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: DENND4C

Gene summary for DENND4C

Gene summary.

Gene information	Species	Human
	Gene symbol	DENND4C
	Gene ID	55667
	Gene name	DENN domain containing 4C
	Gene Alias	C9orf55
	Cytomap	9p22.1
	Gene Type	protein-coding
	GO ID	GO:0006810
	UniProtAcc	Q5VZ89

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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
55667	DENND4C	CCI_1	Human	Cervix	CC	9.71e-04	5.81e-01	0.528
55667	DENND4C	CCI_2	Human	Cervix	CC	1.50e-08	1.13e+00	0.5249
55667	DENND4C	CCI_3	Human	Cervix	CC	1.44e-08	7.96e-01	0.516
55667	DENND4C	HTA11_347_2000001011	Human	Colorectum	AD	8.10e-11	5.74e-01	-0.1954
55667	DENND4C	HTA11_99999965104_69814	Human	Colorectum	MSS	1.14e-02	5.73e-01	0.281
55667	DENND4C	HTA11_99999974143_84620	Human	Colorectum	MSS	1.47e-03	-3.49e-01	0.3005
55667	DENND4C	A002-C-010	Human	Colorectum	FAP	3.23e-02	4.66e-02	0.242
55667	DENND4C	A001-C-207	Human	Colorectum	FAP	4.08e-03	-1.46e-01	0.1278
55667	DENND4C	A015-C-203	Human	Colorectum	FAP	1.33e-34	-3.50e-01	-0.1294
55667	DENND4C	A015-C-204	Human	Colorectum	FAP	5.88e-07	-3.27e-01	-0.0228
55667	DENND4C	A014-C-040	Human	Colorectum	FAP	3.24e-03	-2.28e-01	-0.1184
55667	DENND4C	A002-C-201	Human	Colorectum	FAP	1.70e-13	-2.98e-01	0.0324
55667	DENND4C	A002-C-203	Human	Colorectum	FAP	1.29e-03	-9.22e-02	0.2786
55667	DENND4C	A001-C-119	Human	Colorectum	FAP	6.02e-06	-2.52e-01	-0.1557
55667	DENND4C	A001-C-108	Human	Colorectum	FAP	4.40e-18	-1.63e-01	-0.0272
55667	DENND4C	A002-C-205	Human	Colorectum	FAP	1.43e-23	-4.11e-01	-0.1236
55667	DENND4C	A001-C-104	Human	Colorectum	FAP	3.70e-02	-1.14e-01	0.0184
55667	DENND4C	A015-C-005	Human	Colorectum	FAP	5.02e-03	-2.85e-01	-0.0336
55667	DENND4C	A015-C-006	Human	Colorectum	FAP	3.11e-19	-5.17e-01	-0.0994
55667	DENND4C	A015-C-106	Human	Colorectum	FAP	4.96e-12	-1.61e-01	-0.0511

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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
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
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:190165310	Prostate	BPH	cellular response to peptide	104/3107	359/18723	2.51e-09	1.00e-07	104
GO:199077810	Prostate	BPH	protein localization to cell periphery	95/3107	333/18723	2.78e-08	8.13e-07	95
GO:004343417	Prostate	BPH	response to peptide hormone	109/3107	414/18723	2.73e-07	5.91e-06	109
GO:00713759	Prostate	BPH	cellular response to peptide hormone stimulus	82/3107	290/18723	3.65e-07	7.65e-06	82
GO:003286910	Prostate	BPH	cellular response to insulin stimulus	61/3107	203/18723	1.26e-06	2.20e-05	61
GO:003286810	Prostate	BPH	response to insulin	73/3107	264/18723	3.80e-06	5.83e-05	73
GO:00510568	Prostate	BPH	regulation of small GTPase mediated signal transduction	78/3107	302/18723	2.69e-05	3.16e-04	78
GO:00465787	Prostate	BPH	regulation of Ras protein signal transduction	53/3107	189/18723	5.08e-05	5.24e-04	53
GO:007265917	Prostate	Tumor	protein localization to plasma membrane	90/3246	284/18723	2.07e-09	8.99e-08	90
GO:000726514	Prostate	Tumor	Ras protein signal transduction	101/3246	337/18723	6.29e-09	2.44e-07	101
GO:190165315	Prostate	Tumor	cellular response to peptide	104/3246	359/18723	2.71e-08	8.90e-07	104
GO:199077815	Prostate	Tumor	protein localization to cell periphery	97/3246	333/18723	5.88e-08	1.75e-06	97
GO:004343418	Prostate	Tumor	response to peptide hormone	113/3246	414/18723	2.24e-07	5.42e-06	113
GO:007137514	Prostate	Tumor	cellular response to peptide hormone stimulus	83/3246	290/18723	1.14e-06	2.16e-05	83
GO:003286915	Prostate	Tumor	cellular response to insulin stimulus	63/3246	203/18723	1.15e-06	2.18e-05	63
GO:003286815	Prostate	Tumor	response to insulin	75/3246	264/18723	4.94e-06	7.68e-05	75
GO:005105613	Prostate	Tumor	regulation of small GTPase mediated signal transduction	80/3246	302/18723	3.96e-05	4.57e-04	80
GO:004657814	Prostate	Tumor	regulation of Ras protein signal transduction	53/3246	189/18723	1.63e-04	1.46e-03	53
GO:000726516	Skin	AK	Ras protein signal transduction	68/1910	337/18723	2.83e-08	1.57e-06	68
GO:007265925	Skin	AK	protein localization to plasma membrane	59/1910	284/18723	8.01e-08	3.80e-06	59

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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

DENND4C

SNV

Missense_Mutation

c.950N>T

p.Ser317Leu

p.S317L

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A2-A0T2-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

xeloda

DENND4C

SNV

Missense_Mutation

c.2723N>G

p.Ser908Cys

p.S908C

protein_coding

deleterious(0.02)

possibly_damaging(0.754)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DENND4C

SNV

Missense_Mutation

c.1828N>T

p.Arg610Cys

p.R610C

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

DENND4C

SNV

Missense_Mutation

c.5516N>T

p.Arg1839Met

p.R1839M

protein_coding

deleterious(0)

probably_damaging(0.975)

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

DENND4C

SNV

Missense_Mutation

c.2254G>A

p.Glu752Lys

p.E752K

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-BH-A1FN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

DENND4C

SNV

Missense_Mutation

c.3698G>C

p.Ser1233Thr

p.S1233T

protein_coding

deleterious(0.01)

possibly_damaging(0.831)

TCGA-C8-A27B-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

DENND4C

insertion

Frame_Shift_Ins

novel

c.3706_3707insAT

p.Gly1236AspfsTer16

p.G1236Dfs*16

protein_coding

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

DENND4C

insertion

Nonsense_Mutation

novel

c.3707_3708insAGAATCCTAAATATGAA

p.Ile1237GlufsTer3

p.I1237Efs*3

protein_coding

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

DENND4C

insertion

Frame_Shift_Ins

novel

c.1458_1459insTACTCTCTGAACCCTCAGCTGTACCACTGCTGTACTTA

p.Ile487TyrfsTer13

p.I487Yfs*13

protein_coding

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

DENND4C

SNV

Missense_Mutation

rs772654971

c.1702N>T

p.Arg568Cys

p.R568C

protein_coding

tolerated(0.15)

probably_damaging(0.928)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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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