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: WWP2

Gene summary for WWP2

Gene summary.

Gene information	Species	Human
	Gene symbol	WWP2
	Gene ID	11060
	Gene name	WW domain containing E3 ubiquitin protein ligase 2
	Gene Alias	AIP2
	Cytomap	16q22.1
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	B4DHF6

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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
11060	WWP2	CCI_2	Human	Cervix	CC	2.45e-06	6.99e-01	0.5249
11060	WWP2	CCI_3	Human	Cervix	CC	1.63e-05	5.60e-01	0.516
11060	WWP2	HTA11_3410_2000001011	Human	Colorectum	AD	2.79e-02	-2.28e-01	0.0155
11060	WWP2	HTA11_347_2000001011	Human	Colorectum	AD	1.57e-08	5.23e-01	-0.1954
11060	WWP2	HTA11_696_2000001011	Human	Colorectum	AD	8.53e-03	4.79e-01	-0.1464
11060	WWP2	HTA11_546_2000001011	Human	Colorectum	AD	4.71e-02	4.29e-01	-0.0842
11060	WWP2	HTA11_99999970781_79442	Human	Colorectum	MSS	4.57e-07	-3.57e-01	0.294
11060	WWP2	HTA11_99999974143_84620	Human	Colorectum	MSS	3.44e-13	-4.72e-01	0.3005
11060	WWP2	A002-C-010	Human	Colorectum	FAP	1.16e-02	-1.88e-01	0.242
11060	WWP2	A015-C-203	Human	Colorectum	FAP	9.04e-28	-3.01e-01	-0.1294
11060	WWP2	A015-C-204	Human	Colorectum	FAP	2.42e-05	-1.25e-01	-0.0228
11060	WWP2	A014-C-040	Human	Colorectum	FAP	1.73e-05	-3.17e-01	-0.1184
11060	WWP2	A002-C-201	Human	Colorectum	FAP	1.16e-14	-2.71e-01	0.0324
11060	WWP2	A002-C-203	Human	Colorectum	FAP	1.14e-05	-1.06e-01	0.2786
11060	WWP2	A001-C-119	Human	Colorectum	FAP	3.22e-05	-2.45e-01	-0.1557
11060	WWP2	A001-C-108	Human	Colorectum	FAP	6.09e-17	-1.78e-01	-0.0272
11060	WWP2	A002-C-205	Human	Colorectum	FAP	2.03e-21	-3.86e-01	-0.1236
11060	WWP2	A001-C-104	Human	Colorectum	FAP	2.04e-02	-2.45e-03	0.0184
11060	WWP2	A015-C-005	Human	Colorectum	FAP	2.69e-02	-9.64e-02	-0.0336
11060	WWP2	A015-C-006	Human	Colorectum	FAP	6.68e-15	-1.82e-01	-0.0994

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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

∗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:001603210	Cervix	CC	viral process	109/2311	415/18723	5.40e-15	6.46e-12	109
GO:004217610	Cervix	CC	regulation of protein catabolic process	104/2311	391/18723	9.39e-15	9.36e-12	104
GO:001905810	Cervix	CC	viral life cycle	87/2311	317/18723	2.20e-13	1.20e-10	87
GO:004573210	Cervix	CC	positive regulation of protein catabolic process	65/2311	231/18723	7.44e-11	1.39e-08	65
GO:001049810	Cervix	CC	proteasomal protein catabolic process	111/2311	490/18723	8.98e-11	1.58e-08	111
GO:000989610	Cervix	CC	positive regulation of catabolic process	109/2311	492/18723	5.26e-10	6.99e-08	109
GO:005212610	Cervix	CC	movement in host environment	52/2311	175/18723	7.03e-10	8.76e-08	52
GO:004440910	Cervix	CC	entry into host	47/2311	151/18723	8.45e-10	1.03e-07	47
GO:005170110	Cervix	CC	biological process involved in interaction with host	57/2311	203/18723	1.18e-09	1.41e-07	57
GO:004671810	Cervix	CC	viral entry into host cell	44/2311	144/18723	5.47e-09	5.03e-07	44
GO:004440310	Cervix	CC	biological process involved in symbiotic interaction	71/2311	290/18723	7.94e-09	6.98e-07	71
GO:004316110	Cervix	CC	proteasome-mediated ubiquitin-dependent protein catabolic process	91/2311	412/18723	1.65e-08	1.25e-06	91
GO:00002097	Cervix	CC	protein polyubiquitination	58/2311	236/18723	1.57e-07	7.41e-06	58
GO:00510904	Cervix	CC	regulation of DNA-binding transcription factor activity	87/2311	440/18723	4.85e-06	1.22e-04	87
GO:00072194	Cervix	CC	Notch signaling pathway	39/2311	172/18723	1.08e-04	1.38e-03	39
GO:00085933	Cervix	CC	regulation of Notch signaling pathway	25/2311	95/18723	1.61e-04	1.93e-03	25
GO:00518656	Cervix	CC	protein autoubiquitination	17/2311	73/18723	6.71e-03	3.70e-02	17
GO:00705343	Cervix	CC	protein K63-linked ubiquitination	14/2311	56/18723	6.93e-03	3.74e-02	14
GO:0016032	Colorectum	AD	viral process	168/3918	415/18723	4.67e-20	3.66e-17	168
GO:0042176	Colorectum	AD	regulation of protein catabolic process	160/3918	391/18723	1.06e-19	7.34e-17	160

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0412014	Cervix	CC	Ubiquitin mediated proteolysis	49/1267	142/8465	4.26e-09	7.68e-08	4.54e-08	49
hsa0412015	Cervix	CC	Ubiquitin mediated proteolysis	49/1267	142/8465	4.26e-09	7.68e-08	4.54e-08	49
hsa04120	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa041201	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa041204	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa041205	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa041206	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa041207	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa041208	Colorectum	CRC	Ubiquitin mediated proteolysis	42/1091	142/8465	9.98e-08	6.67e-06	4.52e-06	42
hsa041209	Colorectum	CRC	Ubiquitin mediated proteolysis	42/1091	142/8465	9.98e-08	6.67e-06	4.52e-06	42
hsa0412027	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa0412036	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa0412041	Liver	HCC	Ubiquitin mediated proteolysis	110/4020	142/8465	1.67e-13	3.74e-12	2.08e-12	110
hsa0412051	Liver	HCC	Ubiquitin mediated proteolysis	110/4020	142/8465	1.67e-13	3.74e-12	2.08e-12	110
hsa0412012	Lung	IAC	Ubiquitin mediated proteolysis	40/1053	142/8465	3.24e-07	1.76e-05	1.17e-05	40
hsa0412013	Lung	IAC	Ubiquitin mediated proteolysis	40/1053	142/8465	3.24e-07	1.76e-05	1.17e-05	40
hsa0412022	Lung	AIS	Ubiquitin mediated proteolysis	41/961	142/8465	8.01e-09	4.33e-07	2.77e-07	41
hsa0412032	Lung	AIS	Ubiquitin mediated proteolysis	41/961	142/8465	8.01e-09	4.33e-07	2.77e-07	41

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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

WWP2

SNV

Missense_Mutation

c.2258N>T

p.Gln753Leu

p.Q753L

O00308

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-A2-A0CW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

WWP2

SNV

Missense_Mutation

c.2071N>A

p.Gly691Ser

p.G691S

O00308

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A8-A06O-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

letrozole

WWP2

SNV

Missense_Mutation

rs139052693

c.748N>A

p.Val250Ile

p.V250I

O00308

protein_coding

tolerated(0.31)

benign(0.007)

TCGA-A8-A097-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

WWP2

SNV

Missense_Mutation

rs751603209

c.1225N>G

p.Pro409Ala

p.P409A

O00308

protein_coding

tolerated(0.29)

benign(0.007)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

WWP2

SNV

Missense_Mutation

c.2226N>C

p.Glu742Asp

p.E742D

O00308

protein_coding

deleterious(0.01)

probably_damaging(0.998)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

WWP2

SNV

Missense_Mutation

rs766917559

c.2431N>A

p.Glu811Lys

p.E811K

O00308

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

WWP2

SNV

Missense_Mutation

c.176N>A

p.Arg59His

p.R59H

O00308

protein_coding

tolerated(0.58)

benign(0.226)

TCGA-AR-A1AN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

WWP2

SNV

Missense_Mutation

rs138661773

c.1448N>T

p.Thr483Met

p.T483M

O00308

protein_coding

tolerated(0.14)

benign(0.115)

TCGA-BH-A0DQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

WWP2

SNV

Missense_Mutation

c.1670N>C

p.Gly557Ala

p.G557A

O00308

protein_coding

deleterious(0.02)

possibly_damaging(0.73)

TCGA-BH-A5IZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

WWP2

SNV

Missense_Mutation

c.412N>T

p.Thr138Ser

p.T138S

O00308

protein_coding

tolerated(0.63)

benign(0.026)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

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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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