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: RXRA

Gene summary for RXRA

Gene summary.

Gene information	Species	Human
	Gene symbol	RXRA
	Gene ID	6256
	Gene name	retinoid X receptor alpha
	Gene Alias	NR2B1
	Cytomap	9q34.2
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	Q6P3U7

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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
6256	RXRA	HTA11_3410_2000001011	Human	Colorectum	AD	1.87e-03	5.21e-02	0.0155
6256	RXRA	HTA11_2487_2000001011	Human	Colorectum	SER	2.00e-09	3.72e-01	-0.1808
6256	RXRA	HTA11_1938_2000001011	Human	Colorectum	AD	1.47e-08	2.71e-01	-0.0811
6256	RXRA	HTA11_78_2000001011	Human	Colorectum	AD	1.14e-04	2.96e-01	-0.1088
6256	RXRA	HTA11_347_2000001011	Human	Colorectum	AD	9.24e-12	3.85e-01	-0.1954
6256	RXRA	HTA11_3361_2000001011	Human	Colorectum	AD	2.20e-04	2.85e-01	-0.1207
6256	RXRA	HTA11_83_2000001011	Human	Colorectum	SER	2.34e-02	3.09e-01	-0.1526
6256	RXRA	HTA11_696_2000001011	Human	Colorectum	AD	1.32e-02	3.34e-01	-0.1464
6256	RXRA	HTA11_1391_2000001011	Human	Colorectum	AD	2.51e-08	3.74e-01	-0.059
6256	RXRA	HTA11_5212_2000001011	Human	Colorectum	AD	4.50e-06	4.95e-01	-0.2061
6256	RXRA	HTA11_546_2000001011	Human	Colorectum	AD	2.99e-03	2.65e-01	-0.0842
6256	RXRA	HTA11_866_3004761011	Human	Colorectum	AD	3.71e-02	1.40e-01	0.096
6256	RXRA	HTA11_9408_2000001011	Human	Colorectum	AD	2.37e-02	4.51e-01	0.0451
6256	RXRA	HTA11_10623_2000001011	Human	Colorectum	AD	1.34e-04	4.18e-01	-0.0177
6256	RXRA	HTA11_10711_2000001011	Human	Colorectum	AD	1.21e-02	1.90e-01	0.0338
6256	RXRA	HTA11_7696_3000711011	Human	Colorectum	AD	6.64e-04	3.37e-01	0.0674
6256	RXRA	HTA11_6818_2000001011	Human	Colorectum	AD	6.21e-04	4.31e-01	0.0112
6256	RXRA	HTA11_7469_2000001011	Human	Colorectum	AD	2.00e-03	4.82e-01	-0.0124
6256	RXRA	HTA11_6818_2000001021	Human	Colorectum	AD	1.00e-02	1.65e-01	0.0588
6256	RXRA	HTA11_99999971662_82457	Human	Colorectum	MSS	6.73e-05	4.03e-01	0.3859

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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:0016032	Colorectum	AD	viral process	168/3918	415/18723	4.67e-20	3.66e-17	168
GO:0044403	Colorectum	AD	biological process involved in symbiotic interaction	99/3918	290/18723	1.02e-07	4.93e-06	99
GO:0051701	Colorectum	AD	biological process involved in interaction with host	73/3918	203/18723	5.08e-07	1.88e-05	73
GO:0071383	Colorectum	AD	cellular response to steroid hormone stimulus	73/3918	204/18723	6.31e-07	2.24e-05	73
GO:0030522	Colorectum	AD	intracellular receptor signaling pathway	87/3918	265/18723	3.69e-06	1.03e-04	87
GO:0043401	Colorectum	AD	steroid hormone mediated signaling pathway	51/3918	136/18723	6.52e-06	1.63e-04	51
GO:0048545	Colorectum	AD	response to steroid hormone	104/3918	339/18723	1.33e-05	2.90e-04	104
GO:0009755	Colorectum	AD	hormone-mediated signaling pathway	64/3918	190/18723	2.78e-05	5.24e-04	64
GO:0006066	Colorectum	AD	alcohol metabolic process	106/3918	353/18723	3.02e-05	5.57e-04	106
GO:0010876	Colorectum	AD	lipid localization	120/3918	448/18723	1.59e-03	1.33e-02	120
GO:0006869	Colorectum	AD	lipid transport	108/3918	398/18723	1.67e-03	1.39e-02	108
GO:0019048	Colorectum	AD	modulation by virus of host process	7/3918	11/18723	2.59e-03	1.96e-02	7
GO:0035821	Colorectum	AD	modulation of process of other organism	34/3918	106/18723	4.73e-03	3.22e-02	34
GO:0032411	Colorectum	AD	positive regulation of transporter activity	37/3918	120/18723	6.82e-03	4.22e-02	37
GO:0008202	Colorectum	AD	steroid metabolic process	85/3918	319/18723	8.07e-03	4.75e-02	85
GO:00160321	Colorectum	SER	viral process	118/2897	415/18723	8.36e-12	1.65e-09	118
GO:00517011	Colorectum	SER	biological process involved in interaction with host	55/2897	203/18723	1.42e-05	4.38e-04	55
GO:00713831	Colorectum	SER	cellular response to steroid hormone stimulus	55/2897	204/18723	1.66e-05	5.05e-04	55
GO:00444031	Colorectum	SER	biological process involved in symbiotic interaction	72/2897	290/18723	2.08e-05	6.02e-04	72
GO:00485451	Colorectum	SER	response to steroid hormone	80/2897	339/18723	5.15e-05	1.25e-03	80

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04932	Colorectum	AD	Non-alcoholic fatty liver disease	90/2092	155/8465	4.83e-19	1.80e-17	1.15e-17	90
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa05216	Colorectum	AD	Thyroid cancer	21/2092	37/8465	3.05e-05	2.76e-04	1.76e-04	21
hsa05417	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73
hsa05160	Colorectum	AD	Hepatitis C	54/2092	157/8465	3.87e-03	1.96e-02	1.25e-02	54
hsa04928	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38
hsa049321	Colorectum	AD	Non-alcoholic fatty liver disease	90/2092	155/8465	4.83e-19	1.80e-17	1.15e-17	90
hsa049191	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa052161	Colorectum	AD	Thyroid cancer	21/2092	37/8465	3.05e-05	2.76e-04	1.76e-04	21
hsa054171	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73
hsa051601	Colorectum	AD	Hepatitis C	54/2092	157/8465	3.87e-03	1.96e-02	1.25e-02	54
hsa049281	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38
hsa049322	Colorectum	SER	Non-alcoholic fatty liver disease	75/1580	155/8465	2.16e-17	5.99e-16	4.35e-16	75
hsa049192	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa049282	Colorectum	SER	Parathyroid hormone synthesis, secretion and action	31/1580	106/8465	5.20e-03	3.28e-02	2.38e-02	31
hsa054172	Colorectum	SER	Lipid and atherosclerosis	55/1580	215/8465	6.83e-03	3.77e-02	2.74e-02	55
hsa049323	Colorectum	SER	Non-alcoholic fatty liver disease	75/1580	155/8465	2.16e-17	5.99e-16	4.35e-16	75
hsa049193	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa049283	Colorectum	SER	Parathyroid hormone synthesis, secretion and action	31/1580	106/8465	5.20e-03	3.28e-02	2.38e-02	31
hsa054173	Colorectum	SER	Lipid and atherosclerosis	55/1580	215/8465	6.83e-03	3.77e-02	2.74e-02	55

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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
RXRA	MON	Colorectum	AD	SYT1,MKNK1,RAC1, etc.	8.10e-02
RXRA	HEP	Liver	HCC	TM9SF4,MPC1,ZMYND8, etc.	8.11e-01
RXRA	SPI	Oral cavity	Healthy	DUS1L,ZBED1,NCOA1, etc.	3.02e-01
RXRA	LC	Skin	ADJ	TACSTD2,FCGBP,PLEK2, etc.	2.90e-01
RXRA	LC	Skin	cSCC	TACSTD2,FCGBP,PLEK2, etc.	2.41e-01
RXRA	DPC	Skin	SCCIS	FAM213A,SIK1,AQP3, etc.	1.52e-01
RXRA	GMC	Stomach	Healthy	MUC6,AGO1,INSIG1, etc.	2.29e-01
RXRA	STM	Thyroid	goiters	LAG3,SOX13,ABCF2, etc.	6.93e-01
RXRA	INMON	Thyroid	goiters	HLA-DQB2,ASGR2,ZNF683, etc.	4.38e-02
RXRA	INMON	Thyroid	PTC	HLA-DQB2,ASGR2,ZNF683, etc.	6.76e-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

RXRA

SNV

Missense_Mutation

rs777558913

c.692C>T

p.Pro231Leu

p.P231L

P19793

protein_coding

deleterious(0)

probably_damaging(0.937)

TCGA-A2-A1G4-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

adriamycin

RXRA

SNV

Missense_Mutation

novel

c.1027G>T

p.Gly343Cys

p.G343C

P19793

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C8-A26Y-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

RXRA

SNV

Missense_Mutation

c.635N>T

p.Gly212Val

p.G212V

P19793

protein_coding

tolerated(0.15)

benign(0.036)

TCGA-OL-A66N-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

RXRA

deletion

Frame_Shift_Del

novel

c.167delN

p.Ile58SerfsTer41

p.I58Sfs*41

P19793

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

RXRA

insertion

Frame_Shift_Ins

novel

c.1316_1317insA

p.Phe439LeufsTer10

p.F439Lfs*10

P19793

protein_coding

TCGA-E2-A576-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

RXRA

deletion

Frame_Shift_Del

novel

c.154delA

p.Ser52AlafsTer3

p.S52Afs*3

P19793

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

RXRA

SNV

Missense_Mutation

novel

c.1362N>A

p.Met454Ile

p.M454I

P19793

protein_coding

deleterious(0.02)

possibly_damaging(0.502)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

RXRA

SNV

Missense_Mutation

c.490N>T

p.Arg164Cys

p.R164C

P19793

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-EK-A2RA-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

RXRA

SNV

Missense_Mutation

novel

c.600N>A

p.Met200Ile

p.M200I

P19793

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-VS-A8EL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

RXRA

SNV

Missense_Mutation

novel

c.632N>A

p.Arg211His

p.R211H

P19793

protein_coding

deleterious(0)

probably_damaging(0.932)

TCGA-5M-AAT6-01

Colorectum

colon adenocarcinoma

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
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		ALITRETINOIN	ALITRETINOIN
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		2-PHENYLPHENOL	2-PHENYLPHENOL
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		DOCONEXENT	DOCONEXENT	20695472
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR	antagonist	135650518
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		DOXORUBICIN HYDROCHLORIDE	DOXORUBICIN HYDROCHLORIDE
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		Alitretinoin	ALITRETINOIN
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		MESOTRIONE	MESOTRIONE
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		DIBUTYLDICHLOROSTANNANE	DIBUTYLDICHLOROSTANNANE
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		DACTINOMYCIN	DACTINOMYCIN
6256	RXRA	NUCLEAR HORMONE RECEPTOR, TRANSCRIPTION FACTOR COMPLEX, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR		CHLORFENAPYR	CHLORFENAPYR

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