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: EIF2AK3

Gene summary for EIF2AK3

Gene summary.

Gene information	Species	Human
	Gene symbol	EIF2AK3
	Gene ID	9451
	Gene name	eukaryotic translation initiation factor 2 alpha kinase 3
	Gene Alias	PEK
	Cytomap	2p11.2
	Gene Type	protein-coding
	GO ID	GO:0001501
	UniProtAcc	E7ER02

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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
9451	EIF2AK3	047563_1562-all-cells	Human	Prostate	BPH	5.52e-18	6.48e-01	0.0791
9451	EIF2AK3	048752_1579-all-cells	Human	Prostate	BPH	2.73e-40	7.53e-01	0.1008
9451	EIF2AK3	052095_1628-all-cells	Human	Prostate	BPH	1.50e-15	4.31e-01	0.1032
9451	EIF2AK3	052097_1595-all-cells	Human	Prostate	BPH	4.99e-55	9.17e-01	0.0972
9451	EIF2AK3	052099_1652-all-cells	Human	Prostate	BPH	3.84e-29	6.23e-01	0.1038
9451	EIF2AK3	GSM5353221_PA_PB2A_Pool_1_3_S25_L001	Human	Prostate	Tumor	2.20e-05	4.42e-01	0.1633
9451	EIF2AK3	GSM5353224_PA_PR5186_Pool_1_2_3_S27_L001	Human	Prostate	Tumor	6.91e-03	3.80e-01	0.1621

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Prostate		BPH: Benign Prostatic Hyperplasia

∗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:007124110	Prostate	BPH	cellular response to inorganic substance	62/3107	226/18723	2.57e-05	3.05e-04	62
GO:00364994	Prostate	BPH	PERK-mediated unfolded protein response	11/3107	18/18723	2.62e-05	3.10e-04	11
GO:007005917	Prostate	BPH	intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	24/3107	63/18723	3.48e-05	3.87e-04	24
GO:00459473	Prostate	BPH	negative regulation of translational initiation	11/3107	19/18723	5.28e-05	5.42e-04	11
GO:00364902	Prostate	BPH	regulation of translation in response to endoplasmic reticulum stress	8/3107	11/18723	5.85e-05	5.90e-04	8
GO:00181059	Prostate	BPH	peptidyl-serine phosphorylation	79/3107	315/18723	7.09e-05	6.96e-04	79
GO:00435583	Prostate	BPH	regulation of translational initiation in response to stress	9/3107	14/18723	8.47e-05	8.03e-04	9
GO:00480093	Prostate	BPH	insulin-like growth factor receptor signaling pathway	16/3107	37/18723	1.22e-04	1.10e-03	16
GO:19909282	Prostate	BPH	response to amino acid starvation	19/3107	49/18723	1.70e-04	1.46e-03	19
GO:00182097	Prostate	BPH	peptidyl-serine modification	82/3107	338/18723	1.73e-04	1.48e-03	82
GO:00341982	Prostate	BPH	cellular response to amino acid starvation	18/3107	46/18723	2.19e-04	1.78e-03	18
GO:19022357	Prostate	BPH	regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	14/3107	32/18723	2.77e-04	2.16e-03	14
GO:01404673	Prostate	BPH	integrated stress response signaling	11/3107	22/18723	3.03e-04	2.34e-03	11
GO:007124810	Prostate	BPH	cellular response to metal ion	52/3107	197/18723	3.13e-04	2.39e-03	52
GO:00069832	Prostate	BPH	ER overload response	8/3107	13/18723	3.33e-04	2.52e-03	8
GO:0042149	Prostate	BPH	cellular response to glucose starvation	18/3107	48/18723	4.06e-04	2.96e-03	18
GO:00018199	Prostate	BPH	positive regulation of cytokine production	105/3107	467/18723	5.18e-04	3.66e-03	105
GO:00519604	Prostate	BPH	regulation of nervous system development	100/3107	443/18723	6.02e-04	4.16e-03	100
GO:00069195	Prostate	BPH	activation of cysteine-type endopeptidase activity involved in apoptotic process	24/3107	78/18723	1.39e-03	8.31e-03	24
GO:00070293	Prostate	BPH	endoplasmic reticulum organization	26/3107	87/18723	1.45e-03	8.61e-03	26

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501228	Prostate	BPH	Parkinson disease	143/1718	266/8465	1.19e-34	3.94e-32	2.44e-32	143
hsa0502026	Prostate	BPH	Prion disease	141/1718	273/8465	1.11e-31	1.23e-29	7.58e-30	141
hsa0414128	Prostate	BPH	Protein processing in endoplasmic reticulum	97/1718	174/8465	2.37e-25	1.30e-23	8.07e-24	97
hsa0501026	Prostate	BPH	Alzheimer disease	165/1718	384/8465	4.03e-25	1.66e-23	1.03e-23	165
hsa0501426	Prostate	BPH	Amyotrophic lateral sclerosis	151/1718	364/8465	3.37e-21	1.01e-19	6.25e-20	151
hsa0493226	Prostate	BPH	Non-alcoholic fatty liver disease	83/1718	155/8465	2.49e-20	6.32e-19	3.91e-19	83
hsa0502226	Prostate	BPH	Pathways of neurodegeneration - multiple diseases	180/1718	476/8465	7.70e-20	1.81e-18	1.12e-18	180
hsa0421016	Prostate	BPH	Apoptosis	46/1718	136/8465	1.41e-04	8.31e-04	5.14e-04	46
hsa0541728	Prostate	BPH	Lipid and atherosclerosis	66/1718	215/8465	1.68e-04	9.56e-04	5.92e-04	66
hsa0413726	Prostate	BPH	Mitophagy - animal	28/1718	72/8465	2.12e-04	1.13e-03	6.98e-04	28
hsa051607	Prostate	BPH	Hepatitis C	48/1718	157/8465	1.36e-03	5.85e-03	3.62e-03	48
hsa051624	Prostate	BPH	Measles	42/1718	139/8465	3.35e-03	1.23e-02	7.61e-03	42
hsa041408	Prostate	BPH	Autophagy - animal	42/1718	141/8465	4.46e-03	1.53e-02	9.49e-03	42
hsa05012112	Prostate	BPH	Parkinson disease	143/1718	266/8465	1.19e-34	3.94e-32	2.44e-32	143
hsa05020111	Prostate	BPH	Prion disease	141/1718	273/8465	1.11e-31	1.23e-29	7.58e-30	141
hsa04141112	Prostate	BPH	Protein processing in endoplasmic reticulum	97/1718	174/8465	2.37e-25	1.30e-23	8.07e-24	97
hsa05010111	Prostate	BPH	Alzheimer disease	165/1718	384/8465	4.03e-25	1.66e-23	1.03e-23	165
hsa05014111	Prostate	BPH	Amyotrophic lateral sclerosis	151/1718	364/8465	3.37e-21	1.01e-19	6.25e-20	151
hsa04932111	Prostate	BPH	Non-alcoholic fatty liver disease	83/1718	155/8465	2.49e-20	6.32e-19	3.91e-19	83
hsa05022111	Prostate	BPH	Pathways of neurodegeneration - multiple diseases	180/1718	476/8465	7.70e-20	1.81e-18	1.12e-18	180

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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

EIF2AK3

SNV

Missense_Mutation

novel

c.1153A>C

p.Ser385Arg

p.S385R

Q9NZJ5

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-A2-A0CO-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

EIF2AK3

SNV

Missense_Mutation

novel

c.2068A>G

p.Met690Val

p.M690V

Q9NZJ5

protein_coding

tolerated(0.57)

benign(0.001)

TCGA-A8-A09E-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

EIF2AK3

SNV

Missense_Mutation

c.341N>T

p.Arg114Ile

p.R114I

Q9NZJ5

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

EIF2AK3

SNV

Missense_Mutation

c.3150N>T

p.Glu1050Asp

p.E1050D

Q9NZJ5

protein_coding

deleterious(0.01)

probably_damaging(0.979)

TCGA-AN-A0FJ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

EIF2AK3

SNV

Missense_Mutation

novel

c.910N>T

p.Ala304Ser

p.A304S

Q9NZJ5

protein_coding

tolerated(0.4)

benign(0)

TCGA-LL-A73Z-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

EIF2AK3

insertion

In_Frame_Ins

novel

c.2065_2066insATGAGGACATCAGTGAGT

p.Pro689delinsHisGluAspIleSerGluSer

p.P689delinsHEDISES

Q9NZJ5

protein_coding

TCGA-A8-A09E-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

EIF2AK3

insertion

Frame_Shift_Ins

novel

c.1169_1170insAAAATATAAA

p.Met390IlefsTer6

p.M390Ifs*6

Q9NZJ5

protein_coding

TCGA-AC-A3QQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

EIF2AK3

insertion

Nonsense_Mutation

novel

c.2848_2849insGTTATTAGCATATCCAAGGTATCAAACT

p.Val950GlyfsTer3

p.V950Gfs*3

Q9NZJ5

protein_coding

TCGA-AN-A0FN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

EIF2AK3

insertion

Frame_Shift_Ins

novel

c.1492_1493insATGAGAAAGA

p.Val498AspfsTer62

p.V498Dfs*62

Q9NZJ5

protein_coding

TCGA-AR-A0U2-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

tamoxiphen

EIF2AK3

insertion

Frame_Shift_Ins

novel

c.3241_3242insG

p.Asp1081GlyfsTer31

p.D1081Gfs*31

Q9NZJ5

protein_coding

TCGA-B6-A0IN-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
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Indoline derivative 7
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME	inhibitor	336446930
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Indoline derivative 3
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Phenylpyrrolidinone derivative 1
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Tricyclic isoxazoloquinazoline derivative 3
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Indoline derivative 8
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Tricyclic isoxazoloquinazoline derivative 1
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME	inhibitor	178103351	CHEMBL2171124
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Phenylpyrrolidinone derivative 5
9451	EIF2AK3	SERINE THREONINE KINASE, KINASE, ENZYME, DRUGGABLE GENOME		Indoline derivative 10

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