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: PPP1R15A

Gene summary for PPP1R15A

Gene summary.

Gene information	Species	Human
	Gene symbol	PPP1R15A
	Gene ID	23645
	Gene name	protein phosphatase 1 regulatory subunit 15A
	Gene Alias	GADD34
	Cytomap	19q13.33
	Gene Type	protein-coding
	GO ID	GO:0006412
	UniProtAcc	O75807

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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
23645	PPP1R15A	GSM4909277	Human	Breast	Precancer	1.44e-04	7.56e-01	0.0177
23645	PPP1R15A	GSM4909280	Human	Breast	Precancer	3.14e-02	5.66e-01	0.0305
23645	PPP1R15A	GSM4909281	Human	Breast	IDC	2.53e-08	-4.93e-01	0.21
23645	PPP1R15A	GSM4909285	Human	Breast	IDC	6.29e-05	-2.83e-01	0.21
23645	PPP1R15A	GSM4909286	Human	Breast	IDC	1.73e-09	-3.81e-01	0.1081
23645	PPP1R15A	GSM4909288	Human	Breast	IDC	2.14e-03	-5.07e-01	0.0988
23645	PPP1R15A	GSM4909290	Human	Breast	IDC	1.92e-18	-6.66e-01	0.2096
23645	PPP1R15A	GSM4909293	Human	Breast	IDC	2.89e-07	-3.21e-01	0.1581
23645	PPP1R15A	GSM4909294	Human	Breast	IDC	1.32e-21	-6.79e-01	0.2022
23645	PPP1R15A	GSM4909296	Human	Breast	IDC	1.28e-11	-5.24e-01	0.1524
23645	PPP1R15A	GSM4909297	Human	Breast	IDC	1.85e-06	-3.87e-02	0.1517
23645	PPP1R15A	GSM4909301	Human	Breast	IDC	5.95e-03	-4.28e-01	0.1577
23645	PPP1R15A	GSM4909302	Human	Breast	IDC	1.89e-03	-2.52e-01	0.1545
23645	PPP1R15A	GSM4909307	Human	Breast	IDC	2.57e-15	-6.04e-01	0.1569
23645	PPP1R15A	GSM4909309	Human	Breast	IDC	1.21e-03	-3.06e-01	0.0483
23645	PPP1R15A	GSM4909311	Human	Breast	IDC	1.05e-28	-6.87e-01	0.1534
23645	PPP1R15A	GSM4909315	Human	Breast	IDC	4.95e-13	-5.67e-01	0.21
23645	PPP1R15A	GSM4909316	Human	Breast	IDC	7.32e-11	-7.07e-01	0.21
23645	PPP1R15A	GSM4909319	Human	Breast	IDC	4.18e-34	-4.75e-01	0.1563
23645	PPP1R15A	GSM4909320	Human	Breast	IDC	3.16e-05	-4.73e-01	0.1575

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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:00971939	Breast	Precancer	intrinsic apoptotic signaling pathway	59/1080	288/18723	8.07e-18	3.60e-15	59
GO:00064138	Breast	Precancer	translational initiation	30/1080	118/18723	3.23e-12	5.58e-10	30
GO:00064179	Breast	Precancer	regulation of translation	67/1080	468/18723	4.71e-12	7.64e-10	67
GO:00457279	Breast	Precancer	positive regulation of translation	32/1080	136/18723	5.89e-12	9.27e-10	32
GO:00342509	Breast	Precancer	positive regulation of cellular amide metabolic process	33/1080	162/18723	1.72e-10	1.77e-08	33
GO:00069869	Breast	Precancer	response to unfolded protein	28/1080	137/18723	3.81e-09	3.00e-07	28
GO:00359669	Breast	Precancer	response to topologically incorrect protein	29/1080	159/18723	3.00e-08	1.89e-06	29
GO:00513468	Breast	Precancer	negative regulation of hydrolase activity	50/1080	379/18723	3.85e-08	2.34e-06	50
GO:00349769	Breast	Precancer	response to endoplasmic reticulum stress	38/1080	256/18723	7.89e-08	4.60e-06	38
GO:00064466	Breast	Precancer	regulation of translational initiation	19/1080	79/18723	7.99e-08	4.60e-06	19
GO:00346209	Breast	Precancer	cellular response to unfolded protein	21/1080	96/18723	9.80e-08	5.46e-06	21
GO:00359679	Breast	Precancer	cellular response to topologically incorrect protein	22/1080	116/18723	6.84e-07	2.80e-05	22
GO:19058979	Breast	Precancer	regulation of response to endoplasmic reticulum stress	16/1080	82/18723	1.53e-05	3.75e-04	16
GO:00309687	Breast	Precancer	endoplasmic reticulum unfolded protein response	15/1080	74/18723	1.74e-05	4.17e-04	15
GO:00709725	Breast	Precancer	protein localization to endoplasmic reticulum	15/1080	74/18723	1.74e-05	4.17e-04	15
GO:19035739	Breast	Precancer	negative regulation of response to endoplasmic reticulum stress	10/1080	44/18723	1.61e-04	2.69e-03	10
GO:00700598	Breast	Precancer	intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	12/1080	63/18723	2.21e-04	3.37e-03	12
GO:00353049	Breast	Precancer	regulation of protein dephosphorylation	14/1080	90/18723	6.16e-04	7.72e-03	14
GO:00353086	Breast	Precancer	negative regulation of protein dephosphorylation	7/1080	34/18723	2.84e-03	2.49e-02	7
GO:00364992	Breast	Precancer	PERK-mediated unfolded protein response	5/1080	18/18723	2.88e-03	2.49e-02	5

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0414118	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0414119	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0414124	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0414134	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0414143	Breast	DCIS	Protein processing in endoplasmic reticulum	36/846	174/8465	1.60e-05	1.91e-04	1.41e-04	36
hsa0414153	Breast	DCIS	Protein processing in endoplasmic reticulum	36/846	174/8465	1.60e-05	1.91e-04	1.41e-04	36
hsa0414120	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa04141110	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa0414125	Cervix	HSIL_HPV	Protein processing in endoplasmic reticulum	21/459	174/8465	4.54e-04	3.80e-03	3.07e-03	21
hsa0414135	Cervix	HSIL_HPV	Protein processing in endoplasmic reticulum	21/459	174/8465	4.54e-04	3.80e-03	3.07e-03	21
hsa0414126	Endometrium	AEH	Protein processing in endoplasmic reticulum	62/1197	174/8465	5.97e-13	1.39e-11	1.01e-11	62
hsa04141111	Endometrium	AEH	Protein processing in endoplasmic reticulum	62/1197	174/8465	5.97e-13	1.39e-11	1.01e-11	62
hsa0414127	Endometrium	EEC	Protein processing in endoplasmic reticulum	64/1237	174/8465	2.17e-13	5.09e-12	3.80e-12	64
hsa0414136	Endometrium	EEC	Protein processing in endoplasmic reticulum	64/1237	174/8465	2.17e-13	5.09e-12	3.80e-12	64
hsa0414139	Esophagus	HGIN	Protein processing in endoplasmic reticulum	67/1383	174/8465	1.06e-12	2.16e-11	1.72e-11	67
hsa04141114	Esophagus	HGIN	Protein processing in endoplasmic reticulum	67/1383	174/8465	1.06e-12	2.16e-11	1.72e-11	67
hsa04141211	Esophagus	ESCC	Protein processing in endoplasmic reticulum	147/4205	174/8465	3.29e-22	1.10e-19	5.64e-20	147
hsa04141310	Esophagus	ESCC	Protein processing in endoplasmic reticulum	147/4205	174/8465	3.29e-22	1.10e-19	5.64e-20	147
hsa0414114	Liver	Cirrhotic	Protein processing in endoplasmic reticulum	114/2530	174/8465	1.16e-22	9.67e-21	5.96e-21	114
hsa0414115	Liver	Cirrhotic	Protein processing in endoplasmic reticulum	114/2530	174/8465	1.16e-22	9.67e-21	5.96e-21	114

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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

PPP1R15A

SNV

Missense_Mutation

novel

c.682N>A

p.Glu228Lys

p.E228K

O75807

protein_coding

deleterious(0.03)

probably_damaging(0.914)

TCGA-AR-A2LE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

PPP1R15A

SNV

Missense_Mutation

novel

c.776N>T

p.Ser259Phe

p.S259F

O75807

protein_coding

deleterious(0)

benign(0.087)

TCGA-GM-A2DF-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxol

PPP1R15A

insertion

Nonsense_Mutation

novel

c.2017_2018insATAATGAATAAATAAATAAATAAATA

p.Arg673HisfsTer4

p.R673Hfs*4

O75807

protein_coding

TCGA-B6-A0IB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

PPP1R15A

deletion

Frame_Shift_Del

rs764798313

c.996delN

p.Pro334HisfsTer6

p.P334Hfs*6

O75807

protein_coding

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PPP1R15A

deletion

Frame_Shift_Del

c.1977_1992delNNNNNNNNNNNNNNNN

p.Ser660LeufsTer26

p.S660Lfs*26

O75807

protein_coding

TCGA-D8-A13Z-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

PPP1R15A

SNV

Missense_Mutation

novel

c.545C>T

p.Ser182Leu

p.S182L

O75807

protein_coding

deleterious(0.03)

possibly_damaging(0.588)

TCGA-C5-A2LV-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

PPP1R15A

SNV

Missense_Mutation

c.1412C>T

p.Ser471Phe

p.S471F

O75807

protein_coding

deleterious(0.04)

benign(0.038)

TCGA-Q1-A5R2-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PPP1R15A

SNV

Missense_Mutation

c.403N>A

p.Ala135Thr

p.A135T

O75807

protein_coding

tolerated(1)

benign(0.003)

TCGA-A6-4105-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

PPP1R15A

SNV

Missense_Mutation

novel

c.849N>T

p.Glu283Asp

p.E283D

O75807

protein_coding

tolerated(0.42)

benign(0.003)

TCGA-AA-3877-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

PPP1R15A

SNV

Missense_Mutation

c.697G>A

p.Glu233Lys

p.E233K

O75807

protein_coding

tolerated(0.06)

possibly_damaging(0.876)

TCGA-AA-A00N-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

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