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: N4BP2L2

Gene summary for N4BP2L2

Gene summary.

Gene information	Species	Human
	Gene symbol	N4BP2L2
	Gene ID	10443
	Gene name	NEDD4 binding protein 2 like 2
	Gene Alias	92M18.3
	Cytomap	13q13.1
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	B4DPY1

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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
10443	N4BP2L2	GSM4909282	Human	Breast	IDC	4.33e-10	-4.52e-01	-0.0288
10443	N4BP2L2	GSM4909286	Human	Breast	IDC	5.52e-03	-1.60e-02	0.1081
10443	N4BP2L2	GSM4909287	Human	Breast	IDC	3.60e-07	-4.17e-01	0.2057
10443	N4BP2L2	GSM4909291	Human	Breast	IDC	4.91e-07	-4.96e-01	0.1753
10443	N4BP2L2	GSM4909292	Human	Breast	IDC	2.97e-03	4.26e-01	0.1236
10443	N4BP2L2	GSM4909294	Human	Breast	IDC	4.25e-12	-4.43e-01	0.2022
10443	N4BP2L2	GSM4909296	Human	Breast	IDC	3.01e-28	-6.08e-01	0.1524
10443	N4BP2L2	GSM4909297	Human	Breast	IDC	3.84e-44	4.15e-01	0.1517
10443	N4BP2L2	GSM4909298	Human	Breast	IDC	9.90e-20	5.17e-01	0.1551
10443	N4BP2L2	GSM4909301	Human	Breast	IDC	4.89e-07	-3.46e-01	0.1577
10443	N4BP2L2	GSM4909304	Human	Breast	IDC	1.07e-02	-2.97e-01	0.1636
10443	N4BP2L2	GSM4909309	Human	Breast	IDC	4.83e-04	-2.67e-01	0.0483
10443	N4BP2L2	GSM4909311	Human	Breast	IDC	2.03e-43	-5.44e-01	0.1534
10443	N4BP2L2	GSM4909312	Human	Breast	IDC	1.81e-16	-3.45e-01	0.1552
10443	N4BP2L2	GSM4909313	Human	Breast	IDC	2.41e-03	-2.52e-01	0.0391
10443	N4BP2L2	GSM4909315	Human	Breast	IDC	6.03e-07	-3.88e-01	0.21
10443	N4BP2L2	GSM4909316	Human	Breast	IDC	7.78e-06	-5.94e-01	0.21
10443	N4BP2L2	GSM4909317	Human	Breast	IDC	1.33e-10	4.49e-01	0.1355
10443	N4BP2L2	GSM4909319	Human	Breast	IDC	6.13e-48	-6.38e-01	0.1563
10443	N4BP2L2	GSM4909320	Human	Breast	IDC	1.21e-13	-7.00e-01	0.1575

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
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:00017017	Breast	Precancer	in utero embryonic development	35/1080	367/18723	2.47e-03	2.27e-02	35
GO:000170113	Breast	IDC	in utero embryonic development	42/1434	367/18723	5.85e-03	4.24e-02	42
GO:000170122	Breast	DCIS	in utero embryonic development	41/1390	367/18723	5.74e-03	4.13e-02	41
GO:20007362	Cervix	CC	regulation of stem cell differentiation	19/2311	58/18723	4.01e-05	6.21e-04	19
GO:00488634	Cervix	CC	stem cell differentiation	46/2311	206/18723	4.11e-05	6.36e-04	46
GO:00017018	Cervix	CC	in utero embryonic development	71/2311	367/18723	7.21e-05	1.00e-03	71
GO:20007372	Cervix	CC	negative regulation of stem cell differentiation	10/2311	23/18723	2.00e-04	2.29e-03	10
GO:00022443	Cervix	CC	hematopoietic progenitor cell differentiation	26/2311	114/18723	1.30e-03	1.03e-02	26
GO:0060218	Cervix	CC	hematopoietic stem cell differentiation	10/2311	30/18723	2.33e-03	1.66e-02	10
GO:1901532	Cervix	CC	regulation of hematopoietic progenitor cell differentiation	10/2311	32/18723	3.96e-03	2.48e-02	10
GO:1902036	Cervix	CC	regulation of hematopoietic stem cell differentiation	6/2311	14/18723	4.36e-03	2.67e-02	6
GO:004886313	Cervix	N_HPV	stem cell differentiation	14/534	206/18723	2.43e-03	2.20e-02	14
GO:200073711	Cervix	N_HPV	negative regulation of stem cell differentiation	4/534	23/18723	3.76e-03	3.00e-02	4
GO:200073611	Cervix	N_HPV	regulation of stem cell differentiation	6/534	58/18723	6.04e-03	4.17e-02	6
GO:0001701	Colorectum	AD	in utero embryonic development	110/3918	367/18723	2.36e-05	4.62e-04	110
GO:00017012	Colorectum	MSS	in utero embryonic development	99/3467	367/18723	3.71e-05	7.10e-04	99
GO:0002244	Colorectum	MSS	hematopoietic progenitor cell differentiation	32/3467	114/18723	8.07e-03	4.91e-02	32
GO:00017013	Colorectum	FAP	in utero embryonic development	81/2622	367/18723	1.58e-05	4.10e-04	81
GO:00022441	Colorectum	FAP	hematopoietic progenitor cell differentiation	29/2622	114/18723	8.35e-04	8.71e-03	29
GO:0048863	Colorectum	FAP	stem cell differentiation	44/2622	206/18723	2.48e-03	1.96e-02	44

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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

N4BP2L2

SNV

Missense_Mutation

c.907N>T

p.His303Tyr

p.H303Y

Q92802

protein_coding

deleterious(0.02)

benign(0.047)

TCGA-A2-A0D4-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

N4BP2L2

SNV

Missense_Mutation

novel

c.1801N>A

p.His601Asn

p.H601N

Q92802

protein_coding

deleterious(0.03)

benign(0.08)

TCGA-AC-A3TM-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

N4BP2L2

SNV

Missense_Mutation

novel

c.1452T>A

p.Asn484Lys

p.N484K

Q92802

protein_coding

deleterious(0.02)

benign(0.007)

TCGA-BH-A0BO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

N4BP2L2

SNV

Missense_Mutation

c.294N>C

p.Lys98Asn

p.K98N

Q92802

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A209-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

N4BP2L2

insertion

Frame_Shift_Ins

novel

c.105_106insCTTTTTACTTTGTGCTTTCATGTTGCTCCCACTTT

p.Ala36LeufsTer22

p.A36Lfs*22

Q92802

protein_coding

TCGA-AR-A0TY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Paclitaxel

N4BP2L2

SNV

Missense_Mutation

c.1861G>A

p.Glu621Lys

p.E621K

Q92802

protein_coding

tolerated(1)

benign(0)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

N4BP2L2

SNV

Missense_Mutation

novel

c.172C>T

p.Pro58Ser

p.P58S

Q92802

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-MA-AA42-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

N4BP2L2

SNV

Missense_Mutation

novel

c.459N>T

p.Gln153His

p.Q153H

Q92802

protein_coding

deleterious(0)

possibly_damaging(0.61)

TCGA-VS-A94Z-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

N4BP2L2

insertion

Frame_Shift_Ins

novel

c.1700dupC

p.Leu568PhefsTer4

p.L568Ffs*4

Q92802

protein_coding

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

N4BP2L2

SNV

Missense_Mutation

c.230C>G

p.Thr77Ser

p.T77S

Q92802

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A6-2684-01

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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