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: EYA3

Gene summary for EYA3

Gene summary.

Gene information	Species	Human
	Gene symbol	EYA3
	Gene ID	2140
	Gene name	EYA transcriptional coactivator and phosphatase 3
	Gene Alias	EYA3
	Cytomap	1p35.3
	Gene Type	protein-coding
	GO ID	GO:0003008
	UniProtAcc	Q99504

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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
2140	EYA3	CCI_1	Human	Cervix	CC	4.62e-05	5.95e-01	0.528
2140	EYA3	CCI_2	Human	Cervix	CC	4.77e-06	7.15e-01	0.5249
2140	EYA3	CCI_3	Human	Cervix	CC	1.97e-10	6.25e-01	0.516
2140	EYA3	HTA11_99999974143_84620	Human	Colorectum	MSS	1.43e-04	-3.57e-01	0.3005
2140	EYA3	F007	Human	Colorectum	FAP	4.08e-02	-2.85e-01	0.1176
2140	EYA3	A001-C-207	Human	Colorectum	FAP	2.64e-04	-3.13e-01	0.1278
2140	EYA3	A015-C-203	Human	Colorectum	FAP	1.34e-24	-4.19e-01	-0.1294
2140	EYA3	A015-C-204	Human	Colorectum	FAP	1.41e-05	-2.68e-01	-0.0228
2140	EYA3	A014-C-040	Human	Colorectum	FAP	1.90e-04	-4.25e-01	-0.1184
2140	EYA3	A002-C-201	Human	Colorectum	FAP	3.68e-15	-3.97e-01	0.0324
2140	EYA3	A002-C-203	Human	Colorectum	FAP	4.07e-04	-2.76e-01	0.2786
2140	EYA3	A001-C-119	Human	Colorectum	FAP	1.93e-05	-3.33e-01	-0.1557
2140	EYA3	A001-C-108	Human	Colorectum	FAP	1.44e-17	-4.27e-01	-0.0272
2140	EYA3	A002-C-205	Human	Colorectum	FAP	2.56e-23	-5.11e-01	-0.1236
2140	EYA3	A001-C-104	Human	Colorectum	FAP	2.42e-03	-2.45e-01	0.0184
2140	EYA3	A015-C-005	Human	Colorectum	FAP	3.87e-07	-3.19e-01	-0.0336
2140	EYA3	A015-C-006	Human	Colorectum	FAP	5.85e-17	-4.94e-01	-0.0994
2140	EYA3	A015-C-106	Human	Colorectum	FAP	2.59e-11	-3.96e-01	-0.0511
2140	EYA3	A002-C-114	Human	Colorectum	FAP	1.25e-18	-4.66e-01	-0.1561
2140	EYA3	A015-C-104	Human	Colorectum	FAP	2.82e-26	-5.10e-01	-0.1899

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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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma

∗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:001657012	Lung	AIS	histone modification	81/1849	463/18723	2.30e-07	2.16e-05	81
GO:000647012	Lung	AIS	protein dephosphorylation	56/1849	281/18723	2.47e-07	2.24e-05	56
GO:200123413	Lung	AIS	negative regulation of apoptotic signaling pathway	46/1849	224/18723	1.19e-06	8.00e-05	46
GO:001631112	Lung	AIS	dephosphorylation	69/1849	417/18723	1.27e-05	4.78e-04	69
GO:009719113	Lung	AIS	extrinsic apoptotic signaling pathway	41/1849	219/18723	4.46e-05	1.33e-03	41
GO:200123613	Lung	AIS	regulation of extrinsic apoptotic signaling pathway	31/1849	151/18723	6.27e-05	1.70e-03	31
GO:000931411	Lung	AIS	response to radiation	71/1849	456/18723	7.33e-05	1.91e-03	71
GO:200123713	Lung	AIS	negative regulation of extrinsic apoptotic signaling pathway	22/1849	97/18723	1.58e-04	3.34e-03	22
GO:00353351	Lung	AIS	peptidyl-tyrosine dephosphorylation	21/1849	97/18723	4.32e-04	7.38e-03	21
GO:200102012	Lung	AIS	regulation of response to DNA damage stimulus	37/1849	219/18723	8.22e-04	1.14e-02	37
GO:001021212	Lung	AIS	response to ionizing radiation	26/1849	148/18723	2.64e-03	2.68e-02	26
GO:200123320	Oral cavity	OSCC	regulation of apoptotic signaling pathway	242/7305	356/18723	6.66e-29	3.24e-26	242
GO:00165707	Oral cavity	OSCC	histone modification	270/7305	463/18723	1.59e-17	1.50e-15	270
GO:200123420	Oral cavity	OSCC	negative regulation of apoptotic signaling pathway	148/7305	224/18723	1.71e-16	1.36e-14	148
GO:009719120	Oral cavity	OSCC	extrinsic apoptotic signaling pathway	142/7305	219/18723	7.34e-15	4.55e-13	142
GO:005105210	Oral cavity	OSCC	regulation of DNA metabolic process	207/7305	359/18723	4.45e-13	2.17e-11	207
GO:00102128	Oral cavity	OSCC	response to ionizing radiation	99/7305	148/18723	5.49e-12	2.08e-10	99
GO:005105414	Oral cavity	OSCC	positive regulation of DNA metabolic process	126/7305	201/18723	8.12e-12	3.01e-10	126
GO:200123620	Oral cavity	OSCC	regulation of extrinsic apoptotic signaling pathway	100/7305	151/18723	1.07e-11	3.90e-10	100
GO:000647015	Oral cavity	OSCC	protein dephosphorylation	162/7305	281/18723	1.56e-10	4.56e-09	162

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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

EYA3

SNV

Missense_Mutation

novel

c.1676N>A

p.Gly559Glu

p.G559E

Q99504

protein_coding

deleterious(0.02)

possibly_damaging(0.463)

TCGA-AN-A04C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

EYA3

SNV

Missense_Mutation

c.607N>G

p.Leu203Val

p.L203V

Q99504

protein_coding

tolerated(0.05)

benign(0.355)

TCGA-B6-A0IJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

EYA3

SNV

Missense_Mutation

c.1551N>G

p.Ser517Arg

p.S517R

Q99504

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-E9-A22H-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

EYA3

insertion

Frame_Shift_Ins

novel

c.1324_1325insTGCAGTACACTAATGCTATGAAGCCC

p.Lys442MetfsTer16

p.K442Mfs*16

Q99504

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

EYA3

insertion

Nonsense_Mutation

novel

c.1468_1469insGAGACTCCGTCTCTAAATAAATAAATAAAAGGTATTGACAAGGA

p.Leu490ArgfsTer7

p.L490Rfs*7

Q99504

protein_coding

TCGA-AN-A0FW-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

EYA3

insertion

Frame_Shift_Ins

novel

c.634_635insCTTTCTATGTCCAGGATCCCTTTAAGATTCTGAGGAAAGCATGG

p.Tyr212SerfsTer36

p.Y212Sfs*36

Q99504

protein_coding

TCGA-BH-A0HX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adrimycin

EYA3

SNV

Missense_Mutation

c.292A>C

p.Thr98Pro

p.T98P

Q99504

protein_coding

tolerated(0.14)

benign(0.006)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EYA3

SNV

Missense_Mutation

novel

c.1253N>A

p.Arg418His

p.R418H

Q99504

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-ZJ-AAXN-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

EYA3

SNV

Missense_Mutation

c.1505T>C

p.Phe502Ser

p.F502S

Q99504

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A6-5665-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

EYA3

SNV

Missense_Mutation

c.781N>C

p.Thr261Pro

p.T261P

Q99504

protein_coding

tolerated(0.1)

benign(0)

TCGA-G4-6586-01

Colorectum

colon adenocarcinoma

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

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