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: NEDD4

Gene summary for NEDD4

Gene summary.

Gene information	Species	Human
	Gene symbol	NEDD4
	Gene ID	4734
	Gene name	NEDD4 E3 ubiquitin protein ligase
	Gene Alias	NEDD4-1
	Cytomap	15q21.3
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	P46934

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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
4734	NEDD4	CCI_1	Human	Cervix	CC	5.18e-05	1.37e+00	0.528
4734	NEDD4	CCI_2	Human	Cervix	CC	5.82e-04	5.82e-01	0.5249
4734	NEDD4	LZE4T	Human	Esophagus	ESCC	7.88e-07	2.72e-01	0.0811
4734	NEDD4	LZE24T	Human	Esophagus	ESCC	6.05e-03	5.58e-02	0.0596
4734	NEDD4	LZE6T	Human	Esophagus	ESCC	4.38e-03	1.68e-01	0.0845
4734	NEDD4	P1T-E	Human	Esophagus	ESCC	3.22e-02	1.68e-01	0.0875
4734	NEDD4	P2T-E	Human	Esophagus	ESCC	2.31e-10	2.39e-01	0.1177
4734	NEDD4	P4T-E	Human	Esophagus	ESCC	1.57e-10	2.50e-01	0.1323
4734	NEDD4	P5T-E	Human	Esophagus	ESCC	4.55e-11	1.55e-01	0.1327
4734	NEDD4	P8T-E	Human	Esophagus	ESCC	5.39e-10	1.52e-01	0.0889
4734	NEDD4	P9T-E	Human	Esophagus	ESCC	2.15e-06	1.66e-01	0.1131
4734	NEDD4	P10T-E	Human	Esophagus	ESCC	3.92e-07	1.20e-01	0.116
4734	NEDD4	P11T-E	Human	Esophagus	ESCC	3.64e-03	2.58e-01	0.1426
4734	NEDD4	P12T-E	Human	Esophagus	ESCC	4.86e-11	1.67e-01	0.1122
4734	NEDD4	P15T-E	Human	Esophagus	ESCC	2.32e-09	1.95e-01	0.1149
4734	NEDD4	P16T-E	Human	Esophagus	ESCC	3.00e-09	1.65e-01	0.1153
4734	NEDD4	P17T-E	Human	Esophagus	ESCC	1.58e-02	1.54e-01	0.1278
4734	NEDD4	P19T-E	Human	Esophagus	ESCC	1.97e-04	3.99e-01	0.1662
4734	NEDD4	P20T-E	Human	Esophagus	ESCC	1.30e-06	1.72e-01	0.1124
4734	NEDD4	P21T-E	Human	Esophagus	ESCC	6.46e-08	1.13e-01	0.1617

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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
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

∗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:002260410	Cervix	CC	regulation of cell morphogenesis	84/2311	309/18723	1.00e-12	4.29e-10	84
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:00725949	Cervix	CC	establishment of protein localization to organelle	99/2311	422/18723	1.23e-10	2.11e-08	99
GO:000989610	Cervix	CC	positive regulation of catabolic process	109/2311	492/18723	5.26e-10	6.99e-08	109
GO:004316110	Cervix	CC	proteasome-mediated ubiquitin-dependent protein catabolic process	91/2311	412/18723	1.65e-08	1.25e-06	91
GO:004361810	Cervix	CC	regulation of transcription from RNA polymerase II promoter in response to stress	21/2311	47/18723	3.85e-08	2.53e-06	21
GO:00069139	Cervix	CC	nucleocytoplasmic transport	71/2311	301/18723	4.04e-08	2.54e-06	71
GO:00511699	Cervix	CC	nuclear transport	71/2311	301/18723	4.04e-08	2.54e-06	71
GO:004362010	Cervix	CC	regulation of DNA-templated transcription in response to stress	22/2311	53/18723	9.29e-08	5.19e-06	22
GO:00002097	Cervix	CC	protein polyubiquitination	58/2311	236/18723	1.57e-07	7.41e-06	58
GO:00163587	Cervix	CC	dendrite development	58/2311	243/18723	4.52e-07	1.76e-05	58
GO:004854510	Cervix	CC	response to steroid hormone	74/2311	339/18723	5.71e-07	2.09e-05	74
GO:00305229	Cervix	CC	intracellular receptor signaling pathway	60/2311	265/18723	1.89e-06	5.97e-05	60
GO:000660510	Cervix	CC	protein targeting	68/2311	314/18723	2.17e-06	6.55e-05	68
GO:00468229	Cervix	CC	regulation of nucleocytoplasmic transport	31/2311	106/18723	2.68e-06	7.87e-05	31
GO:00323868	Cervix	CC	regulation of intracellular transport	71/2311	337/18723	3.70e-06	9.74e-05	71

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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
hsa0516920	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0453020	Cervix	CC	Tight junction	49/1267	169/8465	1.87e-06	1.78e-05	1.05e-05	49
hsa0414418	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0412015	Cervix	CC	Ubiquitin mediated proteolysis	49/1267	142/8465	4.26e-09	7.68e-08	4.54e-08	49
hsa05169110	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa04530110	Cervix	CC	Tight junction	49/1267	169/8465	1.87e-06	1.78e-05	1.05e-05	49
hsa0414419	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0412027	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa04144210	Esophagus	ESCC	Endocytosis	186/4205	251/8465	9.74e-16	4.66e-14	2.39e-14	186
hsa05169210	Esophagus	ESCC	Epstein-Barr virus infection	151/4205	202/8465	1.55e-13	3.45e-12	1.77e-12	151
hsa04530211	Esophagus	ESCC	Tight junction	105/4205	169/8465	6.73e-04	2.23e-03	1.14e-03	105
hsa0412036	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa0414437	Esophagus	ESCC	Endocytosis	186/4205	251/8465	9.74e-16	4.66e-14	2.39e-14	186
hsa0516937	Esophagus	ESCC	Epstein-Barr virus infection	151/4205	202/8465	1.55e-13	3.45e-12	1.77e-12	151
hsa04530310	Esophagus	ESCC	Tight junction	105/4205	169/8465	6.73e-04	2.23e-03	1.14e-03	105
hsa0412010	Liver	NAFLD	Ubiquitin mediated proteolysis	44/1043	142/8465	2.59e-09	1.70e-07	1.37e-07	44
hsa0453014	Liver	NAFLD	Tight junction	33/1043	169/8465	4.52e-03	4.12e-02	3.32e-02	33
hsa0412011	Liver	NAFLD	Ubiquitin mediated proteolysis	44/1043	142/8465	2.59e-09	1.70e-07	1.37e-07	44
hsa0453015	Liver	NAFLD	Tight junction	33/1043	169/8465	4.52e-03	4.12e-02	3.32e-02	33

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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

NEDD4

SNV

Missense_Mutation

novel

c.3618N>G

p.Asp1206Glu

p.D1206E

P46934

protein_coding

deleterious(0)

probably_damaging(0.946)

TCGA-A2-A3Y0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

NEDD4

SNV

Missense_Mutation

c.3271N>G

p.His1091Asp

p.H1091D

P46934

protein_coding

deleterious(0.03)

benign(0.05)

TCGA-A8-A08R-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NEDD4

SNV

Missense_Mutation

rs547250575

c.280G>A

p.Glu94Lys

p.E94K

P46934

protein_coding

deleterious(0.05)

probably_damaging(0.965)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NEDD4

SNV

Missense_Mutation

c.1361N>A

p.Arg454Gln

p.R454Q

P46934

protein_coding

tolerated_low_confidence(1)

benign(0)

TCGA-AR-A250-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NEDD4

SNV

Missense_Mutation

c.2611C>T

p.Pro871Ser

p.P871S

P46934

protein_coding

deleterious(0)

probably_damaging(0.966)

TCGA-E2-A1B1-01

Breast

breast invasive carcinoma

Female

<65

I/II

Other, specify in notesbiphosphonate

zoledronic

NEDD4

SNV

Missense_Mutation

novel

c.154N>T

p.Met52Leu

p.M52L

P46934

protein_coding

tolerated(0.3)

benign(0)

TCGA-E2-A576-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

NEDD4

SNV

Missense_Mutation

rs369468383

c.358G>T

p.Asp120Tyr

p.D120Y

P46934

protein_coding

deleterious_low_confidence(0)

benign(0.347)

TCGA-GM-A2DA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

fluorouracil

NEDD4

SNV

Missense_Mutation

novel

c.3895G>C

p.Glu1299Gln

p.E1299Q

P46934

protein_coding

tolerated(0.13)

benign(0.125)

TCGA-XX-A89A-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NEDD4

insertion

Frame_Shift_Ins

novel

c.2747_2748insCCCTGTCTCTACTAAAAATGCAAAAAAAATTAGTTGGG

p.Lys916AsnfsTer26

p.K916Nfs*26

P46934

protein_coding

TCGA-BH-A0H9-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

NEDD4

insertion

Frame_Shift_Ins

novel

c.38_39insGATATTCTTGTGTTTCAGTGCATTTG

p.Ser14IlefsTer45

p.S14Ifs*45

P46934

protein_coding

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

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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
4734	NEDD4	ENZYME		warfarin	WARFARIN	27488176

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