Ser338Cys

p.S338C

P55786

protein_coding

deleterious(0)

probably_damaging(0.992)

TCGA-A2-A0SY-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

arimidex

NPEPPS

SNV

Missense_Mutation

c.2219N>T

p.Ser740Phe

p.S740F

P55786

protein_coding

deleterious(0)

possibly_damaging(0.726)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NPEPPS

SNV

Missense_Mutation

c.2227C>G

p.Leu743Val

p.L743V

P55786

protein_coding

deleterious(0)

possibly_damaging(0.629)

TCGA-C8-A27B-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

NPEPPS

deletion

Frame_Shift_Del

novel

c.1864delC

p.Leu622SerfsTer13

p.L622Sfs*13

P55786

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

NPEPPS

SNV

Missense_Mutation

rs748154171

c.2432N>T

p.Ser811Leu

p.S811L

P55786

protein_coding

tolerated(0.19)

benign(0.028)

TCGA-C5-A2LZ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Unknown

NPEPPS

SNV

Missense_Mutation

c.769N>A

p.Glu257Lys

p.E257K

P55786

protein_coding

deleterious(0.03)

possibly_damaging(0.457)

TCGA-C5-A7UH-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

NPEPPS

SNV

Missense_Mutation

c.916N>C

p.Asp306His

p.D306H

P55786

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C5-A7UH-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

NPEPPS

SNV

Missense_Mutation

novel

c.1705N>T

p.Val569Phe

p.V569F

P55786

protein_coding

tolerated(0.14)

benign(0.015)

TCGA-EA-A3HU-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

NPEPPS

SNV

Missense_Mutation

rs746589578

c.153C>G

p.Phe51Leu

p.F51L

P55786

protein_coding

deleterious(0.01)

benign(0.424)

TCGA-EK-A3GK-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

NPEPPS

SNV

Missense_Mutation

c.95C>T

p.Ser32Phe

p.S32F

P55786

protein_coding

deleterious_low_confidence(0.04)

benign(0)

TCGA-MU-A51Y-01

Cervix

cervical & endocervical cancer

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
9520	NPEPPS	PROTEASE, ENZYME, DRUGGABLE GENOME		CHR-2797	TOSEDOSTAT
9520	NPEPPS	PROTEASE, ENZYME, DRUGGABLE GENOME	inhibitor	CHEMBL2103847	TOSEDOSTAT
9520	NPEPPS	PROTEASE, ENZYME, DRUGGABLE GENOME	inhibitor	252166871	ANTAQ

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