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: PAGE4

Gene summary for PAGE4

Gene summary.

Gene information	Species	Human
	Gene symbol	PAGE4
	Gene ID	9506
	Gene name	PAGE family member 4
	Gene Alias	CT16.7
	Cytomap	Xp11.23
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	O60829

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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
9506	PAGE4	S44	Human	Liver	HCC	2.61e-12	1.33e+00	-0.0083
9506	PAGE4	HCC5	Human	Liver	HCC	2.39e-14	4.24e+00	0.4932
9506	PAGE4	S014	Human	Liver	HCC	4.83e-58	1.83e+00	0.2254
9506	PAGE4	S015	Human	Liver	HCC	2.41e-32	1.49e+00	0.2375
9506	PAGE4	S016	Human	Liver	HCC	2.90e-48	1.64e+00	0.2243

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		NAFLD: Non-alcoholic fatty liver disease

∗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:000697922	Liver	HCC	response to oxidative stress	281/7958	446/18723	9.75e-19	1.24e-16	281
GO:006219722	Liver	HCC	cellular response to chemical stress	216/7958	337/18723	6.86e-16	5.44e-14	216
GO:003459922	Liver	HCC	cellular response to oxidative stress	183/7958	288/18723	3.65e-13	1.93e-11	183
GO:003166722	Liver	HCC	response to nutrient levels	276/7958	474/18723	2.30e-12	1.08e-10	276
GO:004259421	Liver	HCC	response to starvation	121/7958	197/18723	6.08e-08	1.28e-06	121
GO:003109822	Liver	HCC	stress-activated protein kinase signaling cascade	138/7958	247/18723	1.43e-05	1.57e-04	138
GO:005140322	Liver	HCC	stress-activated MAPK cascade	134/7958	239/18723	1.50e-05	1.64e-04	134
GO:200037722	Liver	HCC	regulation of reactive oxygen species metabolic process	92/7958	157/18723	3.34e-05	3.35e-04	92
GO:007030222	Liver	HCC	regulation of stress-activated protein kinase signaling cascade	105/7958	195/18723	8.79e-04	5.20e-03	105
GO:003647312	Liver	HCC	cell death in response to oxidative stress	55/7958	95/18723	1.76e-03	9.12e-03	55
GO:003287222	Liver	HCC	regulation of stress-activated MAPK cascade	102/7958	192/18723	1.86e-03	9.49e-03	102
GO:007259312	Liver	HCC	reactive oxygen species metabolic process	124/7958	239/18723	2.05e-03	1.04e-02	124
GO:190288212	Liver	HCC	regulation of response to oxidative stress	55/7958	98/18723	4.46e-03	1.93e-02	55
GO:190040712	Liver	HCC	regulation of cellular response to oxidative stress	50/7958	89/18723	6.33e-03	2.58e-02	50
GO:190320112	Liver	HCC	regulation of oxidative stress-induced cell death	42/7958	74/18723	9.32e-03	3.57e-02	42
GO:2000378	Liver	HCC	negative regulation of reactive oxygen species metabolic process	31/7958	52/18723	9.52e-03	3.60e-02	31

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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

PAGE4

SNV

Missense_Mutation

c.188G>T

p.Cys63Phe

p.C63F

O60829

protein_coding

tolerated(0.19)

benign(0.003)

TCGA-C5-A7CM-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PAGE4

SNV

Missense_Mutation

novel

c.77N>T

p.Ala26Val

p.A26V

O60829

protein_coding

tolerated(0.57)

benign(0.003)

TCGA-A6-2672-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

PAGE4

SNV

Missense_Mutation

novel

c.53C>T

p.Ala18Val

p.A18V

O60829

protein_coding

tolerated(0.49)

benign(0.046)

TCGA-A5-A1OF-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

PAGE4

SNV

Missense_Mutation

rs202162113

c.17N>T

p.Arg6Ile

p.R6I

O60829

protein_coding

deleterious(0)

possibly_damaging(0.819)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

PAGE4

SNV

Missense_Mutation

c.131N>T

p.Pro44Leu

p.P44L

O60829

protein_coding

deleterious(0.02)

benign(0.042)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

PAGE4

SNV

Missense_Mutation

rs782616442

c.169N>T

p.Arg57Cys

p.R57C

O60829

protein_coding

tolerated(0.06)

possibly_damaging(0.493)

TCGA-AX-A2HC-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

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SNV

Missense_Mutation

c.163N>A

p.Glu55Lys

p.E55K

O60829

protein_coding

deleterious(0.02)

benign(0.209)

TCGA-B5-A0JY-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

PAGE4

SNV

Missense_Mutation

c.163N>A

p.Glu55Lys

p.E55K

O60829

protein_coding

deleterious(0.02)

benign(0.209)

TCGA-BS-A0UF-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

PAGE4

SNV

Missense_Mutation

novel

c.56N>T

p.Pro19Leu

p.P19L

O60829

protein_coding

tolerated(0.67)

benign(0.096)

TCGA-D1-A175-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

paclitaxel

PAGE4

SNV

Missense_Mutation

novel

c.266N>A

p.Pro89His

p.P89H

O60829

protein_coding

deleterious(0.02)

possibly_damaging(0.573)

TCGA-D1-A175-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

paclitaxel

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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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