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: HERC4

Gene summary for HERC4

Gene summary.

Gene information	Species	Human
	Gene symbol	HERC4
	Gene ID	26091
	Gene name	HECT and RLD domain containing E3 ubiquitin protein ligase 4
	Gene Alias	HERC4
	Cytomap	10q21.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	Q5GLZ8

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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
26091	HERC4	CCI_1	Human	Cervix	CC	2.81e-02	7.78e-01	0.528
26091	HERC4	CCI_2	Human	Cervix	CC	3.77e-12	1.46e+00	0.5249
26091	HERC4	CCI_3	Human	Cervix	CC	4.98e-03	5.54e-01	0.516
26091	HERC4	sample3	Human	Cervix	CC	7.36e-03	1.91e-01	0.1387
26091	HERC4	HTA11_3410_2000001011	Human	Colorectum	AD	6.46e-26	-6.42e-01	0.0155
26091	HERC4	HTA11_347_2000001011	Human	Colorectum	AD	9.28e-04	4.56e-01	-0.1954
26091	HERC4	HTA11_3361_2000001011	Human	Colorectum	AD	1.45e-06	-5.19e-01	-0.1207
26091	HERC4	HTA11_5212_2000001011	Human	Colorectum	AD	1.07e-03	-5.58e-01	-0.2061
26091	HERC4	HTA11_866_3004761011	Human	Colorectum	AD	9.39e-10	-5.28e-01	0.096
26091	HERC4	HTA11_9408_2000001011	Human	Colorectum	AD	2.02e-02	-7.52e-01	0.0451
26091	HERC4	HTA11_8622_2000001021	Human	Colorectum	SER	2.35e-02	-4.81e-01	0.0528
26091	HERC4	HTA11_7696_3000711011	Human	Colorectum	AD	1.04e-11	-4.21e-01	0.0674
26091	HERC4	HTA11_99999970781_79442	Human	Colorectum	MSS	1.49e-05	-3.09e-01	0.294
26091	HERC4	HTA11_99999974143_84620	Human	Colorectum	MSS	3.01e-24	-6.25e-01	0.3005
26091	HERC4	F007	Human	Colorectum	FAP	3.93e-03	-2.42e-01	0.1176
26091	HERC4	A001-C-207	Human	Colorectum	FAP	3.64e-03	-2.21e-01	0.1278
26091	HERC4	A015-C-203	Human	Colorectum	FAP	3.61e-34	-6.42e-01	-0.1294
26091	HERC4	A015-C-204	Human	Colorectum	FAP	8.21e-08	-3.27e-01	-0.0228
26091	HERC4	A014-C-040	Human	Colorectum	FAP	4.67e-09	-5.74e-01	-0.1184
26091	HERC4	A002-C-201	Human	Colorectum	FAP	2.60e-22	-5.16e-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
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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:0045879	Thyroid	PTC	negative regulation of smoothened signaling pathway	17/5968	32/18723	1.02e-02	4.11e-02	17
GO:00458791	Thyroid	ATC	negative regulation of smoothened signaling pathway	20/6293	32/18723	7.67e-04	4.24e-03	20
GO:0008589	Thyroid	ATC	regulation of smoothened signaling pathway	40/6293	81/18723	2.36e-03	1.10e-02	40
GO:0007224	Thyroid	ATC	smoothened signaling pathway	60/6293	138/18723	9.75e-03	3.57e-02	60

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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

HERC4

SNV

Missense_Mutation

c.944N>A

p.Arg315Gln

p.R315Q

Q5GLZ8

protein_coding

tolerated(0.09)

possibly_damaging(0.716)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HERC4

SNV

Missense_Mutation

novel

c.467G>C

p.Ser156Thr

p.S156T

Q5GLZ8

protein_coding

deleterious(0)

possibly_damaging(0.646)

TCGA-BH-A0EE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

HERC4

SNV

Missense_Mutation

c.2440N>T

p.Leu814Phe

p.L814F

Q5GLZ8

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

HERC4

SNV

Missense_Mutation

c.1423C>T

p.His475Tyr

p.H475Y

Q5GLZ8

protein_coding

tolerated(0.2)

benign(0.211)

TCGA-C8-A1HM-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

HERC4

insertion

Nonsense_Mutation

novel

c.952_953insGATCATGTCATGCATTGTCTTATATC

p.Ser318Ter

p.S318*

Q5GLZ8

protein_coding

TCGA-BH-A0B1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

HERC4

deletion

Frame_Shift_Del

novel

c.2265delA

p.Glu756AsnfsTer7

p.E756Nfs*7

Q5GLZ8

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

HERC4

SNV

Missense_Mutation

rs751824179

c.2260C>T

p.Arg754Cys

p.R754C

Q5GLZ8

protein_coding

deleterious(0)

probably_damaging(0.972)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HERC4

SNV

Missense_Mutation

c.1674N>T

p.Lys558Asn

p.K558N

Q5GLZ8

protein_coding

deleterious(0.03)

benign(0.25)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HERC4

SNV

Missense_Mutation

c.647N>A

p.Arg216His

p.R216H

Q5GLZ8

protein_coding

deleterious(0.01)

probably_damaging(0.969)

TCGA-A6-2672-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

HERC4

SNV

Missense_Mutation

c.2362N>G

p.Thr788Ala

p.T788A

Q5GLZ8

protein_coding

tolerated(0.1)

possibly_damaging(0.688)

TCGA-AA-3811-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

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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