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: DENND4A

Gene summary for DENND4A

Gene summary.

Gene information	Species	Human
	Gene symbol	DENND4A
	Gene ID	10260
	Gene name	DENN domain containing 4A
	Gene Alias	IRLB
	Cytomap	15q22.31
	Gene Type	protein-coding
	GO ID	GO:0006139
	UniProtAcc	Q05C90

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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
10260	DENND4A	CCI_2	Human	Cervix	CC	2.95e-19	1.96e+00	0.5249
10260	DENND4A	CCI_3	Human	Cervix	CC	5.71e-06	6.21e-01	0.516
10260	DENND4A	HTA11_3410_2000001011	Human	Colorectum	AD	5.95e-17	-6.06e-01	0.0155
10260	DENND4A	HTA11_2487_2000001011	Human	Colorectum	SER	3.07e-10	-6.50e-01	-0.1808
10260	DENND4A	HTA11_78_2000001011	Human	Colorectum	AD	3.28e-03	-4.62e-01	-0.1088
10260	DENND4A	HTA11_3361_2000001011	Human	Colorectum	AD	7.45e-06	-5.92e-01	-0.1207
10260	DENND4A	HTA11_696_2000001011	Human	Colorectum	AD	6.01e-22	-5.78e-01	-0.1464
10260	DENND4A	HTA11_866_2000001011	Human	Colorectum	AD	1.21e-21	-5.90e-01	-0.1001
10260	DENND4A	HTA11_2992_2000001011	Human	Colorectum	SER	3.85e-02	-6.57e-01	-0.1706
10260	DENND4A	HTA11_546_2000001011	Human	Colorectum	AD	2.16e-02	-5.64e-01	-0.0842
10260	DENND4A	HTA11_7862_2000001011	Human	Colorectum	AD	2.83e-05	-7.12e-01	-0.0179
10260	DENND4A	HTA11_866_3004761011	Human	Colorectum	AD	1.75e-17	-6.88e-01	0.096
10260	DENND4A	HTA11_8622_2000001021	Human	Colorectum	SER	3.09e-02	-6.33e-01	0.0528
10260	DENND4A	HTA11_10711_2000001011	Human	Colorectum	AD	5.98e-08	-6.30e-01	0.0338
10260	DENND4A	HTA11_7696_3000711011	Human	Colorectum	AD	5.45e-16	-5.39e-01	0.0674
10260	DENND4A	HTA11_6818_2000001021	Human	Colorectum	AD	2.96e-06	-6.24e-01	0.0588
10260	DENND4A	HTA11_99999970781_79442	Human	Colorectum	MSS	7.79e-24	-6.11e-01	0.294
10260	DENND4A	HTA11_99999965104_69814	Human	Colorectum	MSS	1.90e-04	-5.27e-01	0.281
10260	DENND4A	HTA11_99999971662_82457	Human	Colorectum	MSS	1.55e-20	-5.70e-01	0.3859
10260	DENND4A	HTA11_99999973899_84307	Human	Colorectum	MSS	3.48e-07	-6.99e-01	0.2585

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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
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

∗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:00510566	Cervix	CC	regulation of small GTPase mediated signal transduction	75/2311	302/18723	1.54e-09	1.74e-07	75
GO:00072656	Cervix	CC	Ras protein signal transduction	79/2311	337/18723	9.49e-09	7.77e-07	79
GO:00465785	Cervix	CC	regulation of Ras protein signal transduction	44/2311	189/18723	2.05e-05	3.73e-04	44
GO:0007265	Colorectum	AD	Ras protein signal transduction	104/3918	337/18723	1.01e-05	2.35e-04	104
GO:0051056	Colorectum	AD	regulation of small GTPase mediated signal transduction	94/3918	302/18723	1.81e-05	3.76e-04	94
GO:0046578	Colorectum	AD	regulation of Ras protein signal transduction	56/3918	189/18723	2.85e-03	2.14e-02	56
GO:00072651	Colorectum	MSS	Ras protein signal transduction	91/3467	337/18723	7.20e-05	1.21e-03	91
GO:00510561	Colorectum	MSS	regulation of small GTPase mediated signal transduction	82/3467	302/18723	1.31e-04	1.99e-03	82
GO:00510562	Colorectum	FAP	regulation of small GTPase mediated signal transduction	78/2622	302/18723	3.25e-08	2.85e-06	78
GO:00072652	Colorectum	FAP	Ras protein signal transduction	80/2622	337/18723	9.61e-07	4.33e-05	80
GO:00465781	Colorectum	FAP	regulation of Ras protein signal transduction	47/2622	189/18723	4.67e-05	9.60e-04	47
GO:00510563	Colorectum	CRC	regulation of small GTPase mediated signal transduction	69/2078	302/18723	3.34e-09	9.08e-07	69
GO:00072653	Colorectum	CRC	Ras protein signal transduction	70/2078	337/18723	1.49e-07	1.66e-05	70
GO:00465782	Colorectum	CRC	regulation of Ras protein signal transduction	43/2078	189/18723	3.26e-06	1.47e-04	43
GO:00510567	Endometrium	AEH	regulation of small GTPase mediated signal transduction	59/2100	302/18723	1.43e-05	3.03e-04	59
GO:00072657	Endometrium	AEH	Ras protein signal transduction	63/2100	337/18723	3.09e-05	5.66e-04	63
GO:00465786	Endometrium	AEH	regulation of Ras protein signal transduction	36/2100	189/18723	1.01e-03	8.97e-03	36
GO:005105612	Endometrium	EEC	regulation of small GTPase mediated signal transduction	61/2168	302/18723	9.42e-06	2.08e-04	61
GO:000726513	Endometrium	EEC	Ras protein signal transduction	64/2168	337/18723	4.31e-05	7.10e-04	64
GO:004657813	Endometrium	EEC	regulation of Ras protein signal transduction	37/2168	189/18723	9.23e-04	8.32e-03	37

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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

DENND4A

SNV

Missense_Mutation

c.4609N>C

p.Glu1537Gln

p.E1537Q

Q7Z401

protein_coding

deleterious(0)

probably_damaging(0.99)

TCGA-A2-A0CX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

DENND4A

SNV

Missense_Mutation

rs371626371

c.2208N>A

p.Phe736Leu

p.F736L

Q7Z401

protein_coding

tolerated(0.09)

possibly_damaging(0.703)

TCGA-A2-A4S3-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

DENND4A

SNV

Missense_Mutation

novel

c.4988C>A

p.Ser1663Tyr

p.S1663Y

Q7Z401

protein_coding

tolerated(0.08)

benign(0.241)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DENND4A

SNV

Missense_Mutation

novel

c.1471N>G

p.Thr491Ala

p.T491A

Q7Z401

protein_coding

deleterious(0.01)

probably_damaging(0.999)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DENND4A

SNV

Missense_Mutation

c.4289N>G

p.Gln1430Arg

p.Q1430R

Q7Z401

protein_coding

tolerated(0.6)

benign(0.081)

TCGA-D8-A1JK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DENND4A

SNV

Missense_Mutation

rs368880135

c.2531N>G

p.Asn844Ser

p.N844S

Q7Z401

protein_coding

deleterious(0.04)

probably_damaging(0.996)

TCGA-EW-A1PA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

DENND4A

insertion

Nonsense_Mutation

novel

c.668_669insTTTCAGTAGTAAGGTAACATGAGAATAGCACTATATAGTTCTTAGAT

p.Leu226SerfsTer5

p.L226Sfs*5

Q7Z401

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

DENND4A

insertion

Frame_Shift_Ins

novel

c.1176_1177insAATTTAGC

p.Phe393AsnfsTer11

p.F393Nfs*11

Q7Z401

protein_coding

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DENND4A

insertion

Nonsense_Mutation

novel

c.2385_2386insCCCAGCACCTTGGGAAGCTAAGGTGG

p.Val796ProfsTer7

p.V796Pfs*7

Q7Z401

protein_coding

TCGA-AR-A0TY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Paclitaxel

DENND4A

deletion

Frame_Shift_Del

novel

c.1851delN

p.Asn617LysfsTer2

p.N617Kfs*2

Q7Z401

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

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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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