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: WWOX

Gene summary for WWOX

Gene summary.

Gene information	Species	Human
	Gene symbol	WWOX
	Gene ID	51741
	Gene name	WW domain containing oxidoreductase
	Gene Alias	D16S432E
	Cytomap	16q23.1-q23.2
	Gene Type	protein-coding
	GO ID	GO:0001501
	UniProtAcc	Q9NZC7

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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
51741	WWOX	CA_HPV_2	Human	Cervix	CC	2.36e-04	2.14e-01	0.0391
51741	WWOX	CCI_1	Human	Cervix	CC	2.14e-06	8.07e-01	0.528
51741	WWOX	CCI_2	Human	Cervix	CC	1.89e-07	1.47e+00	0.5249
51741	WWOX	CCI_3	Human	Cervix	CC	3.90e-25	2.04e+00	0.516
51741	WWOX	CCII_1	Human	Cervix	CC	6.32e-08	5.55e-01	0.3249
51741	WWOX	HTA11_3410_2000001011	Human	Colorectum	AD	1.22e-03	2.19e-01	0.0155
51741	WWOX	HTA11_347_2000001011	Human	Colorectum	AD	2.40e-16	1.04e+00	-0.1954
51741	WWOX	HTA11_1391_2000001011	Human	Colorectum	AD	1.28e-06	7.23e-01	-0.059
51741	WWOX	HTA11_546_2000001011	Human	Colorectum	AD	2.10e-02	6.03e-01	-0.0842
51741	WWOX	HTA11_866_3004761011	Human	Colorectum	AD	1.29e-02	4.72e-01	0.096
51741	WWOX	HTA11_7663_2000001011	Human	Colorectum	SER	7.48e-07	1.00e+00	0.0131
51741	WWOX	HTA11_10623_2000001011	Human	Colorectum	AD	4.35e-06	9.08e-01	-0.0177
51741	WWOX	HTA11_10711_2000001011	Human	Colorectum	AD	2.77e-04	6.09e-01	0.0338
51741	WWOX	HTA11_7696_3000711011	Human	Colorectum	AD	1.27e-08	8.20e-01	0.0674
51741	WWOX	HTA11_6818_2000001021	Human	Colorectum	AD	1.02e-06	7.57e-01	0.0588
51741	WWOX	HTA11_99999965104_69814	Human	Colorectum	MSS	4.98e-25	1.51e+00	0.281
51741	WWOX	HTA11_99999973899_84307	Human	Colorectum	MSS	7.24e-06	8.21e-01	0.2585
51741	WWOX	A002-C-010	Human	Colorectum	FAP	4.21e-02	2.65e-01	0.242
51741	WWOX	A015-C-203	Human	Colorectum	FAP	4.69e-08	2.30e-02	-0.1294
51741	WWOX	A001-C-108	Human	Colorectum	FAP	9.25e-03	-1.39e-01	-0.0272

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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
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:009719310	Cervix	CC	intrinsic apoptotic signaling pathway	85/2311	288/18723	4.56e-15	6.46e-12	85
GO:200123310	Cervix	CC	regulation of apoptotic signaling pathway	96/2311	356/18723	4.08e-14	3.05e-11	96
GO:00160557	Cervix	CC	Wnt signaling pathway	98/2311	444/18723	4.82e-09	4.65e-07	98
GO:01987387	Cervix	CC	cell-cell signaling by wnt	98/2311	446/18723	6.16e-09	5.58e-07	98
GO:00301117	Cervix	CC	regulation of Wnt signaling pathway	76/2311	328/18723	3.05e-08	2.08e-06	76
GO:20012357	Cervix	CC	positive regulation of apoptotic signaling pathway	37/2311	126/18723	2.70e-07	1.12e-05	37
GO:009719110	Cervix	CC	extrinsic apoptotic signaling pathway	52/2311	219/18723	2.06e-06	6.34e-05	52
GO:00723329	Cervix	CC	intrinsic apoptotic signaling pathway by p53 class mediator	23/2311	76/18723	2.76e-05	4.60e-04	23
GO:200123610	Cervix	CC	regulation of extrinsic apoptotic signaling pathway	37/2311	151/18723	2.80e-05	4.65e-04	37
GO:007233110	Cervix	CC	signal transduction by p53 class mediator	38/2311	163/18723	7.06e-05	9.85e-04	38
GO:00016497	Cervix	CC	osteoblast differentiation	47/2311	229/18723	2.88e-04	3.11e-03	47
GO:00715595	Cervix	CC	response to transforming growth factor beta	50/2311	256/18723	6.31e-04	5.91e-03	50
GO:00715605	Cervix	CC	cellular response to transforming growth factor beta stimulus	49/2311	250/18723	6.55e-04	6.05e-03	49
GO:20012386	Cervix	CC	positive regulation of extrinsic apoptotic signaling pathway	14/2311	48/18723	1.48e-03	1.15e-02	14
GO:00301784	Cervix	CC	negative regulation of Wnt signaling pathway	35/2311	170/18723	1.52e-03	1.17e-02	35
GO:00015037	Cervix	CC	ossification	71/2311	408/18723	1.67e-03	1.28e-02	71
GO:0097193	Colorectum	AD	intrinsic apoptotic signaling pathway	108/3918	288/18723	6.25e-11	6.41e-09	108
GO:2001233	Colorectum	AD	regulation of apoptotic signaling pathway	119/3918	356/18723	2.14e-08	1.21e-06	119
GO:0030111	Colorectum	AD	regulation of Wnt signaling pathway	102/3918	328/18723	8.51e-06	2.03e-04	102
GO:0072331	Colorectum	AD	signal transduction by p53 class mediator	58/3918	163/18723	1.04e-05	2.40e-04	58

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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

WWOX

SNV

Missense_Mutation

novel

c.863N>T

p.Trp288Leu

p.W288L

Q9NZC7

protein_coding

tolerated(0.18)

benign(0.112)

TCGA-AN-A0AM-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

WWOX

SNV

Missense_Mutation

c.947T>C

p.Val316Ala

p.V316A

Q9NZC7

protein_coding

deleterious(0)

possibly_damaging(0.64)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

WWOX

insertion

In_Frame_Ins

novel

c.1054_1055insTATTATCTT

p.Met352delinsIleLeuSerLeu

p.M352delinsILSL

Q9NZC7

protein_coding

TCGA-AN-A0G0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

WWOX

insertion

Frame_Shift_Ins

novel

c.1056_1056+1insAACTTCCTGTTGAAGGTTTTGAAAAATATAT

p.Gln353AsnfsTer186

p.Q353Nfs*186

Q9NZC7

protein_coding

TCGA-AN-A0G0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

WWOX

SNV

Missense_Mutation

c.812C>G

p.Ser271Cys

p.S271C

Q9NZC7

protein_coding

deleterious(0.01)

benign(0.285)

TCGA-C5-A1BQ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

cisplatin

WWOX

SNV

Missense_Mutation

c.978N>A

p.Met326Ile

p.M326I

Q9NZC7

protein_coding

deleterious(0.01)

possibly_damaging(0.718)

TCGA-Q1-A6DT-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

WWOX

SNV

Missense_Mutation

c.944N>A

p.Gly315Glu

p.G315E

Q9NZC7

protein_coding

deleterious(0)

probably_damaging(0.985)

TCGA-UC-A7PF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

WWOX

SNV

Missense_Mutation

c.497N>T

p.Ser166Leu

p.S166L

Q9NZC7

protein_coding

tolerated(0.29)

benign(0.011)

TCGA-AA-3811-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

WWOX

SNV

Missense_Mutation

rs200815431

c.1196N>T

p.Ala399Val

p.A399V

Q9NZC7

protein_coding

tolerated(0.23)

benign(0.014)

TCGA-AA-3854-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

WWOX

SNV

Missense_Mutation

rs764089824

c.415N>A

p.Glu139Lys

p.E139K

Q9NZC7

protein_coding

deleterious(0)

probably_damaging(0.919)

TCGA-AA-A00N-01

Colorectum

colon adenocarcinoma

Male

>=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
51741	WWOX	DRUGGABLE GENOME, SHORT CHAIN DEHYDROGENASE REDUCTASE		TUMOR NECROSIS FACTOR		11058590

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