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: CUL4A

Gene summary for CUL4A

Gene summary.

Gene information	Species	Human
	Gene symbol	CUL4A
	Gene ID	8451
	Gene name	cullin 4A
	Gene Alias	CUL4A
	Cytomap	13q34
	Gene Type	protein-coding
	GO ID	GO:0000075
	UniProtAcc	Q13619

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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
8451	CUL4A	CCI_1	Human	Cervix	CC	1.81e-08	7.52e-01	0.528
8451	CUL4A	CCI_2	Human	Cervix	CC	9.41e-13	1.14e+00	0.5249
8451	CUL4A	CCI_3	Human	Cervix	CC	1.52e-07	6.15e-01	0.516
8451	CUL4A	sample3	Human	Cervix	CC	2.29e-02	1.25e-01	0.1387
8451	CUL4A	HTA11_3410_2000001011	Human	Colorectum	AD	5.59e-05	-3.04e-01	0.0155
8451	CUL4A	HTA11_866_3004761011	Human	Colorectum	AD	2.18e-02	-2.46e-01	0.096
8451	CUL4A	HTA11_99999965104_69814	Human	Colorectum	MSS	5.41e-11	7.83e-01	0.281
8451	CUL4A	HTA11_99999971662_82457	Human	Colorectum	MSS	1.44e-04	6.25e-01	0.3859
8451	CUL4A	A001-C-207	Human	Colorectum	FAP	2.58e-02	-1.95e-01	0.1278
8451	CUL4A	A015-C-203	Human	Colorectum	FAP	8.69e-25	-3.23e-01	-0.1294
8451	CUL4A	A015-C-204	Human	Colorectum	FAP	3.92e-05	-2.41e-01	-0.0228
8451	CUL4A	A014-C-040	Human	Colorectum	FAP	6.73e-03	-3.34e-01	-0.1184
8451	CUL4A	A002-C-201	Human	Colorectum	FAP	5.55e-11	-2.84e-01	0.0324
8451	CUL4A	A002-C-203	Human	Colorectum	FAP	1.12e-03	-1.75e-01	0.2786
8451	CUL4A	A001-C-119	Human	Colorectum	FAP	5.14e-03	-2.24e-01	-0.1557
8451	CUL4A	A001-C-108	Human	Colorectum	FAP	2.13e-12	-1.80e-01	-0.0272
8451	CUL4A	A002-C-205	Human	Colorectum	FAP	4.60e-18	-3.02e-01	-0.1236
8451	CUL4A	A001-C-104	Human	Colorectum	FAP	5.32e-04	-1.80e-01	0.0184
8451	CUL4A	A015-C-005	Human	Colorectum	FAP	1.25e-02	-1.45e-01	-0.0336
8451	CUL4A	A015-C-006	Human	Colorectum	FAP	6.71e-13	-9.44e-02	-0.0994

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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
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

∗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:00457879	Oral cavity	OSCC	positive regulation of cell cycle	173/7305	313/18723	3.28e-09	7.44e-08	173
GO:00457864	Oral cavity	OSCC	negative regulation of cell cycle	206/7305	385/18723	4.28e-09	9.55e-08	206
GO:00459319	Oral cavity	OSCC	positive regulation of mitotic cell cycle	77/7305	121/18723	3.49e-08	6.64e-07	77
GO:00000753	Oral cavity	OSCC	cell cycle checkpoint	101/7305	169/18723	3.53e-08	6.68e-07	101
GO:00427707	Oral cavity	OSCC	signal transduction in response to DNA damage	102/7305	172/18723	5.27e-08	9.68e-07	102
GO:000257310	Oral cavity	OSCC	myeloid leukocyte differentiation	119/7305	208/18723	7.29e-08	1.29e-06	119
GO:00000826	Oral cavity	OSCC	G1/S transition of mitotic cell cycle	120/7305	214/18723	2.86e-07	4.40e-06	120
GO:19019882	Oral cavity	OSCC	negative regulation of cell cycle phase transition	136/7305	249/18723	3.81e-07	5.70e-06	136
GO:00987277	Oral cavity	OSCC	maintenance of cell number	81/7305	134/18723	3.96e-07	5.90e-06	81
GO:00198276	Oral cavity	OSCC	stem cell population maintenance	79/7305	131/18723	6.28e-07	8.96e-06	79
GO:00448436	Oral cavity	OSCC	cell cycle G1/S phase transition	131/7305	241/18723	8.77e-07	1.20e-05	131
GO:004851116	Oral cavity	OSCC	rhythmic process	157/7305	298/18723	1.00e-06	1.36e-05	157
GO:00109483	Oral cavity	OSCC	negative regulation of cell cycle process	155/7305	294/18723	1.11e-06	1.48e-05	155
GO:00900688	Oral cavity	OSCC	positive regulation of cell cycle process	126/7305	236/18723	4.75e-06	5.44e-05	126
GO:00315704	Oral cavity	OSCC	DNA integrity checkpoint	72/7305	123/18723	8.77e-06	9.31e-05	72
GO:00062825	Oral cavity	OSCC	regulation of DNA repair	75/7305	130/18723	1.19e-05	1.21e-04	75
GO:00000774	Oral cavity	OSCC	DNA damage checkpoint	67/7305	115/18723	2.20e-05	2.08e-04	67
GO:19019924	Oral cavity	OSCC	positive regulation of mitotic cell cycle phase transition	56/7305	93/18723	2.76e-05	2.56e-04	56
GO:190370618	Oral cavity	OSCC	regulation of hemopoiesis	180/7305	367/18723	5.16e-05	4.30e-04	180
GO:19019895	Oral cavity	OSCC	positive regulation of cell cycle phase transition	65/7305	115/18723	1.03e-04	7.69e-04	65

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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
hsa0517016	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa0412015	Cervix	CC	Ubiquitin mediated proteolysis	49/1267	142/8465	4.26e-09	7.68e-08	4.54e-08	49
hsa0517017	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa04120	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa05170	Colorectum	AD	Human immunodeficiency virus 1 infection	72/2092	212/8465	1.40e-03	8.46e-03	5.39e-03	72
hsa041201	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa051701	Colorectum	AD	Human immunodeficiency virus 1 infection	72/2092	212/8465	1.40e-03	8.46e-03	5.39e-03	72
hsa041204	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa051704	Colorectum	MSS	Human immunodeficiency virus 1 infection	69/1875	212/8465	2.66e-04	1.98e-03	1.21e-03	69
hsa041205	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa051705	Colorectum	MSS	Human immunodeficiency virus 1 infection	69/1875	212/8465	2.66e-04	1.98e-03	1.21e-03	69
hsa041206	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa051706	Colorectum	FAP	Human immunodeficiency virus 1 infection	51/1404	212/8465	2.98e-03	1.29e-02	7.87e-03	51
hsa041207	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa051707	Colorectum	FAP	Human immunodeficiency virus 1 infection	51/1404	212/8465	2.98e-03	1.29e-02	7.87e-03	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
hsa034205	Esophagus	HGIN	Nucleotide excision repair	29/1383	63/8465	2.96e-08	5.36e-07	4.26e-07	29
hsa0412026	Esophagus	HGIN	Ubiquitin mediated proteolysis	49/1383	142/8465	7.78e-08	1.33e-06	1.06e-06	49

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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

CUL4A

SNV

Missense_Mutation

novel

c.2189N>A

p.Gly730Glu

p.G730E

Q13619

protein_coding

tolerated(0.06)

benign(0.027)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

CUL4A

SNV

Missense_Mutation

novel

c.281G>C

p.Cys94Ser

p.C94S

Q13619

protein_coding

deleterious(0)

probably_damaging(0.933)

TCGA-5T-A9QA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxol

CUL4A

SNV

Missense_Mutation

novel

c.635N>T

p.Ser212Ile

p.S212I

Q13619

protein_coding

deleterious(0.03)

benign(0.312)

TCGA-C8-A26X-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

CUL4A

SNV

Missense_Mutation

c.1305N>C

p.Lys435Asn

p.K435N

Q13619

protein_coding

deleterious(0)

benign(0.223)

TCGA-D8-A1XF-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin+cyclophosphamide

CUL4A

SNV

Missense_Mutation

rs749479685

c.2081N>G

p.Tyr694Cys

p.Y694C

Q13619

protein_coding

deleterious(0.02)

possibly_damaging(0.805)

TCGA-GM-A2DB-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxol

CUL4A

deletion

Frame_Shift_Del

novel

c.709delG

p.Glu237LysfsTer14

p.E237Kfs*14

Q13619

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

CUL4A

SNV

Missense_Mutation

c.2017N>G

p.Gln673Glu

p.Q673E

Q13619

protein_coding

deleterious(0)

possibly_damaging(0.63)

TCGA-DS-A0VN-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CUL4A

SNV

Missense_Mutation

c.2112N>A

p.Met704Ile

p.M704I

Q13619

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CUL4A

SNV

Missense_Mutation

novel

c.1372N>A

p.Ala458Thr

p.A458T

Q13619

protein_coding

deleterious(0)

probably_damaging(0.97)

TCGA-VS-A94Z-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CUL4A

SNV

Missense_Mutation

rs201623121

c.820G>A

p.Val274Ile

p.V274I

Q13619

protein_coding

tolerated(0.2)

benign(0.009)

TCGA-A6-6653-01

Colorectum

colon adenocarcinoma

Male

>=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
8451	CUL4A	ENZYME, DNA REPAIR, CLINICALLY ACTIONABLE	inhibitor	CHEMBL848	LENALIDOMIDE
8451	CUL4A	ENZYME, DNA REPAIR, CLINICALLY ACTIONABLE	inhibitor	CHEMBL468	THALIDOMIDE
8451	CUL4A	ENZYME, DNA REPAIR, CLINICALLY ACTIONABLE	inhibitor	CHEMBL43452	POMALIDOMIDE

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