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: EIF2AK1

Gene summary for EIF2AK1

Gene summary.

Gene information	Species	Human
	Gene symbol	EIF2AK1
	Gene ID	27102
	Gene name	eukaryotic translation initiation factor 2 alpha kinase 1
	Gene Alias	HCR
	Cytomap	7p22.1
	Gene Type	protein-coding
	GO ID	GO:0001932
	UniProtAcc	Q9BQI3

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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
27102	EIF2AK1	HTA11_1938_2000001011	Human	Colorectum	AD	9.58e-04	5.75e-01	-0.0811
27102	EIF2AK1	HTA11_78_2000001011	Human	Colorectum	AD	3.07e-05	5.12e-01	-0.1088
27102	EIF2AK1	HTA11_347_2000001011	Human	Colorectum	AD	2.84e-15	6.63e-01	-0.1954
27102	EIF2AK1	HTA11_1391_2000001011	Human	Colorectum	AD	1.26e-02	4.34e-01	-0.059
27102	EIF2AK1	HTA11_99999970781_79442	Human	Colorectum	MSS	1.80e-04	4.34e-01	0.294
27102	EIF2AK1	HTA11_99999965062_69753	Human	Colorectum	MSI-H	2.83e-02	9.72e-01	0.3487
27102	EIF2AK1	HTA11_99999965104_69814	Human	Colorectum	MSS	4.04e-05	6.05e-01	0.281
27102	EIF2AK1	HTA11_99999971662_82457	Human	Colorectum	MSS	5.11e-07	5.43e-01	0.3859
27102	EIF2AK1	A015-C-203	Human	Colorectum	FAP	1.35e-09	-1.56e-01	-0.1294
27102	EIF2AK1	A002-C-201	Human	Colorectum	FAP	2.74e-02	-7.97e-02	0.0324
27102	EIF2AK1	A001-C-108	Human	Colorectum	FAP	2.38e-03	-1.13e-01	-0.0272
27102	EIF2AK1	A002-C-205	Human	Colorectum	FAP	3.85e-05	-7.96e-02	-0.1236
27102	EIF2AK1	A015-C-006	Human	Colorectum	FAP	4.38e-03	-9.76e-02	-0.0994
27102	EIF2AK1	A002-C-114	Human	Colorectum	FAP	4.53e-05	-1.37e-01	-0.1561
27102	EIF2AK1	A015-C-104	Human	Colorectum	FAP	8.93e-09	-1.71e-01	-0.1899
27102	EIF2AK1	A001-C-014	Human	Colorectum	FAP	4.57e-02	-1.63e-02	0.0135
27102	EIF2AK1	A002-C-016	Human	Colorectum	FAP	6.48e-05	-9.40e-02	0.0521
27102	EIF2AK1	A002-C-116	Human	Colorectum	FAP	1.25e-11	-8.11e-02	-0.0452
27102	EIF2AK1	A014-C-008	Human	Colorectum	FAP	2.87e-03	-8.93e-02	-0.191
27102	EIF2AK1	A018-E-020	Human	Colorectum	FAP	3.56e-07	-2.23e-01	-0.2034

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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:0030099	Colorectum	AD	myeloid cell differentiation	119/3918	381/18723	1.24e-06	4.01e-05	119
GO:0006417	Colorectum	AD	regulation of translation	141/3918	468/18723	1.32e-06	4.22e-05	141
GO:0055076	Colorectum	AD	transition metal ion homeostasis	53/3918	138/18723	1.89e-06	5.65e-05	53
GO:0031667	Colorectum	AD	response to nutrient levels	138/3918	474/18723	1.22e-05	2.68e-04	138
GO:0006413	Colorectum	AD	translational initiation	45/3918	118/18723	1.35e-05	2.92e-04	45
GO:0046777	Colorectum	AD	protein autophosphorylation	74/3918	227/18723	2.48e-05	4.76e-04	74
GO:0042594	Colorectum	AD	response to starvation	63/3918	197/18723	1.77e-04	2.38e-03	63
GO:0055072	Colorectum	AD	iron ion homeostasis	32/3918	85/18723	2.97e-04	3.60e-03	32
GO:0006446	Colorectum	AD	regulation of translational initiation	28/3918	79/18723	2.02e-03	1.63e-02	28
GO:0002573	Colorectum	AD	myeloid leukocyte differentiation	60/3918	208/18723	4.03e-03	2.81e-02	60
GO:00064172	Colorectum	MSS	regulation of translation	134/3467	468/18723	4.43e-08	2.38e-06	134
GO:00300992	Colorectum	MSS	myeloid cell differentiation	110/3467	381/18723	4.48e-07	1.75e-05	110
GO:00064132	Colorectum	MSS	translational initiation	43/3467	118/18723	3.19e-06	9.38e-05	43
GO:00316672	Colorectum	MSS	response to nutrient levels	125/3467	474/18723	1.24e-05	2.88e-04	125
GO:00550762	Colorectum	MSS	transition metal ion homeostasis	45/3467	138/18723	4.99e-05	9.02e-04	45
GO:00467772	Colorectum	MSS	protein autophosphorylation	63/3467	227/18723	3.96e-04	4.91e-03	63
GO:00425942	Colorectum	MSS	response to starvation	56/3467	197/18723	4.25e-04	5.21e-03	56
GO:00550722	Colorectum	MSS	iron ion homeostasis	29/3467	85/18723	4.44e-04	5.32e-03	29
GO:00025731	Colorectum	MSS	myeloid leukocyte differentiation	57/3467	208/18723	1.01e-03	1.01e-02	57
GO:00064461	Colorectum	MSS	regulation of translational initiation	26/3467	79/18723	1.56e-03	1.42e-02	26

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04141	Colorectum	AD	Protein processing in endoplasmic reticulum	80/2092	174/8465	5.96e-10	1.25e-08	7.96e-09	80
hsa05160	Colorectum	AD	Hepatitis C	54/2092	157/8465	3.87e-03	1.96e-02	1.25e-02	54
hsa041411	Colorectum	AD	Protein processing in endoplasmic reticulum	80/2092	174/8465	5.96e-10	1.25e-08	7.96e-09	80
hsa051601	Colorectum	AD	Hepatitis C	54/2092	157/8465	3.87e-03	1.96e-02	1.25e-02	54
hsa041414	Colorectum	MSS	Protein processing in endoplasmic reticulum	75/1875	174/8465	3.78e-10	8.44e-09	5.17e-09	75
hsa051602	Colorectum	MSS	Hepatitis C	52/1875	157/8465	9.29e-04	5.58e-03	3.42e-03	52
hsa041415	Colorectum	MSS	Protein processing in endoplasmic reticulum	75/1875	174/8465	3.78e-10	8.44e-09	5.17e-09	75
hsa051603	Colorectum	MSS	Hepatitis C	52/1875	157/8465	9.29e-04	5.58e-03	3.42e-03	52
hsa041416	Colorectum	MSI-H	Protein processing in endoplasmic reticulum	46/797	174/8465	4.53e-11	9.78e-10	8.19e-10	46
hsa041417	Colorectum	MSI-H	Protein processing in endoplasmic reticulum	46/797	174/8465	4.53e-11	9.78e-10	8.19e-10	46
hsa041418	Colorectum	FAP	Protein processing in endoplasmic reticulum	50/1404	174/8465	3.64e-05	3.68e-04	2.24e-04	50
hsa041419	Colorectum	FAP	Protein processing in endoplasmic reticulum	50/1404	174/8465	3.64e-05	3.68e-04	2.24e-04	50
hsa04141211	Esophagus	ESCC	Protein processing in endoplasmic reticulum	147/4205	174/8465	3.29e-22	1.10e-19	5.64e-20	147
hsa051609	Esophagus	ESCC	Hepatitis C	107/4205	157/8465	1.75e-06	1.08e-05	5.55e-06	107
hsa051629	Esophagus	ESCC	Measles	90/4205	139/8465	2.16e-04	7.87e-04	4.03e-04	90
hsa04141310	Esophagus	ESCC	Protein processing in endoplasmic reticulum	147/4205	174/8465	3.29e-22	1.10e-19	5.64e-20	147
hsa0516016	Esophagus	ESCC	Hepatitis C	107/4205	157/8465	1.75e-06	1.08e-05	5.55e-06	107
hsa0516213	Esophagus	ESCC	Measles	90/4205	139/8465	2.16e-04	7.87e-04	4.03e-04	90
hsa0414114	Liver	Cirrhotic	Protein processing in endoplasmic reticulum	114/2530	174/8465	1.16e-22	9.67e-21	5.96e-21	114
hsa051605	Liver	Cirrhotic	Hepatitis C	63/2530	157/8465	3.67e-03	1.49e-02	9.20e-03	63

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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

EIF2AK1

SNV

Missense_Mutation

novel

c.794N>T

p.Glu265Val

p.E265V

Q9BQI3

protein_coding

deleterious(0.01)

benign(0.023)

TCGA-A2-A3XU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

EIF2AK1

SNV

Missense_Mutation

c.880G>A

p.Glu294Lys

p.E294K

Q9BQI3

protein_coding

tolerated(0.25)

benign(0.001)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

EIF2AK1

SNV

Missense_Mutation

c.1228N>A

p.Ala410Thr

p.A410T

Q9BQI3

protein_coding

tolerated(0.11)

benign(0.124)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

EIF2AK1

SNV

Missense_Mutation

c.686N>T

p.Tyr229Phe

p.Y229F

Q9BQI3

protein_coding

deleterious(0.03)

probably_damaging(0.986)

TCGA-GM-A2DC-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

xeloda

EIF2AK1

insertion

In_Frame_Ins

novel

c.1243_1244insCCCGACATTTTTCTG

p.Met415delinsThrArgHisPheSerVal

p.M415delinsTRHFSV

Q9BQI3

protein_coding

TCGA-A2-A0CU-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

EIF2AK1

insertion

Frame_Shift_Ins

novel

c.1241_1242insCTCTGCTCTCC

p.Met415SerfsTer17

p.M415Sfs*17

Q9BQI3

protein_coding

TCGA-A2-A0CU-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

EIF2AK1

insertion

Nonsense_Mutation

novel

c.1126_1127insGAGGCATTCCAGATGATTGAATC

p.Tyr376Ter

p.Y376*

Q9BQI3

protein_coding

TCGA-A7-A0CJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

EIF2AK1

deletion

Frame_Shift_Del

novel

c.1277delN

p.Leu426TrpfsTer2

p.L426Wfs*2

Q9BQI3

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

EIF2AK1

SNV

Missense_Mutation

novel

c.1483C>G

p.Leu495Val

p.L495V

Q9BQI3

protein_coding

tolerated(0.3)

possibly_damaging(0.759)

TCGA-DS-A1OB-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

carboplatin

EIF2AK1

SNV

Missense_Mutation

c.1348N>T

p.Leu450Phe

p.L450F

Q9BQI3

protein_coding

deleterious(0)

possibly_damaging(0.719)

TCGA-EK-A3GK-01

Cervix

cervical & endocervical cancer

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
27102	EIF2AK1	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	381118865
27102	EIF2AK1	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME	inhibitor	249565848
27102	EIF2AK1	DRUGGABLE GENOME, KINASE, SERINE THREONINE KINASE, ENZYME		TCMDC-123956	CHEMBL534675	22153346

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