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: N4BP1

Gene summary for N4BP1

Gene summary.

Gene information	Species	Human
	Gene symbol	N4BP1
	Gene ID	9683
	Gene name	NEDD4 binding protein 1
	Gene Alias	N4BP1
	Cytomap	16q12.1
	Gene Type	protein-coding
	GO ID	GO:0001816
	UniProtAcc	O75113

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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
9683	N4BP1	CCI_1	Human	Cervix	CC	1.52e-03	6.20e-01	0.528
9683	N4BP1	CCI_2	Human	Cervix	CC	2.70e-07	1.04e+00	0.5249
9683	N4BP1	CCI_3	Human	Cervix	CC	5.41e-06	8.63e-01	0.516
9683	N4BP1	sample3	Human	Cervix	CC	1.14e-04	2.31e-01	0.1387
9683	N4BP1	T3	Human	Cervix	CC	1.94e-04	2.46e-01	0.1389
9683	N4BP1	LZE4T	Human	Esophagus	ESCC	2.67e-11	3.32e-01	0.0811
9683	N4BP1	LZE7T	Human	Esophagus	ESCC	5.24e-07	2.85e-01	0.0667
9683	N4BP1	LZE8T	Human	Esophagus	ESCC	9.08e-07	1.35e-01	0.067
9683	N4BP1	LZE20T	Human	Esophagus	ESCC	3.68e-07	3.43e-01	0.0662
9683	N4BP1	LZE22T	Human	Esophagus	ESCC	8.82e-04	2.97e-01	0.068
9683	N4BP1	LZE24T	Human	Esophagus	ESCC	2.50e-17	4.24e-01	0.0596
9683	N4BP1	LZE21T	Human	Esophagus	ESCC	3.02e-05	2.78e-01	0.0655
9683	N4BP1	P1T-E	Human	Esophagus	ESCC	8.86e-17	7.60e-01	0.0875
9683	N4BP1	P2T-E	Human	Esophagus	ESCC	7.05e-32	1.67e-01	0.1177
9683	N4BP1	P4T-E	Human	Esophagus	ESCC	9.70e-20	5.09e-01	0.1323
9683	N4BP1	P5T-E	Human	Esophagus	ESCC	4.29e-22	3.85e-01	0.1327
9683	N4BP1	P8T-E	Human	Esophagus	ESCC	9.09e-16	2.80e-01	0.0889
9683	N4BP1	P9T-E	Human	Esophagus	ESCC	1.06e-09	1.74e-01	0.1131
9683	N4BP1	P10T-E	Human	Esophagus	ESCC	2.67e-15	1.23e-01	0.116
9683	N4BP1	P11T-E	Human	Esophagus	ESCC	2.06e-10	4.49e-01	0.1426

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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
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:00450887	Thyroid	PTC	regulation of innate immune response	89/5968	218/18723	3.16e-03	1.55e-02	89
GO:0045861113	Thyroid	PTC	negative regulation of proteolysis	136/5968	351/18723	3.54e-03	1.71e-02	136
GO:190179914	Thyroid	PTC	negative regulation of proteasomal protein catabolic process	25/5968	49/18723	4.09e-03	1.95e-02	25
GO:00714823	Thyroid	PTC	cellular response to light stimulus	53/5968	123/18723	5.73e-03	2.59e-02	53
GO:001049832	Thyroid	ATC	proteasomal protein catabolic process	309/6293	490/18723	1.78e-41	1.13e-37	309
GO:0043161210	Thyroid	ATC	proteasome-mediated ubiquitin-dependent protein catabolic process	265/6293	412/18723	7.09e-38	1.49e-34	265
GO:004217635	Thyroid	ATC	regulation of protein catabolic process	239/6293	391/18723	2.63e-29	1.85e-26	239
GO:190336235	Thyroid	ATC	regulation of cellular protein catabolic process	168/6293	255/18723	3.50e-26	1.58e-23	168
GO:001603234	Thyroid	ATC	viral process	241/6293	415/18723	5.50e-25	2.04e-22	241
GO:190305035	Thyroid	ATC	regulation of proteolysis involved in cellular protein catabolic process	146/6293	221/18723	4.18e-23	1.20e-20	146
GO:006113633	Thyroid	ATC	regulation of proteasomal protein catabolic process	128/6293	187/18723	1.63e-22	4.30e-20	128
GO:2000058210	Thyroid	ATC	regulation of ubiquitin-dependent protein catabolic process	116/6293	164/18723	2.15e-22	5.43e-20	116
GO:0032434210	Thyroid	ATC	regulation of proteasomal ubiquitin-dependent protein catabolic process	100/6293	134/18723	2.41e-22	5.86e-20	100
GO:190332034	Thyroid	ATC	regulation of protein modification by small protein conjugation or removal	152/6293	242/18723	9.76e-21	1.71e-18	152
GO:003139634	Thyroid	ATC	regulation of protein ubiquitination	132/6293	210/18723	3.13e-18	3.98e-16	132
GO:001905835	Thyroid	ATC	viral life cycle	173/6293	317/18723	9.22e-15	5.50e-13	173
GO:007121427	Thyroid	ATC	cellular response to abiotic stimulus	169/6293	331/18723	3.24e-11	1.08e-09	169
GO:010400427	Thyroid	ATC	cellular response to environmental stimulus	169/6293	331/18723	3.24e-11	1.08e-09	169
GO:003139734	Thyroid	ATC	negative regulation of protein ubiquitination	56/6293	83/18723	2.90e-10	8.20e-09	56
GO:003133035	Thyroid	ATC	negative regulation of cellular catabolic process	136/6293	262/18723	6.47e-10	1.71e-08	136

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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

N4BP1

SNV

Missense_Mutation

rs773100602

c.2605G>C

p.Glu869Gln

p.E869Q

O75113

protein_coding

tolerated(0.08)

probably_damaging(0.987)

TCGA-A8-A095-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

N4BP1

SNV

Missense_Mutation

c.722G>A

p.Gly241Glu

p.G241E

O75113

protein_coding

deleterious(0)

possibly_damaging(0.762)

TCGA-AC-A23C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

chemo

N4BP1

SNV

Missense_Mutation

c.1184N>C

p.Arg395Thr

p.R395T

O75113

protein_coding

tolerated(0.18)

benign(0.003)

TCGA-AR-A0TT-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

N4BP1

SNV

Missense_Mutation

c.855N>C

p.Arg285Ser

p.R285S

O75113

protein_coding

deleterious(0)

probably_damaging(0.996)

TCGA-AR-A0TT-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

N4BP1

SNV

Missense_Mutation

novel

c.799N>G

p.Asn267Asp

p.N267D

O75113

protein_coding

deleterious(0.02)

possibly_damaging(0.541)

TCGA-AR-A0TU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Doxorubicin

N4BP1

SNV

Missense_Mutation

c.2113G>A

p.Asp705Asn

p.D705N

O75113

protein_coding

deleterious(0)

probably_damaging(0.966)

TCGA-C8-A12Q-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

N4BP1

insertion

Frame_Shift_Ins

novel

c.2559_2560insTGTGG

p.Thr854CysfsTer6

p.T854Cfs*6

O75113

protein_coding

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

N4BP1

insertion

Frame_Shift_Ins

novel

c.2558_2559insTGCGTCCGTGATGCCTCCTA

p.Glu853AspfsTer12

p.E853Dfs*12

O75113

protein_coding

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

N4BP1

insertion

Nonsense_Mutation

novel

c.1735_1736insATGGAGGCACCTTTAGGCCAAATTTAATTTAATTTAA

p.Ser579TyrfsTer11

p.S579Yfs*11

O75113

protein_coding

TCGA-AO-A03T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

N4BP1

insertion

Frame_Shift_Ins

novel

c.797_798insGGTTCAGT

p.Ile266MetfsTer4

p.I266Mfs*4

O75113

protein_coding

TCGA-AR-A0TU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Doxorubicin

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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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