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: THRB

Gene summary for THRB

Gene summary.

Gene information	Species	Human
	Gene symbol	THRB
	Gene ID	7068
	Gene name	thyroid hormone receptor beta
	Gene Alias	C-ERBA-2
	Cytomap	3p24.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	F1D8N7

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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
7068	THRB	A008-E-015	Human	Colorectum	FAP	1.30e-10	5.15e-01	0.0177
7068	THRB	A014-C-008	Human	Colorectum	FAP	1.10e-10	-4.90e-01	-0.191
7068	THRB	A018-E-020	Human	Colorectum	FAP	3.77e-18	-5.24e-01	-0.2034
7068	THRB	F034	Human	Colorectum	FAP	2.59e-13	-4.81e-01	-0.0665
7068	THRB	F072B	Human	Colorectum	FAP	1.46e-04	-3.27e-01	0.257
7068	THRB	CRC-1-8810	Human	Colorectum	CRC	3.39e-11	-4.98e-01	0.6257
7068	THRB	CRC-3-11773	Human	Colorectum	CRC	3.73e-09	-4.50e-01	0.2564
7068	THRB	NAFLD1	Human	Liver	NAFLD	1.07e-12	1.33e+00	-0.04
7068	THRB	S41	Human	Liver	Cirrhotic	1.16e-02	6.31e-01	-0.0343
7068	THRB	S43	Human	Liver	Cirrhotic	1.22e-03	-2.94e-01	-0.0187
7068	THRB	HCC1_Meng	Human	Liver	HCC	5.06e-61	-2.95e-01	0.0246
7068	THRB	HCC2_Meng	Human	Liver	HCC	1.26e-21	-3.32e-01	0.0107
7068	THRB	cirrhotic1	Human	Liver	Cirrhotic	4.93e-09	-3.55e-01	0.0202
7068	THRB	cirrhotic2	Human	Liver	Cirrhotic	5.07e-09	-3.28e-01	0.0201
7068	THRB	cirrhotic3	Human	Liver	Cirrhotic	3.40e-04	-3.21e-01	0.0215
7068	THRB	HCC2	Human	Liver	HCC	4.38e-05	2.52e+00	0.5341
7068	THRB	Pt13.a	Human	Liver	HCC	2.25e-07	-3.59e-01	0.021
7068	THRB	Pt13.b	Human	Liver	HCC	4.79e-05	-3.39e-01	0.0251
7068	THRB	Pt14.a	Human	Liver	HCC	1.43e-04	-8.41e-02	0.0169
7068	THRB	Pt14.d	Human	Liver	HCC	2.38e-06	-2.37e-01	0.0143

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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
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
Prostate		BPH: Benign Prostatic Hyperplasia

∗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:0070997	Colorectum	AD	neuron death	114/3918	361/18723	1.13e-06	3.72e-05	114
GO:0030522	Colorectum	AD	intracellular receptor signaling pathway	87/3918	265/18723	3.69e-06	1.03e-04	87
GO:0009755	Colorectum	AD	hormone-mediated signaling pathway	64/3918	190/18723	2.78e-05	5.24e-04	64
GO:0051402	Colorectum	AD	neuron apoptotic process	77/3918	246/18723	8.07e-05	1.28e-03	77
GO:00709971	Colorectum	SER	neuron death	84/2897	361/18723	5.76e-05	1.35e-03	84
GO:00097551	Colorectum	SER	hormone-mediated signaling pathway	49/2897	190/18723	1.54e-04	3.00e-03	49
GO:00514021	Colorectum	SER	neuron apoptotic process	60/2897	246/18723	1.65e-04	3.13e-03	60
GO:00305221	Colorectum	SER	intracellular receptor signaling pathway	63/2897	265/18723	2.47e-04	4.20e-03	63
GO:00305222	Colorectum	MSS	intracellular receptor signaling pathway	84/3467	265/18723	1.47e-07	6.79e-06	84
GO:00097552	Colorectum	MSS	hormone-mediated signaling pathway	63/3467	190/18723	9.26e-07	3.23e-05	63
GO:00709972	Colorectum	MSS	neuron death	97/3467	361/18723	5.21e-05	9.31e-04	97
GO:00514022	Colorectum	MSS	neuron apoptotic process	66/3467	246/18723	7.94e-04	8.36e-03	66
GO:00305223	Colorectum	FAP	intracellular receptor signaling pathway	67/2622	265/18723	6.84e-07	3.28e-05	67
GO:00097554	Colorectum	FAP	hormone-mediated signaling pathway	51/2622	190/18723	2.23e-06	8.87e-05	51
GO:00709974	Colorectum	FAP	neuron death	81/2622	361/18723	8.35e-06	2.46e-04	81
GO:00514024	Colorectum	FAP	neuron apoptotic process	55/2622	246/18723	2.42e-04	3.37e-03	55
GO:0060428	Colorectum	FAP	lung epithelium development	12/2622	37/18723	3.43e-03	2.48e-02	12
GO:0030323	Colorectum	FAP	respiratory tube development	39/2622	181/18723	3.60e-03	2.58e-02	39
GO:0048593	Colorectum	FAP	camera-type eye morphogenesis	28/2622	120/18723	3.98e-03	2.76e-02	28
GO:0030324	Colorectum	FAP	lung development	38/2622	177/18723	4.28e-03	2.93e-02	38

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa049191	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa049192	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa049193	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa049194	Colorectum	MSS	Thyroid hormone signaling pathway	46/1875	121/8465	5.04e-05	4.97e-04	3.05e-04	46
hsa049195	Colorectum	MSS	Thyroid hormone signaling pathway	46/1875	121/8465	5.04e-05	4.97e-04	3.05e-04	46
hsa049198	Colorectum	FAP	Thyroid hormone signaling pathway	41/1404	121/8465	2.28e-06	4.28e-05	2.60e-05	41
hsa049199	Colorectum	FAP	Thyroid hormone signaling pathway	41/1404	121/8465	2.28e-06	4.28e-05	2.60e-05	41
hsa0491910	Colorectum	CRC	Thyroid hormone signaling pathway	35/1091	121/8465	2.05e-06	6.85e-05	4.64e-05	35
hsa0491911	Colorectum	CRC	Thyroid hormone signaling pathway	35/1091	121/8465	2.05e-06	6.85e-05	4.64e-05	35
hsa0491912	Liver	HCC	Thyroid hormone signaling pathway	75/4020	121/8465	8.76e-04	3.38e-03	1.88e-03	75
hsa0491913	Liver	HCC	Thyroid hormone signaling pathway	75/4020	121/8465	8.76e-04	3.38e-03	1.88e-03	75
hsa0491914	Lung	IAC	Thyroid hormone signaling pathway	27/1053	121/8465	1.61e-03	9.49e-03	6.30e-03	27
hsa0491915	Lung	IAC	Thyroid hormone signaling pathway	27/1053	121/8465	1.61e-03	9.49e-03	6.30e-03	27
hsa0491921	Lung	AIS	Thyroid hormone signaling pathway	27/961	121/8465	3.92e-04	3.85e-03	2.47e-03	27
hsa0491931	Lung	AIS	Thyroid hormone signaling pathway	27/961	121/8465	3.92e-04	3.85e-03	2.47e-03	27
hsa0491941	Lung	MIAC	Thyroid hormone signaling pathway	16/507	121/8465	2.23e-03	2.03e-02	1.47e-02	16
hsa0491951	Lung	MIAC	Thyroid hormone signaling pathway	16/507	121/8465	2.23e-03	2.03e-02	1.47e-02	16
hsa0491924	Prostate	BPH	Thyroid hormone signaling pathway	39/1718	121/8465	1.27e-03	5.58e-03	3.45e-03	39
hsa04919111	Prostate	BPH	Thyroid hormone signaling pathway	39/1718	121/8465	1.27e-03	5.58e-03	3.45e-03	39

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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
THRB	CD8TEREX	Colorectum	MSS	ZBTB16,FAM126A,LPGAT1, etc.	6.42e-02
THRB	BMEM	Colorectum	MSS	ZBTB16,FAM126A,LPGAT1, etc.	5.98e-02
THRB	LC	Lung	AAH	CPVL,C1orf54,CPNE3, etc.	2.29e-01
THRB	BN	Lung	AAH	CPVL,C1orf54,CPNE3, etc.	3.38e-02
THRB	cDC	Lung	AAH	CPVL,C1orf54,CPNE3, etc.	7.03e-02
THRB	pDC	Lung	MIAC	CHIT1,CALM3,FN1, etc.	7.57e-04
THRB	PLA	Lung	MIAC	CHIT1,CALM3,FN1, etc.	1.77e-02
THRB	cDC	Lung	MIAC	CHIT1,CALM3,FN1, etc.	4.19e-03
THRB	M2MAC	Lung	MIAC	CHIT1,CALM3,FN1, etc.	4.90e-01
THRB	INMON	Lung	MIAC	CHIT1,CALM3,FN1, etc.	2.23e-03

∗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

THRB

SNV

Missense_Mutation

c.1099N>A

p.Asp367Asn

p.D367N

P10828

protein_coding

deleterious(0)

benign(0.019)

TCGA-A8-A06X-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

THRB

SNV

Missense_Mutation

novel

c.1126N>A

p.Val376Ile

p.V376I

P10828

protein_coding

tolerated(1)

benign(0.045)

TCGA-A8-A08G-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

THRB

SNV

Missense_Mutation

c.104C>A

p.Ala35Asp

p.A35D

P10828

protein_coding

tolerated_low_confidence(0.54)

benign(0)

TCGA-E2-A1IE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

THRB

SNV

Missense_Mutation

novel

c.50N>A

p.Pro17Gln

p.P17Q

P10828

protein_coding

tolerated_low_confidence(0.24)

benign(0.099)

TCGA-E9-A1NA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

THRB

insertion

Frame_Shift_Ins

novel

c.994_995insATGTCACCCCTTGT

p.Gly332AspfsTer10

p.G332Dfs*10

P10828

protein_coding

TCGA-AQ-A04J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

THRB

SNV

Missense_Mutation

c.1147C>T

p.Arg383Cys

p.R383C

P10828

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

THRB

SNV

Missense_Mutation

rs556429294

c.137G>A

p.Arg46His

p.R46H

P10828

protein_coding

deleterious_low_confidence(0.03)

benign(0)

TCGA-5M-AAT6-01

Colorectum

colon adenocarcinoma

Female

<65

III/IV

Unknown

THRB

SNV

Missense_Mutation

c.497N>A

p.Phe166Tyr

p.F166Y

P10828

protein_coding

tolerated(0.16)

benign(0.156)

TCGA-AA-3692-01

Colorectum

colon adenocarcinoma

Female

<65

III/IV

Chemotherapy

folinic

THRB

SNV

Missense_Mutation

c.97N>C

p.Ser33Pro

p.S33P

P10828

protein_coding

deleterious_low_confidence(0)

benign(0.044)

TCGA-AA-A00N-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

THRB

SNV

Missense_Mutation

c.1348C>A

p.Leu450Ile

p.L450I

P10828

protein_coding

tolerated(0.22)

probably_damaging(0.947)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

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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
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		LEVOTHYROXINE	LEVOTHYROXINE
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		VK-2809
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		BENZO[D]ISOTHIAZOL-3-ONE	CHEMBL297304
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		(+)-THALIPORPHINE	CHEMBL1397308
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		ROSE BENGAL	ROSE BENGAL
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		GNF-PF-321	CHEMBL581044
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		3-METHYLCHOLANTHRENE	3-METHYLCHOLANTHRENE
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		PROTOPORPHYRIN	PROTOPORPHYRIN
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		ERYTHROSINE	ERYTHROSINE
7068	THRB	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		AMMONIA SOLUTION, STRONG	AMMONIA SOLUTION, STRONG	22324546

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