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-F

Gene summary for HLA-F

Gene summary.

Gene information	Species	Human
	Gene symbol	HLA-F
	Gene ID	3134
	Gene name	major histocompatibility complex, class I, F
	Gene Alias	CDA12
	Cytomap	6p22.1
	Gene Type	protein-coding
	GO ID	GO:0001775
	UniProtAcc	P30511

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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
3134	HLA-F	CA_HPV_1	Human	Cervix	CC	5.17e-07	3.50e-01	0.0264
3134	HLA-F	CA_HPV_2	Human	Cervix	CC	1.34e-14	5.11e-01	0.0391
3134	HLA-F	N_HPV_2	Human	Cervix	N_HPV	5.16e-04	2.74e-01	-0.0131
3134	HLA-F	Tumor	Human	Cervix	CC	4.43e-09	3.85e-01	0.1241
3134	HLA-F	sample1	Human	Cervix	CC	1.36e-35	1.09e+00	0.0959
3134	HLA-F	sample3	Human	Cervix	CC	1.05e-16	4.29e-01	0.1387
3134	HLA-F	L1	Human	Cervix	CC	6.10e-04	-1.12e-01	0.0802
3134	HLA-F	T1	Human	Cervix	CC	1.19e-52	1.06e+00	0.0918
3134	HLA-F	T3	Human	Cervix	CC	1.89e-10	3.66e-01	0.1389
3134	HLA-F	HTA11_3410_2000001011	Human	Colorectum	AD	3.82e-09	3.42e-01	0.0155
3134	HLA-F	HTA11_2487_2000001011	Human	Colorectum	SER	4.81e-24	8.22e-01	-0.1808
3134	HLA-F	HTA11_2951_2000001011	Human	Colorectum	AD	3.76e-04	5.57e-01	0.0216
3134	HLA-F	HTA11_1938_2000001011	Human	Colorectum	AD	3.20e-13	6.43e-01	-0.0811
3134	HLA-F	HTA11_78_2000001011	Human	Colorectum	AD	3.04e-13	5.95e-01	-0.1088
3134	HLA-F	HTA11_347_2000001011	Human	Colorectum	AD	1.22e-50	1.14e+00	-0.1954
3134	HLA-F	HTA11_411_2000001011	Human	Colorectum	SER	1.50e-03	6.73e-01	-0.2602
3134	HLA-F	HTA11_2112_2000001011	Human	Colorectum	SER	5.03e-07	8.89e-01	-0.2196
3134	HLA-F	HTA11_3361_2000001011	Human	Colorectum	AD	5.64e-24	1.01e+00	-0.1207
3134	HLA-F	HTA11_83_2000001011	Human	Colorectum	SER	1.52e-07	5.02e-01	-0.1526
3134	HLA-F	HTA11_696_2000001011	Human	Colorectum	AD	5.56e-52	1.13e+00	-0.1464

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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:000248324	Oral cavity	EOLP	antigen processing and presentation of endogenous peptide antigen	10/2218	19/18723	1.79e-05	2.89e-04	10
GO:00508677	Oral cavity	EOLP	positive regulation of cell activation	79/2218	420/18723	1.91e-05	3.02e-04	79
GO:007099726	Oral cavity	EOLP	neuron death	70/2218	361/18723	2.01e-05	3.18e-04	70
GO:00026968	Oral cavity	EOLP	positive regulation of leukocyte activation	77/2218	409/18723	2.34e-05	3.52e-04	77
GO:00313482	Oral cavity	EOLP	negative regulation of defense response	53/2218	258/18723	4.05e-05	5.54e-04	53
GO:000283221	Oral cavity	EOLP	negative regulation of response to biotic stimulus	28/2218	108/18723	4.29e-05	5.82e-04	28
GO:001988524	Oral cavity	EOLP	antigen processing and presentation of endogenous peptide antigen via MHC class I	9/2218	17/18723	4.50e-05	6.01e-04	9
GO:00022633	Oral cavity	EOLP	cell activation involved in immune response	56/2218	279/18723	4.91e-05	6.47e-04	56
GO:00028332	Oral cavity	EOLP	positive regulation of response to biotic stimulus	38/2218	168/18723	5.81e-05	7.33e-04	38
GO:00023662	Oral cavity	EOLP	leukocyte activation involved in immune response	55/2218	275/18723	6.32e-05	7.90e-04	55
GO:00512503	Oral cavity	EOLP	negative regulation of lymphocyte activation	36/2218	157/18723	6.66e-05	8.27e-04	36
GO:00022852	Oral cavity	EOLP	lymphocyte activation involved in immune response	42/2218	194/18723	7.17e-05	8.82e-04	42
GO:001988324	Oral cavity	EOLP	antigen processing and presentation of endogenous antigen	11/2218	26/18723	8.86e-05	1.04e-03	11
GO:00508663	Oral cavity	EOLP	negative regulation of cell activation	44/2218	210/18723	1.09e-04	1.23e-03	44
GO:00321023	Oral cavity	EOLP	negative regulation of response to external stimulus	75/2218	420/18723	1.74e-04	1.80e-03	75
GO:190121423	Oral cavity	EOLP	regulation of neuron death	60/2218	319/18723	1.83e-04	1.87e-03	60
GO:00450891	Oral cavity	EOLP	positive regulation of innate immune response	30/2218	131/18723	2.66e-04	2.56e-03	30
GO:00026953	Oral cavity	EOLP	negative regulation of leukocyte activation	39/2218	187/18723	2.89e-04	2.74e-03	39
GO:003134912	Oral cavity	EOLP	positive regulation of defense response	53/2218	278/18723	3.00e-04	2.81e-03	53
GO:00028193	Oral cavity	EOLP	regulation of adaptive immune response	38/2218	183/18723	3.75e-04	3.40e-03	38

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0461220	Cervix	CC	Antigen processing and presentation	34/1267	78/8465	1.06e-09	2.14e-08	1.26e-08	34
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0541620	Cervix	CC	Viral myocarditis	27/1267	60/8465	2.43e-08	3.57e-07	2.11e-07	27
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0421810	Cervix	CC	Cellular senescence	49/1267	156/8465	1.30e-07	1.63e-06	9.61e-07	49
hsa0414520	Cervix	CC	Phagosome	47/1267	152/8465	3.95e-07	4.26e-06	2.52e-06	47
hsa0516920	Cervix	CC	Epstein-Barr virus infection	57/1267	202/8465	7.30e-07	7.39e-06	4.37e-06	57
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0414418	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0517016	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa0494016	Cervix	CC	Type I diabetes mellitus	17/1267	43/8465	7.47e-05	5.04e-04	2.98e-04	17
hsa051657	Cervix	CC	Human papillomavirus infection	74/1267	331/8465	1.70e-04	1.02e-03	6.03e-04	74
hsa0533014	Cervix	CC	Allograft rejection	15/1267	38/8465	2.01e-04	1.14e-03	6.75e-04	15
hsa0533212	Cervix	CC	Graft-versus-host disease	15/1267	42/8465	7.12e-04	3.25e-03	1.92e-03	15
hsa045147	Cervix	CC	Cell adhesion molecules	36/1267	157/8465	4.94e-03	1.67e-02	9.86e-03	36
hsa0532012	Cervix	CC	Autoimmune thyroid disease	15/1267	53/8465	9.08e-03	2.85e-02	1.69e-02	15
hsa04612110	Cervix	CC	Antigen processing and presentation	34/1267	78/8465	1.06e-09	2.14e-08	1.26e-08	34
hsa05167110	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa05416110	Cervix	CC	Viral myocarditis	27/1267	60/8465	2.43e-08	3.57e-07	2.11e-07	27
hsa0516319	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65

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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-F	CD8A	HLA-F_CD8A	MHC-I	Breast	ADJ
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Breast	ADJ
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Breast	DCIS
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Breast	DCIS
HLA-F	LILRB1	HLA-F_LILRB1	MHC-I	Breast	DCIS
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Breast	Healthy
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Breast	Healthy
HLA-F	LILRB1	HLA-F_LILRB1	MHC-I	Breast	Healthy
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Breast	IDC
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Breast	IDC
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Breast	Precancer
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Breast	Precancer
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Cervix	ADJ
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Cervix	ADJ
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Cervix	CC
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Cervix	CC
HLA-F	LILRB1	HLA-F_LILRB1	MHC-I	Cervix	CC
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Cervix	Healthy
HLA-F	CD8B	HLA-F_CD8B	MHC-I	Cervix	Healthy
HLA-F	CD8A	HLA-F_CD8A	MHC-I	Cervix	Precancer

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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-F

SNV

Missense_Mutation

c.695C>G

p.Ala232Gly

p.A232G

P30511

protein_coding

deleterious_low_confidence(0)

benign(0.022)

TCGA-D8-A147-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

HLA-F

SNV

Missense_Mutation

c.659C>T

p.Ala220Val

p.A220V

P30511

protein_coding

tolerated_low_confidence(0.68)

benign(0)

TCGA-D8-A27M-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

methotrexate+5

HLA-F

SNV

Missense_Mutation

rs541971824

c.719N>A

p.Arg240Gln

p.R240Q

P30511

protein_coding

tolerated_low_confidence(0.06)

possibly_damaging(0.598)

TCGA-PL-A8LX-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

HLA-F

SNV

Missense_Mutation

novel

c.996G>T

p.Lys332Asn

p.K332N

P30511

protein_coding

deleterious_low_confidence(0.02)

benign(0.197)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-F

SNV

Missense_Mutation

c.593N>G

p.Glu198Gly

p.E198G

P30511

protein_coding

deleterious_low_confidence(0)

possibly_damaging(0.847)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-F

SNV

Missense_Mutation

novel

c.191N>T

p.Pro64Leu

p.P64L

P30511

protein_coding

deleterious_low_confidence(0)

benign(0.297)

TCGA-VS-A94Z-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-F

SNV

Missense_Mutation

rs764964427

c.584N>G

p.Asn195Ser

p.N195S

P30511

protein_coding

tolerated_low_confidence(0.05)

benign(0.371)

TCGA-AA-3877-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HLA-F

SNV

Missense_Mutation

c.604N>T

p.Arg202Cys

p.R202C

P30511

protein_coding

deleterious_low_confidence(0.01)

possibly_damaging(0.466)

TCGA-F4-6856-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Ancillary

leucovorin

HLA-F

SNV

Missense_Mutation

rs57486551

c.1237N>T

p.Arg413Cys

p.R413C

P30511

protein_coding

deleterious_low_confidence(0)

benign(0)

TCGA-AG-A002-01

Colorectum

rectum adenocarcinoma

Male

<65

I/II

Unknown

HLA-F

deletion

Frame_Shift_Del

c.1180delN

p.Leu396CysfsTer38

p.L396Cfs*38

P30511

protein_coding

TCGA-AA-3966-01

Colorectum

colon adenocarcinoma

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

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