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: AHR

Gene summary for AHR

Gene summary.

Gene information	Species	Human
	Gene symbol	AHR
	Gene ID	196
	Gene name	aryl hydrocarbon receptor
	Gene Alias	RP85
	Cytomap	7p21.1
	Gene Type	protein-coding
	GO ID	GO:0001568
	UniProtAcc	A0A024R9Z8

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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
196	AHR	CA_HPV_1	Human	Cervix	CC	7.28e-10	-3.12e-01	0.0264
196	AHR	CA_HPV_3	Human	Cervix	CC	2.93e-06	-3.24e-01	0.0414
196	AHR	N_HPV_1	Human	Cervix	N_HPV	1.78e-02	-1.48e-01	0.0079
196	AHR	N_HPV_2	Human	Cervix	N_HPV	1.23e-03	-2.79e-01	-0.0131
196	AHR	CCI_1	Human	Cervix	CC	2.05e-02	5.16e-02	0.528
196	AHR	CCI_2	Human	Cervix	CC	5.38e-03	-4.14e-01	0.5249
196	AHR	CCI_3	Human	Cervix	CC	1.57e-09	-6.24e-01	0.516
196	AHR	CCII_1	Human	Cervix	CC	6.47e-17	-6.39e-01	0.3249
196	AHR	sample3	Human	Cervix	CC	4.16e-04	2.29e-01	0.1387
196	AHR	L1	Human	Cervix	CC	1.21e-02	-2.80e-01	0.0802
196	AHR	AEH-subject1	Human	Endometrium	AEH	1.47e-14	5.17e-01	-0.3059
196	AHR	AEH-subject2	Human	Endometrium	AEH	4.33e-09	4.43e-01	-0.2525
196	AHR	AEH-subject4	Human	Endometrium	AEH	7.97e-06	4.07e-01	-0.2657
196	AHR	AEH-subject5	Human	Endometrium	AEH	3.20e-14	5.01e-01	-0.2953
196	AHR	EEC-subject3	Human	Endometrium	EEC	8.19e-03	2.19e-01	-0.2525
196	AHR	EEC-subject4	Human	Endometrium	EEC	4.24e-03	3.25e-01	-0.2571
196	AHR	EEC-subject5	Human	Endometrium	EEC	2.62e-08	4.22e-01	-0.249
196	AHR	GSM6177620_NYU_UCEC1_lib1_lib1	Human	Endometrium	EEC	8.03e-08	4.23e-01	-0.1869
196	AHR	GSM6177620_NYU_UCEC1_lib2_lib2	Human	Endometrium	EEC	2.71e-06	3.20e-01	-0.1875
196	AHR	GSM6177620_NYU_UCEC1_lib3_lib3	Human	Endometrium	EEC	1.17e-09	4.80e-01	-0.1883

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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
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:00026837	Cervix	CC	negative regulation of immune system process	94/2311	434/18723	2.63e-08	1.87e-06	94
GO:00305229	Cervix	CC	intracellular receptor signaling pathway	60/2311	265/18723	1.89e-06	5.97e-05	60
GO:00485118	Cervix	CC	rhythmic process	65/2311	298/18723	2.79e-06	8.04e-05	65
GO:00706637	Cervix	CC	regulation of leukocyte proliferation	55/2311	245/18723	6.51e-06	1.56e-04	55
GO:00506705	Cervix	CC	regulation of lymphocyte proliferation	51/2311	225/18723	1.05e-05	2.32e-04	51
GO:00329444	Cervix	CC	regulation of mononuclear cell proliferation	51/2311	227/18723	1.36e-05	2.73e-04	51
GO:00028315	Cervix	CC	regulation of response to biotic stimulus	67/2311	327/18723	1.79e-05	3.36e-04	67
GO:190165410	Cervix	CC	response to ketone	45/2311	194/18723	1.83e-05	3.44e-04	45
GO:00706617	Cervix	CC	leukocyte proliferation	65/2311	318/18723	2.56e-05	4.32e-04	65
GO:00466516	Cervix	CC	lymphocyte proliferation	59/2311	288/18723	5.53e-05	8.10e-04	59
GO:00076238	Cervix	CC	circadian rhythm	46/2311	210/18723	6.76e-05	9.60e-04	46
GO:00329435	Cervix	CC	mononuclear cell proliferation	59/2311	291/18723	7.51e-05	1.03e-03	59
GO:00028322	Cervix	CC	negative regulation of response to biotic stimulus	27/2311	108/18723	2.27e-04	2.55e-03	27
GO:00096369	Cervix	CC	response to toxic substance	52/2311	262/18723	3.34e-04	3.52e-03	52
GO:00507773	Cervix	CC	negative regulation of immune response	41/2311	194/18723	3.63e-04	3.76e-03	41
GO:00024564	Cervix	CC	T cell mediated immunity	26/2311	109/18723	6.39e-04	5.97e-03	26
GO:00026983	Cervix	CC	negative regulation of immune effector process	26/2311	110/18723	7.40e-04	6.63e-03	26
GO:00026973	Cervix	CC	regulation of immune effector process	62/2311	339/18723	9.25e-04	7.84e-03	62
GO:00329226	Cervix	CC	circadian regulation of gene expression	18/2311	68/18723	1.18e-03	9.56e-03	18
GO:00094109	Cervix	CC	response to xenobiotic stimulus	78/2311	462/18723	2.39e-03	1.70e-02	78

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0520826	Endometrium	AEH	Chemical carcinogenesis - reactive oxygen species	91/1197	223/8465	3.28e-23	1.33e-21	9.76e-22	91
hsa05208112	Endometrium	AEH	Chemical carcinogenesis - reactive oxygen species	91/1197	223/8465	3.28e-23	1.33e-21	9.76e-22	91
hsa0520827	Endometrium	EEC	Chemical carcinogenesis - reactive oxygen species	94/1237	223/8465	4.11e-24	1.93e-22	1.44e-22	94
hsa0520836	Endometrium	EEC	Chemical carcinogenesis - reactive oxygen species	94/1237	223/8465	4.11e-24	1.93e-22	1.44e-22	94
hsa05208211	Esophagus	ESCC	Chemical carcinogenesis - reactive oxygen species	168/4205	223/8465	1.83e-15	6.81e-14	3.49e-14	168
hsa05208310	Esophagus	ESCC	Chemical carcinogenesis - reactive oxygen species	168/4205	223/8465	1.83e-15	6.81e-14	3.49e-14	168
hsa0520842	Liver	HCC	Chemical carcinogenesis - reactive oxygen species	167/4020	223/8465	2.85e-17	1.91e-15	1.06e-15	167
hsa0520852	Liver	HCC	Chemical carcinogenesis - reactive oxygen species	167/4020	223/8465	2.85e-17	1.91e-15	1.06e-15	167
hsa0520823	Lung	AIS	Chemical carcinogenesis - reactive oxygen species	47/961	223/8465	1.63e-05	3.77e-04	2.41e-04	47
hsa0520833	Lung	AIS	Chemical carcinogenesis - reactive oxygen species	47/961	223/8465	1.63e-05	3.77e-04	2.41e-04	47
hsa046594	Lung	MIAC	Th17 cell differentiation	14/507	108/8465	4.92e-03	3.50e-02	2.53e-02	14
hsa046595	Lung	MIAC	Th17 cell differentiation	14/507	108/8465	4.92e-03	3.50e-02	2.53e-02	14
hsa0520830	Oral cavity	OSCC	Chemical carcinogenesis - reactive oxygen species	150/3704	223/8465	6.45e-13	1.20e-11	6.11e-12	150
hsa046598	Oral cavity	OSCC	Th17 cell differentiation	65/3704	108/8465	4.02e-04	1.25e-03	6.35e-04	65
hsa05208114	Oral cavity	OSCC	Chemical carcinogenesis - reactive oxygen species	150/3704	223/8465	6.45e-13	1.20e-11	6.11e-12	150
hsa0465913	Oral cavity	OSCC	Th17 cell differentiation	65/3704	108/8465	4.02e-04	1.25e-03	6.35e-04	65
hsa0520845	Oral cavity	EOLP	Chemical carcinogenesis - reactive oxygen species	66/1218	223/8465	2.50e-09	5.76e-08	3.40e-08	66
hsa0520855	Oral cavity	EOLP	Chemical carcinogenesis - reactive oxygen species	66/1218	223/8465	2.50e-09	5.76e-08	3.40e-08	66
hsa0520863	Oral cavity	NEOLP	Chemical carcinogenesis - reactive oxygen species	68/1112	223/8465	5.39e-12	2.86e-10	1.80e-10	68
hsa0520873	Oral cavity	NEOLP	Chemical carcinogenesis - reactive oxygen species	68/1112	223/8465	5.39e-12	2.86e-10	1.80e-10	68

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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
AHR	ILC	Colorectum	ADJ	PTCH1,RGS10,SOX6, etc.	5.67e-02
AHR	TH1	Colorectum	CRC	PTCH1,RGS10,SOX6, etc.	-2.22e-16
AHR	ILC	Colorectum	FAP	PTCH1,RGS10,SOX6, etc.	3.62e-02
AHR	ILC	Colorectum	Healthy	PTCH1,RGS10,SOX6, etc.	8.36e-02
AHR	DC	Colorectum	MSI-H	PTCH1,RGS10,SOX6, etc.	3.51e-02
AHR	ILC	Colorectum	MSI-H	PTCH1,RGS10,SOX6, etc.	3.78e-02
AHR	ILC	Colorectum	MSS	PTCH1,RGS10,SOX6, etc.	3.95e-02
AHR	ILC	Colorectum	SER	PTCH1,RGS10,SOX6, etc.	6.63e-02
AHR	DC	Liver	HCC	NUTM2A-AS1,SRGAP1,CD3E, etc.	4.91e-02
AHR	TREG	Pancreas	PDAC	AC073332.1,JAML,GNA15, etc.	1.20e-01

∗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

AHR

SNV

Missense_Mutation

c.119G>C

p.Arg40Thr

p.R40T

P35869

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A8-A06X-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

AHR

SNV

Missense_Mutation

c.1516N>A

p.Asp506Asn

p.D506N

P35869

protein_coding

tolerated(0.73)

benign(0.006)

TCGA-C8-A26Y-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

AHR

SNV

Missense_Mutation

novel

c.1973N>G

p.Gln658Arg

p.Q658R

P35869

protein_coding

tolerated_low_confidence(0.37)

benign(0.001)

TCGA-EW-A6SA-01

Breast

breast invasive carcinoma

Male

<65

I/II

Unknown

AHR

insertion

Nonsense_Mutation

novel

c.1594_1595insTGTCACCTATGCTGGAATGCAGTGGCACAAATGTGGCTCACTG

p.Gln532LeufsTer15

p.Q532Lfs*15

P35869

protein_coding

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

AHR

insertion

Frame_Shift_Ins

novel

c.2538_2539insCATAATGTCAGTAACTGCTGTC

p.Phe847HisfsTer24

p.F847Hfs*24

P35869

protein_coding

TCGA-B6-A0RG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

AHR

SNV

Missense_Mutation

novel

c.112C>T

p.Arg38Trp

p.R38W

P35869

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C5-A8XH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

AHR

SNV

Missense_Mutation

c.1379N>G

p.Met460Arg

p.M460R

P35869

protein_coding

deleterious(0.02)

possibly_damaging(0.52)

TCGA-AA-3715-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

AHR

SNV

Missense_Mutation

rs769847453

c.914N>A

p.Arg305Lys

p.R305K

P35869

protein_coding

tolerated(1)

benign(0)

TCGA-AA-3866-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

AHR

SNV

Missense_Mutation

novel

c.1510G>A

p.Gly504Arg

p.G504R

P35869

protein_coding

deleterious(0.02)

benign(0.053)

TCGA-AA-3939-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

AHR

SNV

Missense_Mutation

novel

c.1172N>T

p.Gly391Val

p.G391V

P35869

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-AZ-4315-01

Colorectum

colon adenocarcinoma

Male

<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
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		1-NAPHTHYLISOTHIOCYANATE	1-NAPHTHYLISOTHIOCYANATE
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		CHRYSENE	CHRYSENE
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		methylcholanthrene		17481570
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		DICHLON	DICHLON
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		omeprazole	OMEPRAZOLE	15860653
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		CARBARIL	CARBARIL
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		DESMEDIPHAM	DESMEDIPHAM
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		SALICYLANILIDE	SALICYLANILIDE
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		DIFLUBENZURON	DIFLUBENZURON
196	AHR	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, TRANSCRIPTION FACTOR, ENZYME, DRUGGABLE GENOME		2-AMINO-ANTHRAQUINONE	CHEMBL84685

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