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: CUL3

Gene summary for CUL3

Gene summary.

Gene information	Species	Human
	Gene symbol	CUL3
	Gene ID	8452
	Gene name	cullin 3
	Gene Alias	CUL-3
	Cytomap	2q36.2
	Gene Type	protein-coding
	GO ID	GO:0000070
	UniProtAcc	B7Z600

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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
8452	CUL3	CA_HPV_1	Human	Cervix	CC	2.93e-02	-9.15e-02	0.0264
8452	CUL3	CCI_2	Human	Cervix	CC	1.18e-09	1.46e+00	0.5249
8452	CUL3	CCI_3	Human	Cervix	CC	3.21e-11	9.71e-01	0.516
8452	CUL3	HTA11_3410_2000001011	Human	Colorectum	AD	2.39e-18	-6.25e-01	0.0155
8452	CUL3	HTA11_2487_2000001011	Human	Colorectum	SER	5.29e-05	-5.01e-01	-0.1808
8452	CUL3	HTA11_78_2000001011	Human	Colorectum	AD	4.72e-03	-4.09e-01	-0.1088
8452	CUL3	HTA11_3361_2000001011	Human	Colorectum	AD	6.88e-03	-4.44e-01	-0.1207
8452	CUL3	HTA11_696_2000001011	Human	Colorectum	AD	2.27e-10	-3.59e-01	-0.1464
8452	CUL3	HTA11_866_2000001011	Human	Colorectum	AD	1.64e-08	-3.54e-01	-0.1001
8452	CUL3	HTA11_866_3004761011	Human	Colorectum	AD	1.03e-11	-5.67e-01	0.096
8452	CUL3	HTA11_8622_2000001021	Human	Colorectum	SER	3.87e-02	-5.66e-01	0.0528
8452	CUL3	HTA11_10711_2000001011	Human	Colorectum	AD	4.42e-03	-4.45e-01	0.0338
8452	CUL3	HTA11_7696_3000711011	Human	Colorectum	AD	5.29e-12	-4.69e-01	0.0674
8452	CUL3	HTA11_99999970781_79442	Human	Colorectum	MSS	4.85e-17	-5.01e-01	0.294
8452	CUL3	HTA11_99999971662_82457	Human	Colorectum	MSS	6.46e-09	-4.00e-01	0.3859
8452	CUL3	HTA11_99999974143_84620	Human	Colorectum	MSS	7.25e-10	-3.80e-01	0.3005
8452	CUL3	A015-C-203	Human	Colorectum	FAP	9.45e-30	-3.93e-01	-0.1294
8452	CUL3	A015-C-204	Human	Colorectum	FAP	4.39e-07	-2.72e-01	-0.0228
8452	CUL3	A014-C-040	Human	Colorectum	FAP	1.34e-09	-6.78e-01	-0.1184
8452	CUL3	A002-C-201	Human	Colorectum	FAP	3.34e-19	-3.61e-01	0.0324

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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
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:000726515	Oral cavity	LP	Ras protein signal transduction	109/4623	337/18723	8.44e-04	7.36e-03	109
GO:000081911	Oral cavity	LP	sister chromatid segregation	70/4623	202/18723	9.20e-04	7.82e-03	70
GO:190198912	Oral cavity	LP	positive regulation of cell cycle phase transition	42/4623	115/18723	3.06e-03	2.09e-02	42
GO:005186512	Oral cavity	LP	protein autoubiquitination	29/4623	73/18723	3.20e-03	2.18e-02	29
GO:007121812	Oral cavity	LP	cellular response to misfolded protein	12/4623	23/18723	4.14e-03	2.66e-02	12
GO:004828511	Oral cavity	LP	organelle fission	145/4623	488/18723	6.02e-03	3.57e-02	145
GO:0051017110	Oral cavity	LP	actin filament bundle assembly	53/4623	157/18723	6.54e-03	3.83e-02	53
GO:00988131	Oral cavity	LP	nuclear chromosome segregation	88/4623	281/18723	6.72e-03	3.91e-02	88
GO:190199211	Oral cavity	LP	positive regulation of mitotic cell cycle phase transition	34/4623	93/18723	7.08e-03	3.98e-02	34
GO:00070881	Oral cavity	LP	regulation of mitotic nuclear division	39/4623	110/18723	7.45e-03	4.14e-02	39
GO:003502412	Oral cavity	LP	negative regulation of Rho protein signal transduction	11/4623	22/18723	9.01e-03	4.83e-02	11
GO:004578715	Oral cavity	LP	positive regulation of cell cycle	96/4623	313/18723	9.08e-03	4.85e-02	96
GO:002261215	Oral cavity	LP	gland morphogenesis	41/4623	118/18723	9.09e-03	4.85e-02	41
GO:009719326	Oral cavity	EOLP	intrinsic apoptotic signaling pathway	84/2218	288/18723	1.29e-15	7.05e-13	84
GO:190332026	Oral cavity	EOLP	regulation of protein modification by small protein conjugation or removal	73/2218	242/18723	1.41e-14	6.47e-12	73
GO:003596624	Oral cavity	EOLP	response to topologically incorrect protein	54/2218	159/18723	1.93e-13	6.44e-11	54
GO:007093622	Oral cavity	EOLP	protein K48-linked ubiquitination	31/2218	65/18723	9.08e-13	2.27e-10	31
GO:003139626	Oral cavity	EOLP	regulation of protein ubiquitination	62/2218	210/18723	3.86e-12	7.34e-10	62
GO:000701526	Oral cavity	EOLP	actin filament organization	102/2218	442/18723	1.61e-11	2.48e-09	102
GO:001049825	Oral cavity	EOLP	proteasomal protein catabolic process	108/2218	490/18723	7.79e-11	9.51e-09	108

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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
hsa0412015	Cervix	CC	Ubiquitin mediated proteolysis	49/1267	142/8465	4.26e-09	7.68e-08	4.54e-08	49
hsa04120	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa041201	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa041202	Colorectum	SER	Ubiquitin mediated proteolysis	39/1580	142/8465	6.18e-03	3.66e-02	2.66e-02	39
hsa041203	Colorectum	SER	Ubiquitin mediated proteolysis	39/1580	142/8465	6.18e-03	3.66e-02	2.66e-02	39
hsa041204	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa041205	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa041206	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa041207	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa041208	Colorectum	CRC	Ubiquitin mediated proteolysis	42/1091	142/8465	9.98e-08	6.67e-06	4.52e-06	42
hsa041209	Colorectum	CRC	Ubiquitin mediated proteolysis	42/1091	142/8465	9.98e-08	6.67e-06	4.52e-06	42
hsa0412016	Endometrium	AEH	Ubiquitin mediated proteolysis	41/1197	142/8465	3.42e-06	4.27e-05	3.13e-05	41
hsa0412017	Endometrium	AEH	Ubiquitin mediated proteolysis	41/1197	142/8465	3.42e-06	4.27e-05	3.13e-05	41
hsa0412023	Endometrium	EEC	Ubiquitin mediated proteolysis	41/1237	142/8465	7.86e-06	9.58e-05	7.14e-05	41
hsa0412033	Endometrium	EEC	Ubiquitin mediated proteolysis	41/1237	142/8465	7.86e-06	9.58e-05	7.14e-05	41
hsa0412027	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa0412036	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa0412010	Liver	NAFLD	Ubiquitin mediated proteolysis	44/1043	142/8465	2.59e-09	1.70e-07	1.37e-07	44
hsa0412011	Liver	NAFLD	Ubiquitin mediated proteolysis	44/1043	142/8465	2.59e-09	1.70e-07	1.37e-07	44

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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

CUL3

SNV

Missense_Mutation

c.274G>A

p.Asp92Asn

p.D92N

Q13618

protein_coding

tolerated(0.13)

possibly_damaging(0.816)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

CUL3

SNV

Missense_Mutation

c.2059N>A

p.Glu687Lys

p.E687K

Q13618

protein_coding

deleterious(0)

possibly_damaging(0.785)

TCGA-A2-A0YK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

CUL3

SNV

Missense_Mutation

c.464N>A

p.Gly155Glu

p.G155E

Q13618

protein_coding

tolerated(1)

benign(0.438)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CUL3

SNV

Missense_Mutation

novel

c.1855N>C

p.Glu619Gln

p.E619Q

Q13618

protein_coding

tolerated(0.18)

possibly_damaging(0.541)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CUL3

SNV

Missense_Mutation

c.1285N>A

p.Glu429Lys

p.E429K

Q13618

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0EE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

CUL3

insertion

Frame_Shift_Ins

novel

c.700_701insCACCTTTTATCTTCTGGATTAAATGTAAAATGAGACT

p.Ile234ThrfsTer19

p.I234Tfs*19

Q13618

protein_coding

TCGA-AR-A0TU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Doxorubicin

CUL3

insertion

Frame_Shift_Ins

novel

c.1358dupA

p.Asn453LysfsTer5

p.N453Kfs*5

Q13618

protein_coding

TCGA-AR-A0U0-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CUL3

SNV

Missense_Mutation

c.124N>G

p.Gln42Glu

p.Q42E

Q13618

protein_coding

tolerated(0.13)

possibly_damaging(0.803)

TCGA-C5-A7X5-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

carboplatin

CUL3

SNV

Missense_Mutation

novel

c.1880T>G

p.Leu627Arg

p.L627R

Q13618

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-ZJ-AAXT-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

CUL3

insertion

Frame_Shift_Ins

novel

c.892_893insACACA

p.Cys298TyrfsTer15

p.C298Yfs*15

Q13618

protein_coding

TCGA-DS-A1OB-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

carboplatin

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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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