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: HERC2

Gene summary for HERC2

Gene summary.

Gene information	Species	Human
	Gene symbol	HERC2
	Gene ID	8924
	Gene name	HECT and RLD domain containing E3 ubiquitin protein ligase 2
	Gene Alias	D15F37S1
	Cytomap	15q13.1
	Gene Type	protein-coding
	GO ID	GO:0006139
	UniProtAcc	A8KAQ8

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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
8924	HERC2	P83T-E	Human	Esophagus	ESCC	2.10e-25	6.94e-01	0.1738
8924	HERC2	P84T-E	Human	Esophagus	ESCC	1.17e-12	6.93e-01	0.0933
8924	HERC2	P89T-E	Human	Esophagus	ESCC	4.77e-11	6.40e-01	0.1752
8924	HERC2	P91T-E	Human	Esophagus	ESCC	4.66e-15	1.18e+00	0.1828
8924	HERC2	P104T-E	Human	Esophagus	ESCC	3.35e-14	7.38e-01	0.0931
8924	HERC2	P107T-E	Human	Esophagus	ESCC	5.89e-45	9.06e-01	0.171
8924	HERC2	P126T-E	Human	Esophagus	ESCC	8.86e-09	6.69e-01	0.1125
8924	HERC2	P127T-E	Human	Esophagus	ESCC	2.13e-18	2.71e-01	0.0826
8924	HERC2	P128T-E	Human	Esophagus	ESCC	2.00e-37	9.53e-01	0.1241
8924	HERC2	P130T-E	Human	Esophagus	ESCC	3.49e-54	9.53e-01	0.1676
8924	HERC2	NAFLD1	Human	Liver	NAFLD	1.26e-02	5.09e-01	-0.04
8924	HERC2	S43	Human	Liver	Cirrhotic	4.97e-04	1.31e-02	-0.0187
8924	HERC2	HCC1_Meng	Human	Liver	HCC	6.34e-57	-3.75e-02	0.0246
8924	HERC2	HCC2_Meng	Human	Liver	HCC	1.03e-11	-9.72e-03	0.0107
8924	HERC2	HCC1	Human	Liver	HCC	5.63e-05	3.21e+00	0.5336
8924	HERC2	HCC2	Human	Liver	HCC	1.53e-17	4.51e+00	0.5341
8924	HERC2	S014	Human	Liver	HCC	1.88e-08	5.68e-01	0.2254
8924	HERC2	S015	Human	Liver	HCC	2.79e-16	1.13e+00	0.2375
8924	HERC2	S016	Human	Liver	HCC	1.22e-12	7.05e-01	0.2243
8924	HERC2	S027	Human	Liver	HCC	2.26e-06	8.64e-01	0.2446

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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
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

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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
hsa0412026	Esophagus	HGIN	Ubiquitin mediated proteolysis	49/1383	142/8465	7.78e-08	1.33e-06	1.06e-06	49
hsa04120111	Esophagus	HGIN	Ubiquitin mediated proteolysis	49/1383	142/8465	7.78e-08	1.33e-06	1.06e-06	49
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
hsa0412021	Liver	Cirrhotic	Ubiquitin mediated proteolysis	72/2530	142/8465	1.32e-07	1.97e-06	1.21e-06	72
hsa0412031	Liver	Cirrhotic	Ubiquitin mediated proteolysis	72/2530	142/8465	1.32e-07	1.97e-06	1.21e-06	72

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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

HERC2

SNV

Missense_Mutation

c.7674N>C

p.Leu2558Phe

p.L2558F

O95714

protein_coding

tolerated(0.24)

possibly_damaging(0.761)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

HERC2

SNV

Missense_Mutation

novel

c.8491N>G

p.His2831Asp

p.H2831D

O95714

protein_coding

deleterious(0.05)

possibly_damaging(0.808)

TCGA-A2-A0CL-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

HERC2

SNV

Missense_Mutation

c.5162C>A

p.Pro1721Gln

p.P1721Q

O95714

protein_coding

deleterious(0.01)

possibly_damaging(0.839)

TCGA-A7-A0DB-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

HERC2

SNV

Missense_Mutation

c.3630A>G

p.Ile1210Met

p.I1210M

O95714

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-A7-A26I-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

HERC2

SNV

Missense_Mutation

c.9566N>A

p.Gly3189Glu

p.G3189E

O95714

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-A8-A06U-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HERC2

SNV

Missense_Mutation

c.836N>T

p.Gly279Val

p.G279V

O95714

protein_coding

tolerated(0.08)

probably_damaging(0.996)

TCGA-A8-A06U-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HERC2

SNV

Missense_Mutation

c.4401N>T

p.Gln1467His

p.Q1467H

O95714

protein_coding

tolerated(0.11)

possibly_damaging(0.735)

TCGA-A8-A08B-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

HERC2

SNV

Missense_Mutation

c.4513N>T

p.Val1505Phe

p.V1505F

O95714

protein_coding

deleterious(0)

probably_damaging(0.969)

TCGA-A8-A08L-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

HERC2

SNV

Missense_Mutation

c.8783C>T

p.Ser2928Leu

p.S2928L

O95714

protein_coding

deleterious(0.03)

benign(0.173)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HERC2

SNV

Missense_Mutation

rs559745379

c.10639C>T

p.Arg3547Cys

p.R3547C

O95714

protein_coding

deleterious(0)

probably_damaging(0.987)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=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
8924	HERC2	DNA REPAIR, ENZYME		NERATINIB	NERATINIB	23220880

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