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: HIF1A

Gene summary for HIF1A

Gene summary.

Gene information	Species	Human
	Gene symbol	HIF1A
	Gene ID	3091
	Gene name	hypoxia inducible factor 1 subunit alpha
	Gene Alias	HIF-1-alpha
	Cytomap	14q23.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	Q16665

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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
3091	HIF1A	CA_HPV_1	Human	Cervix	CC	3.42e-08	-1.49e-01	0.0264
3091	HIF1A	CCI_1	Human	Cervix	CC	1.35e-02	5.19e-01	0.528
3091	HIF1A	CCII_1	Human	Cervix	CC	3.07e-07	-5.91e-01	0.3249
3091	HIF1A	L1	Human	Cervix	CC	3.04e-07	-3.37e-01	0.0802
3091	HIF1A	HTA11_3410_2000001011	Human	Colorectum	AD	1.22e-08	-4.68e-01	0.0155
3091	HIF1A	HTA11_2487_2000001011	Human	Colorectum	SER	4.96e-03	-4.19e-01	-0.1808
3091	HIF1A	HTA11_3361_2000001011	Human	Colorectum	AD	2.76e-05	-5.63e-01	-0.1207
3091	HIF1A	HTA11_866_2000001011	Human	Colorectum	AD	2.52e-06	-3.52e-01	-0.1001
3091	HIF1A	HTA11_866_3004761011	Human	Colorectum	AD	1.03e-08	-5.20e-01	0.096
3091	HIF1A	HTA11_10711_2000001011	Human	Colorectum	AD	3.14e-04	-4.84e-01	0.0338
3091	HIF1A	HTA11_7696_3000711011	Human	Colorectum	AD	4.48e-11	-4.66e-01	0.0674
3091	HIF1A	HTA11_6818_2000001011	Human	Colorectum	AD	1.39e-02	-5.82e-01	0.0112
3091	HIF1A	HTA11_6818_2000001021	Human	Colorectum	AD	1.70e-05	-5.79e-01	0.0588
3091	HIF1A	HTA11_99999970781_79442	Human	Colorectum	MSS	1.54e-05	-3.27e-01	0.294
3091	HIF1A	HTA11_99999971662_82457	Human	Colorectum	MSS	7.33e-21	-5.64e-01	0.3859
3091	HIF1A	HTA11_99999973899_84307	Human	Colorectum	MSS	3.53e-04	-5.75e-01	0.2585
3091	HIF1A	HTA11_99999974143_84620	Human	Colorectum	MSS	2.45e-22	-5.56e-01	0.3005
3091	HIF1A	F007	Human	Colorectum	FAP	7.91e-04	-3.52e-01	0.1176
3091	HIF1A	A002-C-010	Human	Colorectum	FAP	3.19e-03	-2.53e-01	0.242
3091	HIF1A	A001-C-207	Human	Colorectum	FAP	3.99e-07	-4.61e-01	0.1278

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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:004603410	Cervix	CC	ATP metabolic process	90/2311	277/18723	7.90e-19	2.36e-15	90
GO:009719310	Cervix	CC	intrinsic apoptotic signaling pathway	85/2311	288/18723	4.56e-15	6.46e-12	85
GO:004206010	Cervix	CC	wound healing	109/2311	422/18723	1.84e-14	1.57e-11	109
GO:200123310	Cervix	CC	regulation of apoptotic signaling pathway	96/2311	356/18723	4.08e-14	3.05e-11	96
GO:00090609	Cervix	CC	aerobic respiration	60/2311	189/18723	1.59e-12	6.36e-10	60
GO:00453339	Cervix	CC	cellular respiration	66/2311	230/18723	2.07e-11	5.39e-09	66
GO:009013210	Cervix	CC	epithelium migration	90/2311	360/18723	2.45e-11	6.11e-09	90
GO:00016679	Cervix	CC	ameboidal-type cell migration	110/2311	475/18723	2.66e-11	6.36e-09	110
GO:001063110	Cervix	CC	epithelial cell migration	89/2311	357/18723	3.72e-11	8.54e-09	89
GO:200124210	Cervix	CC	regulation of intrinsic apoptotic signaling pathway	52/2311	164/18723	5.06e-11	1.01e-08	52
GO:009013010	Cervix	CC	tissue migration	90/2311	365/18723	5.42e-11	1.05e-08	90
GO:190332010	Cervix	CC	regulation of protein modification by small protein conjugation or removal	66/2311	242/18723	2.31e-10	3.46e-08	66
GO:000697910	Cervix	CC	response to oxidative stress	102/2311	446/18723	2.99e-10	4.36e-08	102
GO:000989610	Cervix	CC	positive regulation of catabolic process	109/2311	492/18723	5.26e-10	6.99e-08	109
GO:00506737	Cervix	CC	epithelial cell proliferation	98/2311	437/18723	2.01e-09	2.15e-07	98
GO:001063210	Cervix	CC	regulation of epithelial cell migration	72/2311	292/18723	4.52e-09	4.43e-07	72
GO:00060919	Cervix	CC	generation of precursor metabolites and energy	105/2311	490/18723	7.40e-09	6.61e-07	105
GO:005122210	Cervix	CC	positive regulation of protein transport	72/2311	303/18723	2.36e-08	1.70e-06	72
GO:00159809	Cervix	CC	energy derivation by oxidation of organic compounds	74/2311	318/18723	3.83e-08	2.53e-06	74
GO:004361810	Cervix	CC	regulation of transcription from RNA polymerase II promoter in response to stress	21/2311	47/18723	3.85e-08	2.53e-06	21

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0520820	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0520516	Cervix	CC	Proteoglycans in cancer	60/1267	205/8465	9.13e-08	1.18e-06	7.00e-07	60
hsa0491918	Cervix	CC	Thyroid hormone signaling pathway	33/1267	121/8465	3.11e-04	1.65e-03	9.78e-04	33
hsa0413718	Cervix	CC	Mitophagy - animal	22/1267	72/8465	5.77e-04	2.75e-03	1.63e-03	22
hsa046596	Cervix	CC	Th17 cell differentiation	28/1267	108/8465	1.99e-03	7.98e-03	4.72e-03	28
hsa052119	Cervix	CC	Renal cell carcinoma	20/1267	69/8465	2.07e-03	8.17e-03	4.83e-03	20
hsa0406618	Cervix	CC	HIF-1 signaling pathway	27/1267	109/8465	4.72e-03	1.64e-02	9.72e-03	27
hsa0523010	Cervix	CC	Central carbon metabolism in cancer	18/1267	70/8465	1.29e-02	3.87e-02	2.29e-02	18
hsa05208110	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa05167110	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0520517	Cervix	CC	Proteoglycans in cancer	60/1267	205/8465	9.13e-08	1.18e-06	7.00e-07	60
hsa0491919	Cervix	CC	Thyroid hormone signaling pathway	33/1267	121/8465	3.11e-04	1.65e-03	9.78e-04	33
hsa0413719	Cervix	CC	Mitophagy - animal	22/1267	72/8465	5.77e-04	2.75e-03	1.63e-03	22
hsa0465911	Cervix	CC	Th17 cell differentiation	28/1267	108/8465	1.99e-03	7.98e-03	4.72e-03	28
hsa0521114	Cervix	CC	Renal cell carcinoma	20/1267	69/8465	2.07e-03	8.17e-03	4.83e-03	20
hsa0406619	Cervix	CC	HIF-1 signaling pathway	27/1267	109/8465	4.72e-03	1.64e-02	9.72e-03	27
hsa0523013	Cervix	CC	Central carbon metabolism in cancer	18/1267	70/8465	1.29e-02	3.87e-02	2.29e-02	18
hsa05208	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa04066	Colorectum	AD	HIF-1 signaling pathway	48/2092	109/8465	7.25e-06	7.84e-05	5.00e-05	48

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
HIF1A	MLUM	Breast	Healthy	TGM2,BZW1,NAMPT, etc.	4.62e-01
HIF1A	MES	Cervix	CC	HIF1A-AS3,SNAPC1,KRT6C, etc.	7.02e-01
HIF1A	PERI	Colorectum	FAP	SSH1,NUAK1,RUNX1, etc.	4.34e-02
HIF1A	ICAF	Colorectum	SER	SSH1,NUAK1,RUNX1, etc.	3.93e-01
HIF1A	PMC	Stomach	CAG with IM	PLPP3,SERPINA3,SOD2, etc.	2.12e-01
HIF1A	GMC	Stomach	CAG with IM	PLPP3,SERPINA3,SOD2, etc.	1.31e-01
HIF1A	PMC	Stomach	SIM	PLPP3,SERPINA3,SOD2, etc.	4.96e-01
HIF1A	GMC	Stomach	WIM	PLPP3,SERPINA3,SOD2, etc.	7.45e-02

∗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

HIF1A

SNV

Missense_Mutation

novel

c.1022T>G

p.Val341Gly

p.V341G

Q16665

protein_coding

deleterious(0)

probably_damaging(0.969)

TCGA-A8-A095-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

HIF1A

SNV

Missense_Mutation

rs540883086

c.853N>A

p.Glu285Lys

p.E285K

Q16665

protein_coding

deleterious(0)

possibly_damaging(0.473)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HIF1A

SNV

Missense_Mutation

c.1713N>T

p.Lys571Asn

p.K571N

Q16665

protein_coding

tolerated(0.1)

probably_damaging(0.916)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HIF1A

SNV

Missense_Mutation

novel

c.1752N>T

p.Glu584Asp

p.E584D

Q16665

protein_coding

deleterious(0.01)

possibly_damaging(0.557)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HIF1A

SNV

Missense_Mutation

rs746540920

c.157N>T

p.Arg53Trp

p.R53W

Q16665

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HIF1A

SNV

Missense_Mutation

c.2485N>G

p.Pro829Ala

p.P829A

Q16665

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0H5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

HIF1A

SNV

Missense_Mutation

c.1996C>T

p.Pro666Ser

p.P666S

Q16665

protein_coding

tolerated(0.1)

benign(0.01)

TCGA-BH-A18P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HIF1A

SNV

Missense_Mutation

rs776377120

c.196C>T

p.His66Tyr

p.H66Y

Q16665

protein_coding

deleterious(0.02)

benign(0.023)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

HIF1A

SNV

Missense_Mutation

novel

c.2122C>G

p.His708Asp

p.H708D

Q16665

protein_coding

tolerated(0.2)

benign(0.07)

TCGA-EA-A3HU-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HIF1A

SNV

Missense_Mutation

c.412G>C

p.Asp138His

p.D138H

Q16665

protein_coding

deleterious(0)

possibly_damaging(0.811)

TCGA-EK-A2PL-01

Cervix

cervical & endocervical cancer

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
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		SP-600125	SP-600125
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		LEVONORDEFRIN	LEVONORDEFRIN
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		DNDI1417388	CHEMBL1528359
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		NOSCAPINE	NOSCAPINE
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		NSC-117079	CHEMBL471225
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		TYRPHOSTIN A9	TYRPHOSTIN A9
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		PX-478	PX-478
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		PIMOZIDE	PIMOZIDE
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		BECLOMETHASONE	BECLOMETHASONE
3091	HIF1A	TRANSPORTER, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME, TRANSCRIPTION FACTOR COMPLEX, CLINICALLY ACTIONABLE		GELDANAMYCIN	GELDANAMYCIN	12811834

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