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: THRA

Gene summary for THRA

Gene summary.

Gene information	Species	Human
	Gene symbol	THRA
	Gene ID	7067
	Gene name	thyroid hormone receptor alpha
	Gene Alias	AR7
	Cytomap	17q21.1
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P10827

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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
7067	THRA	HTA11_2951_2000001011	Human	Colorectum	AD	6.08e-03	4.62e-01	0.0216
7067	THRA	HTA11_78_2000001011	Human	Colorectum	AD	2.12e-02	2.68e-01	-0.1088
7067	THRA	HTA11_347_2000001011	Human	Colorectum	AD	5.52e-07	3.18e-01	-0.1954
7067	THRA	HTA11_83_2000001011	Human	Colorectum	SER	3.46e-02	2.51e-01	-0.1526
7067	THRA	HTA11_696_2000001011	Human	Colorectum	AD	2.93e-09	4.15e-01	-0.1464
7067	THRA	HTA11_866_2000001011	Human	Colorectum	AD	2.01e-07	3.33e-01	-0.1001
7067	THRA	HTA11_1391_2000001011	Human	Colorectum	AD	6.44e-09	4.80e-01	-0.059
7067	THRA	HTA11_866_3004761011	Human	Colorectum	AD	6.43e-13	5.53e-01	0.096
7067	THRA	HTA11_10711_2000001011	Human	Colorectum	AD	1.47e-05	5.38e-01	0.0338
7067	THRA	HTA11_7696_3000711011	Human	Colorectum	AD	6.40e-16	4.83e-01	0.0674
7067	THRA	HTA11_6818_2000001021	Human	Colorectum	AD	9.17e-03	4.07e-01	0.0588
7067	THRA	HTA11_99999970781_79442	Human	Colorectum	MSS	8.05e-04	2.46e-01	0.294
7067	THRA	HTA11_99999965104_69814	Human	Colorectum	MSS	5.21e-03	4.79e-01	0.281
7067	THRA	HTA11_99999971662_82457	Human	Colorectum	MSS	1.07e-23	7.27e-01	0.3859
7067	THRA	HTA11_99999973899_84307	Human	Colorectum	MSS	5.07e-10	7.30e-01	0.2585
7067	THRA	HTA11_99999974143_84620	Human	Colorectum	MSS	5.07e-32	9.13e-01	0.3005
7067	THRA	LZE24T	Human	Esophagus	ESCC	2.69e-12	3.35e-01	0.0596
7067	THRA	P1T-E	Human	Esophagus	ESCC	1.37e-16	5.35e-01	0.0875
7067	THRA	P2T-E	Human	Esophagus	ESCC	4.54e-21	4.22e-01	0.1177
7067	THRA	P4T-E	Human	Esophagus	ESCC	1.71e-09	1.85e-01	0.1323

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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

∗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:004802616	Oral cavity	LP	positive regulation of mRNA splicing, via spliceosome	14/4623	22/18723	1.23e-04	1.44e-03	14
GO:006101317	Oral cavity	LP	regulation of mRNA catabolic process	62/4623	166/18723	1.87e-04	2.06e-03	62
GO:004348717	Oral cavity	LP	regulation of RNA stability	62/4623	170/18723	3.94e-04	3.82e-03	62
GO:000038117	Oral cavity	LP	regulation of alternative mRNA splicing, via spliceosome	27/4623	60/18723	4.71e-04	4.43e-03	27
GO:004348817	Oral cavity	LP	regulation of mRNA stability	58/4623	158/18723	4.93e-04	4.62e-03	58
GO:190236914	Oral cavity	LP	negative regulation of RNA catabolic process	29/4623	75/18723	5.06e-03	3.15e-02	29
GO:190331124	Oral cavity	EOLP	regulation of mRNA metabolic process	102/2218	288/18723	8.13e-26	2.44e-22	102
GO:004348426	Oral cavity	EOLP	regulation of RNA splicing	59/2218	148/18723	2.64e-18	5.27e-15	59
GO:000838025	Oral cavity	EOLP	RNA splicing	115/2218	434/18723	2.24e-17	3.04e-14	115
GO:005068424	Oral cavity	EOLP	regulation of mRNA processing	55/2218	137/18723	2.54e-17	3.04e-14	55
GO:000640224	Oral cavity	EOLP	mRNA catabolic process	74/2218	232/18723	3.36e-16	2.51e-13	74
GO:004802425	Oral cavity	EOLP	regulation of mRNA splicing, via spliceosome	42/2218	101/18723	3.41e-14	1.28e-11	42
GO:006101323	Oral cavity	EOLP	regulation of mRNA catabolic process	55/2218	166/18723	3.70e-13	1.11e-10	55
GO:000640124	Oral cavity	EOLP	RNA catabolic process	77/2218	278/18723	3.92e-13	1.12e-10	77
GO:004348823	Oral cavity	EOLP	regulation of mRNA stability	50/2218	158/18723	2.91e-11	4.15e-09	50
GO:000037725	Oral cavity	EOLP	RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	80/2218	320/18723	4.20e-11	5.60e-09	80
GO:000039825	Oral cavity	EOLP	mRNA splicing, via spliceosome	80/2218	320/18723	4.20e-11	5.60e-09	80
GO:000037525	Oral cavity	EOLP	RNA splicing, via transesterification reactions	80/2218	324/18723	8.11e-11	9.53e-09	80
GO:004348723	Oral cavity	EOLP	regulation of RNA stability	51/2218	170/18723	1.63e-10	1.68e-08	51
GO:190331323	Oral cavity	EOLP	positive regulation of mRNA metabolic process	40/2218	118/18723	2.69e-10	2.45e-08	40

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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
hsa0491928	Esophagus	ESCC	Thyroid hormone signaling pathway	78/4205	121/8465	6.79e-04	2.23e-03	1.14e-03	78
hsa04919113	Esophagus	ESCC	Thyroid hormone signaling pathway	78/4205	121/8465	6.79e-04	2.23e-03	1.14e-03	78
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

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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
THRA	CD8TEXINT	Colorectum	ADJ	SEMA3C,AGPAT4,NCEH1, etc.	1.08e-01
THRA	INCAF	Colorectum	CRC	RABL2B,NDUFAF6,PIGN, etc.	4.72e-01
THRA	ICAF	Colorectum	MSS	RABL2B,NDUFAF6,PIGN, etc.	5.18e-01
THRA	M1MAC	Endometrium	Healthy	USF1,ZNF483,AL356234.2, etc.	4.31e-01
THRA	SMC	Endometrium	ADJ	GUCY1A3,BRSK2,AC097724.3, etc.	2.73e-01
THRA	SMC	Endometrium	AEH	GUCY1A3,BRSK2,AC097724.3, etc.	1.94e-01
THRA	PERI	Liver	Cirrhotic	BAMBI,C2orf40,C15orf39, etc.	1.40e-01
THRA	SMC	Liver	Cirrhotic	BAMBI,C2orf40,C15orf39, etc.	1.58e-01
THRA	SMC	Liver	HCC	BAMBI,C2orf40,C15orf39, etc.	3.49e-01
THRA	CD8TEREX	Lung	MIAC	PLPP3,ZNF683,TRAF3IP2-AS1, etc.	4.57e-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

THRA

SNV

Missense_Mutation

novel

c.1007N>G

p.Asp336Gly

p.D336G

P10827

protein_coding

tolerated(0.13)

benign(0.133)

TCGA-A8-A07U-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

THRA

SNV

Missense_Mutation

novel

c.612N>T

p.Met204Ile

p.M204I

P10827

protein_coding

tolerated(0.23)

benign(0.155)

TCGA-AC-A6IW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

THRA

SNV

Missense_Mutation

c.32N>T

p.Gly11Val

p.G11V

P10827

protein_coding

deleterious_low_confidence(0.01)

benign(0.08)

TCGA-E2-A14V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

THRA

insertion

In_Frame_Ins

novel

c.878_879insAAGGTCTGGCTGCTCTAAGAAATCAGC

p.Gly293_Val294insArgSerGlyCysSerLysLysSerAla

p.G293_V294insRSGCSKKSA

P10827

protein_coding

TCGA-AN-A04A-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

THRA

SNV

Missense_Mutation

c.1175N>T

p.Ser392Leu

p.S392L

P10827

protein_coding

deleterious_low_confidence(0)

benign(0.039)

TCGA-EK-A2H0-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

THRA

SNV

Missense_Mutation

c.1175N>T

p.Ser392Leu

p.S392L

P10827

protein_coding

deleterious_low_confidence(0)

benign(0.039)

TCGA-ZJ-A8QQ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

THRA

SNV

Missense_Mutation

c.871G>A

p.Gly291Ser

p.G291S

P10827

protein_coding

deleterious(0.04)

probably_damaging(0.964)

TCGA-AA-3821-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

THRA

SNV

Missense_Mutation

c.854A>G

p.Glu285Gly

p.E285G

P10827

protein_coding

tolerated(0.23)

benign(0.012)

TCGA-AA-A010-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Chemotherapy

folinic

THRA

SNV

Missense_Mutation

c.473N>A

p.Pro158Gln

p.P158Q

P10827

protein_coding

deleterious(0.02)

benign(0.077)

TCGA-DM-A1DA-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

THRA

SNV

Missense_Mutation

c.709N>T

p.Pro237Ser

p.P237S

P10827

protein_coding

deleterious(0.01)

possibly_damaging(0.85)

TCGA-WS-AB45-01

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
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		LEVOTHYROXINE	LEVOTHYROXINE
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR	agonist	135651405	TIRATRICOL
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR	agonist	135651574	LEVOTHYROXINE SODIUM
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		Dextrothyroxine Sodium
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR	agonist	178103533	DEXTROTHYROXINE
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR	agonist	135651573	LIOTHYRONINE SODIUM
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR	agonist	CHEMBL1544	LIOTHYRONINE
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		tiratricol	TIRATRICOL
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR		TRIIODOTHYRONINE (T3)
7067	THRA	DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR	antagonist	135650713

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