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: HLA-E

Gene summary for HLA-E

Gene summary.

Gene information	Species	Human
	Gene symbol	HLA-E
	Gene ID	3133
	Gene name	major histocompatibility complex, class I, E
	Gene Alias	HLA-6.2
	Cytomap	6p22.1
	Gene Type	protein-coding
	GO ID	GO:0001775
	UniProtAcc	A8K8M6

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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
3133	HLA-E	GSM4909281	Human	Breast	IDC	5.33e-08	4.07e-01	0.21
3133	HLA-E	GSM4909285	Human	Breast	IDC	2.76e-18	-5.55e-01	0.21
3133	HLA-E	GSM4909286	Human	Breast	IDC	2.38e-17	-5.74e-01	0.1081
3133	HLA-E	GSM4909287	Human	Breast	IDC	4.64e-03	-3.22e-01	0.2057
3133	HLA-E	GSM4909294	Human	Breast	IDC	5.50e-18	-5.44e-01	0.2022
3133	HLA-E	GSM4909296	Human	Breast	IDC	3.21e-19	-5.70e-01	0.1524
3133	HLA-E	GSM4909297	Human	Breast	IDC	3.10e-16	-3.39e-01	0.1517
3133	HLA-E	GSM4909301	Human	Breast	IDC	1.58e-13	-5.33e-01	0.1577
3133	HLA-E	GSM4909302	Human	Breast	IDC	1.19e-06	-3.92e-01	0.1545
3133	HLA-E	GSM4909304	Human	Breast	IDC	5.14e-21	-6.00e-01	0.1636
3133	HLA-E	GSM4909306	Human	Breast	IDC	1.61e-07	-4.08e-01	0.1564
3133	HLA-E	GSM4909311	Human	Breast	IDC	1.43e-34	-4.04e-01	0.1534
3133	HLA-E	GSM4909312	Human	Breast	IDC	5.57e-20	-5.00e-01	0.1552
3133	HLA-E	GSM4909315	Human	Breast	IDC	6.85e-13	-5.44e-01	0.21
3133	HLA-E	GSM4909316	Human	Breast	IDC	6.09e-05	-5.12e-01	0.21
3133	HLA-E	GSM4909319	Human	Breast	IDC	1.36e-38	-4.48e-01	0.1563
3133	HLA-E	GSM4909320	Human	Breast	IDC	5.48e-13	-7.17e-01	0.1575
3133	HLA-E	GSM4909321	Human	Breast	IDC	6.51e-15	-2.69e-01	0.1559
3133	HLA-E	brca2	Human	Breast	Precancer	3.39e-03	-2.33e-02	-0.024
3133	HLA-E	brca3	Human	Breast	Precancer	1.63e-07	1.33e-01	-0.0263

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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
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
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:00457859	Breast	Precancer	positive regulation of cell adhesion	52/1080	437/18723	5.74e-07	2.49e-05	52
GO:00018196	Breast	Precancer	positive regulation of cytokine production	52/1080	467/18723	4.18e-06	1.29e-04	52
GO:00024839	Breast	Precancer	antigen processing and presentation of endogenous peptide antigen	8/1080	19/18723	5.10e-06	1.53e-04	8
GO:00507293	Breast	Precancer	positive regulation of inflammatory response	23/1080	142/18723	6.51e-06	1.81e-04	23
GO:00198839	Breast	Precancer	antigen processing and presentation of endogenous antigen	9/1080	26/18723	8.75e-06	2.34e-04	9
GO:0050727	Breast	Precancer	regulation of inflammatory response	44/1080	386/18723	1.26e-05	3.22e-04	44
GO:00421107	Breast	Precancer	T cell activation	52/1080	487/18723	1.37e-05	3.42e-04	52
GO:00508707	Breast	Precancer	positive regulation of T cell activation	29/1080	216/18723	1.94e-05	4.58e-04	29
GO:00321034	Breast	Precancer	positive regulation of response to external stimulus	46/1080	427/18723	3.41e-05	7.40e-04	46
GO:19030396	Breast	Precancer	positive regulation of leukocyte cell-cell adhesion	30/1080	239/18723	5.13e-05	1.07e-03	30
GO:00027117	Breast	Precancer	positive regulation of T cell mediated immunity	12/1080	56/18723	6.72e-05	1.35e-03	12
GO:00313493	Breast	Precancer	positive regulation of defense response	33/1080	278/18723	6.79e-05	1.36e-03	33
GO:00197307	Breast	Precancer	antimicrobial humoral response	19/1080	122/18723	7.02e-05	1.40e-03	19
GO:00508637	Breast	Precancer	regulation of T cell activation	37/1080	329/18723	8.04e-05	1.56e-03	37
GO:00224098	Breast	Precancer	positive regulation of cell-cell adhesion	33/1080	284/18723	1.03e-04	1.89e-03	33
GO:00071597	Breast	Precancer	leukocyte cell-cell adhesion	40/1080	371/18723	1.07e-04	1.94e-03	40
GO:00019168	Breast	Precancer	positive regulation of T cell mediated cytotoxicity	8/1080	29/18723	1.73e-04	2.83e-03	8
GO:00480029	Breast	Precancer	antigen processing and presentation of peptide antigen	12/1080	62/18723	1.89e-04	3.04e-03	12
GO:00224079	Breast	Precancer	regulation of cell-cell adhesion	45/1080	448/18723	2.12e-04	3.30e-03	45
GO:00198859	Breast	Precancer	antigen processing and presentation of endogenous peptide antigen via MHC class I	6/1080	17/18723	2.59e-04	3.83e-03	6

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0516718	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0461218	Breast	Precancer	Antigen processing and presentation	19/684	78/8465	9.61e-06	1.12e-04	8.62e-05	19
hsa0516918	Breast	Precancer	Epstein-Barr virus infection	35/684	202/8465	1.15e-05	1.26e-04	9.64e-05	35
hsa042189	Breast	Precancer	Cellular senescence	29/684	156/8465	1.66e-05	1.69e-04	1.30e-04	29
hsa0414518	Breast	Precancer	Phagosome	27/684	152/8465	7.37e-05	6.85e-04	5.25e-04	27
hsa0541618	Breast	Precancer	Viral myocarditis	14/684	60/8465	2.32e-04	1.98e-03	1.52e-03	14
hsa0516618	Breast	Precancer	Human T-cell leukemia virus 1 infection	33/684	222/8465	4.29e-04	3.31e-03	2.53e-03	33
hsa0516316	Breast	Precancer	Human cytomegalovirus infection	32/684	225/8465	1.13e-03	7.57e-03	5.80e-03	32
hsa052036	Breast	Precancer	Viral carcinogenesis	27/684	204/8465	7.19e-03	4.06e-02	3.11e-02	27
hsa0516719	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0461219	Breast	Precancer	Antigen processing and presentation	19/684	78/8465	9.61e-06	1.12e-04	8.62e-05	19
hsa0516919	Breast	Precancer	Epstein-Barr virus infection	35/684	202/8465	1.15e-05	1.26e-04	9.64e-05	35
hsa0421814	Breast	Precancer	Cellular senescence	29/684	156/8465	1.66e-05	1.69e-04	1.30e-04	29
hsa0414519	Breast	Precancer	Phagosome	27/684	152/8465	7.37e-05	6.85e-04	5.25e-04	27
hsa0541619	Breast	Precancer	Viral myocarditis	14/684	60/8465	2.32e-04	1.98e-03	1.52e-03	14
hsa0516619	Breast	Precancer	Human T-cell leukemia virus 1 infection	33/684	222/8465	4.29e-04	3.31e-03	2.53e-03	33
hsa0516317	Breast	Precancer	Human cytomegalovirus infection	32/684	225/8465	1.13e-03	7.57e-03	5.80e-03	32
hsa0520312	Breast	Precancer	Viral carcinogenesis	27/684	204/8465	7.19e-03	4.06e-02	3.11e-02	27
hsa0516922	Breast	IDC	Epstein-Barr virus infection	45/867	202/8465	3.16e-07	6.05e-06	4.52e-06	45
hsa0461223	Breast	IDC	Antigen processing and presentation	24/867	78/8465	4.61e-07	8.33e-06	6.23e-06	24

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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
HLA-E	CD8A	HLA-E_CD8A	MHC-I	Breast	ADJ
HLA-E	CD8B	HLA-E_CD8B	MHC-I	Breast	ADJ
HLA-E	KLRC1	HLA-E_KLRC1	MHC-I	Breast	ADJ
HLA-E	KLRC2	HLA-E_KLRC2	MHC-I	Breast	ADJ
HLA-E	CD94:NKG2A	HLA-E_CD94:NKG2A	MHC-I	Breast	ADJ
HLA-E	CD94:NKG2C	HLA-E_CD94:NKG2C	MHC-I	Breast	ADJ
HLA-E	CD8A	HLA-E_CD8A	MHC-I	Breast	DCIS
HLA-E	CD8B	HLA-E_CD8B	MHC-I	Breast	DCIS
HLA-E	KLRC1	HLA-E_KLRC1	MHC-I	Breast	DCIS
HLA-E	CD94:NKG2A	HLA-E_CD94:NKG2A	MHC-I	Breast	DCIS
HLA-E	CD8A	HLA-E_CD8A	MHC-I	Breast	Healthy
HLA-E	CD8B	HLA-E_CD8B	MHC-I	Breast	Healthy
HLA-E	KLRC1	HLA-E_KLRC1	MHC-I	Breast	Healthy
HLA-E	CD94:NKG2A	HLA-E_CD94:NKG2A	MHC-I	Breast	Healthy
HLA-E	CD8A	HLA-E_CD8A	MHC-I	Breast	IDC
HLA-E	CD8B	HLA-E_CD8B	MHC-I	Breast	IDC
HLA-E	KLRC1	HLA-E_KLRC1	MHC-I	Breast	IDC
HLA-E	KLRC2	HLA-E_KLRC2	MHC-I	Breast	IDC
HLA-E	CD94:NKG2A	HLA-E_CD94:NKG2A	MHC-I	Breast	IDC
HLA-E	CD94:NKG2C	HLA-E_CD94:NKG2C	MHC-I	Breast	IDC

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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

HLA-E

SNV

Missense_Mutation

c.1038N>T

p.Trp346Cys

p.W346C

protein_coding

tolerated_low_confidence(0.27)

benign(0)

TCGA-E2-A1IJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

HLA-E

insertion

Nonsense_Mutation

novel

c.81_82insAATTAA

p.Lys27_Tyr28insAsnTer

p.K27_Y28insN*

protein_coding

TCGA-E9-A1NI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

HLA-E

SNV

Missense_Mutation

c.757N>A

p.Glu253Lys

p.E253K

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.98)

TCGA-C5-A1ME-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HLA-E

SNV

Missense_Mutation

c.517N>A

p.Glu173Lys

p.E173K

protein_coding

tolerated_low_confidence(0.39)

probably_damaging(0.991)

TCGA-IR-A3LH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-E

SNV

Missense_Mutation

c.517N>C

p.Glu173Gln

p.E173Q

protein_coding

tolerated_low_confidence(0.35)

probably_damaging(0.991)

TCGA-VS-A8EI-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-E

SNV

Missense_Mutation

c.469N>A

p.Val157Met

p.V157M

protein_coding

deleterious_low_confidence(0.01)

benign(0.034)

TCGA-AA-3672-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

HLA-E

SNV

Missense_Mutation

c.400N>C

p.Tyr134His

p.Y134H

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.998)

TCGA-AA-3811-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

HLA-E

SNV

Missense_Mutation

novel

c.1012N>A

p.Gly338Arg

p.G338R

protein_coding

tolerated_low_confidence(0.16)

probably_damaging(0.996)

TCGA-AA-3864-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

HLA-E

SNV

Missense_Mutation

c.725N>A

p.Gly242Glu

p.G242E

protein_coding

deleterious_low_confidence(0.04)

probably_damaging(0.999)

TCGA-AU-6004-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HLA-E

SNV

Missense_Mutation

novel

c.911N>T

p.Pro304Leu

p.P304L

protein_coding

tolerated_low_confidence(0.46)

probably_damaging(0.991)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

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
3133	HLA-E	CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE		glucocorticoids
3133	HLA-E	CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE		infliximab	INFLIXIMAB
3133	HLA-E	CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE		adalimumab	ADALIMUMAB
3133	HLA-E	CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE		methotrexate	METHOTREXATE
3133	HLA-E	CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE		certolizumab pegol
3133	HLA-E	CELL SURFACE, EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE		etanercept	ETANERCEPT

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