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: CPA4

Gene summary for CPA4

Gene summary.

Gene information	Species	Human
	Gene symbol	CPA4
	Gene ID	51200
	Gene name	carboxypeptidase A4
	Gene Alias	CPA3
	Cytomap	7q32.2
	Gene Type	protein-coding
	GO ID	GO:0006464
	UniProtAcc	Q9UI42

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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
51200	CPA4	P17T-E	Human	Esophagus	ESCC	2.61e-02	1.77e-01	0.1278
51200	CPA4	P24T-E	Human	Esophagus	ESCC	2.10e-17	6.03e-01	0.1287
51200	CPA4	P42T-E	Human	Esophagus	ESCC	1.95e-02	9.54e-02	0.1175
51200	CPA4	P80T-E	Human	Esophagus	ESCC	1.85e-20	8.36e-01	0.155
51200	CPA4	P89T-E	Human	Esophagus	ESCC	6.37e-12	1.00e+00	0.1752
51200	CPA4	P107T-E	Human	Esophagus	ESCC	2.36e-03	2.26e-01	0.171
51200	CPA4	P130T-E	Human	Esophagus	ESCC	7.13e-39	1.19e+00	0.1676
51200	CPA4	C04	Human	Oral cavity	OSCC	1.17e-12	6.54e-01	0.2633
51200	CPA4	C30	Human	Oral cavity	OSCC	2.22e-10	9.97e-01	0.3055
51200	CPA4	C51	Human	Oral cavity	OSCC	2.86e-07	4.88e-01	0.2674
51200	CPA4	SYSMH3	Human	Oral cavity	OSCC	1.71e-02	2.51e-01	0.2442
51200	CPA4	ATC2	Human	Thyroid	ATC	5.16e-32	2.62e+00	0.34
51200	CPA4	ATC3	Human	Thyroid	ATC	6.43e-04	4.23e-01	0.338

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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
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:001657015	Esophagus	ESCC	histone modification	323/8552	463/18723	2.61e-26	7.88e-24	323
GO:001820514	Esophagus	ESCC	peptidyl-lysine modification	259/8552	376/18723	3.90e-20	5.26e-18	259
GO:001839413	Esophagus	ESCC	peptidyl-lysine acetylation	123/8552	169/18723	6.58e-13	2.94e-11	123
GO:004354313	Esophagus	ESCC	protein acylation	165/8552	243/18723	1.69e-12	7.14e-11	165
GO:000647313	Esophagus	ESCC	protein acetylation	140/8552	201/18723	4.37e-12	1.69e-10	140
GO:001839313	Esophagus	ESCC	internal peptidyl-lysine acetylation	114/8552	158/18723	1.16e-11	4.24e-10	114
GO:000647513	Esophagus	ESCC	internal protein amino acid acetylation	115/8552	160/18723	1.43e-11	5.08e-10	115
GO:00165735	Esophagus	ESCC	histone acetylation	110/8552	152/18723	1.95e-11	6.81e-10	110
GO:00165707	Oral cavity	OSCC	histone modification	270/7305	463/18723	1.59e-17	1.50e-15	270
GO:00182056	Oral cavity	OSCC	peptidyl-lysine modification	216/7305	376/18723	2.32e-13	1.16e-11	216
GO:00435434	Oral cavity	OSCC	protein acylation	149/7305	243/18723	1.33e-12	5.80e-11	149
GO:00183944	Oral cavity	OSCC	peptidyl-lysine acetylation	108/7305	169/18723	4.55e-11	1.45e-09	108
GO:00064734	Oral cavity	OSCC	protein acetylation	124/7305	201/18723	5.59e-11	1.74e-09	124
GO:00165734	Oral cavity	OSCC	histone acetylation	96/7305	152/18723	1.35e-09	3.29e-08	96
GO:00183934	Oral cavity	OSCC	internal peptidyl-lysine acetylation	99/7305	158/18723	1.41e-09	3.39e-08	99
GO:00064754	Oral cavity	OSCC	internal protein amino acid acetylation	100/7305	160/18723	1.43e-09	3.41e-08	100
GO:001657017	Thyroid	ATC	histone modification	243/6293	463/18723	2.23e-17	2.27e-15	243
GO:001820516	Thyroid	ATC	peptidyl-lysine modification	193/6293	376/18723	6.92e-13	3.06e-11	193
GO:000647315	Thyroid	ATC	protein acetylation	116/6293	201/18723	1.75e-12	7.33e-11	116
GO:004354315	Thyroid	ATC	protein acylation	134/6293	243/18723	3.46e-12	1.40e-10	134

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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

CPA4

SNV

Missense_Mutation

novel

c.714N>T

p.Trp238Cys

p.W238C

Q9UI42

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

CPA4

insertion

Nonsense_Mutation

novel

c.550_551insTAATGACATAAATTACATAAAAATCCAGTTGAATGAATA

p.Glu184delinsValMetThrTerIleThrTerLysSerSerTerMetAsnLys

p.E184delinsVMT*IT*KSS*MNK

Q9UI42

protein_coding

TCGA-A2-A04V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

CPA4

insertion

Nonsense_Mutation

novel

c.578_579insCTCACTGTA

p.Trp193delinsCysSerLeuTer

p.W193delinsCSL*

Q9UI42

protein_coding

TCGA-A2-A0CQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CPA4

SNV

Missense_Mutation

rs372031946

c.202G>A

p.Val68Ile

p.V68I

Q9UI42

protein_coding

tolerated(0.07)

possibly_damaging(0.489)

TCGA-VS-A94Z-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CPA4

SNV

Missense_Mutation

c.60N>C

p.Lys20Asn

p.K20N

Q9UI42

protein_coding

tolerated(0.6)

benign(0.003)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

CPA4

SNV

Missense_Mutation

novel

c.827T>C

p.Val276Ala

p.V276A

Q9UI42

protein_coding

deleterious(0.02)

benign(0.013)

TCGA-AA-A01I-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

CPA4

SNV

Missense_Mutation

rs368498370

c.1004N>T

p.Ala335Val

p.A335V

Q9UI42

protein_coding

deleterious(0.04)

benign(0.374)

TCGA-AZ-4315-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

CPA4

SNV

Missense_Mutation

rs367921847

c.466N>T

p.Arg156Trp

p.R156W

Q9UI42

protein_coding

deleterious(0.01)

probably_damaging(0.937)

TCGA-D5-6924-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

CPA4

SNV

Missense_Mutation

novel

c.1004N>A

p.Ala335Glu

p.A335E

Q9UI42

protein_coding

deleterious(0)

probably_damaging(0.976)

TCGA-CI-6621-01

Colorectum

rectum adenocarcinoma

Male

<65

III/IV

Unknown

CPA4

insertion

In_Frame_Ins

novel

c.486_486+1insCATGAAAGA

p.Lys162_Phe163insHisGluArg

p.K162_F163insHER

Q9UI42

protein_coding

TCGA-AM-5820-01

Colorectum

colon adenocarcinoma

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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