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: TET2

Gene summary for TET2

Gene summary.

Gene information	Species	Human
	Gene symbol	TET2
	Gene ID	54790
	Gene name	tet methylcytosine dioxygenase 2
	Gene Alias	IMD75
	Cytomap	4q24
	Gene Type	protein-coding
	GO ID	GO:0002376
	UniProtAcc	A0A158SIU0

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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
54790	TET2	HTA11_3410_2000001011	Human	Colorectum	AD	1.09e-22	-7.04e-01	0.0155
54790	TET2	HTA11_2487_2000001011	Human	Colorectum	SER	1.79e-04	-4.90e-01	-0.1808
54790	TET2	HTA11_2951_2000001011	Human	Colorectum	AD	1.32e-03	-7.70e-01	0.0216
54790	TET2	HTA11_78_2000001011	Human	Colorectum	AD	5.20e-04	-4.14e-01	-0.1088
54790	TET2	HTA11_3361_2000001011	Human	Colorectum	AD	9.78e-08	-6.24e-01	-0.1207
54790	TET2	HTA11_696_2000001011	Human	Colorectum	AD	1.07e-13	-5.40e-01	-0.1464
54790	TET2	HTA11_866_2000001011	Human	Colorectum	AD	1.35e-04	-4.16e-01	-0.1001
54790	TET2	HTA11_1391_2000001011	Human	Colorectum	AD	1.74e-07	-4.39e-01	-0.059
54790	TET2	HTA11_5212_2000001011	Human	Colorectum	AD	1.04e-02	-6.68e-01	-0.2061
54790	TET2	HTA11_7862_2000001011	Human	Colorectum	AD	1.74e-02	-5.33e-01	-0.0179
54790	TET2	HTA11_866_3004761011	Human	Colorectum	AD	7.23e-17	-6.49e-01	0.096
54790	TET2	HTA11_8622_2000001021	Human	Colorectum	SER	2.76e-04	-7.20e-01	0.0528
54790	TET2	HTA11_10711_2000001011	Human	Colorectum	AD	1.34e-09	-6.26e-01	0.0338
54790	TET2	HTA11_7696_3000711011	Human	Colorectum	AD	9.57e-16	-6.00e-01	0.0674
54790	TET2	HTA11_99999970781_79442	Human	Colorectum	MSS	1.67e-13	-4.65e-01	0.294
54790	TET2	HTA11_99999965104_69814	Human	Colorectum	MSS	2.03e-02	-4.39e-01	0.281
54790	TET2	HTA11_99999971662_82457	Human	Colorectum	MSS	5.01e-22	-6.62e-01	0.3859
54790	TET2	HTA11_99999973899_84307	Human	Colorectum	MSS	6.18e-10	-7.73e-01	0.2585
54790	TET2	HTA11_99999974143_84620	Human	Colorectum	MSS	4.55e-28	-7.33e-01	0.3005
54790	TET2	F007	Human	Colorectum	FAP	1.04e-02	-3.27e-01	0.1176

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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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
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:0008213	Colorectum	FAP	protein alkylation	39/2622	181/18723	3.60e-03	2.58e-02	39
GO:00194394	Colorectum	FAP	aromatic compound catabolic process	100/2622	467/18723	6.75e-06	2.08e-04	100
GO:19013614	Colorectum	FAP	organic cyclic compound catabolic process	101/2622	495/18723	4.87e-05	9.93e-04	101
GO:00300994	Colorectum	FAP	myeloid cell differentiation	81/2622	381/18723	6.33e-05	1.22e-03	81
GO:00165701	Colorectum	FAP	histone modification	94/2622	463/18723	1.06e-04	1.76e-03	94
GO:00064861	Colorectum	FAP	protein glycosylation	48/2622	226/18723	1.85e-03	1.57e-02	48
GO:00434131	Colorectum	FAP	macromolecule glycosylation	48/2622	226/18723	1.85e-03	1.57e-02	48
GO:00700851	Colorectum	FAP	glycosylation	50/2622	240/18723	2.30e-03	1.85e-02	50
GO:0009101	Colorectum	FAP	glycoprotein biosynthetic process	63/2622	317/18723	2.31e-03	1.86e-02	63
GO:0006479	Colorectum	FAP	protein methylation	39/2622	181/18723	3.60e-03	2.58e-02	39
GO:00300995	Colorectum	CRC	myeloid cell differentiation	66/2078	381/18723	1.59e-04	2.87e-03	66
GO:0044270	Colorectum	AD	cellular nitrogen compound catabolic process	147/3918	451/18723	3.35e-09	2.23e-07	147
GO:00165702	Colorectum	CRC	histone modification	75/2078	463/18723	4.95e-04	7.06e-03	75
GO:19013615	Colorectum	CRC	organic cyclic compound catabolic process	80/2078	495/18723	3.52e-04	5.34e-03	80
GO:00194395	Colorectum	CRC	aromatic compound catabolic process	77/2078	467/18723	2.42e-04	4.00e-03	77
GO:00442705	Colorectum	CRC	cellular nitrogen compound catabolic process	78/2078	451/18723	4.48e-05	1.07e-03	78
GO:0034968	Colorectum	FAP	histone lysine methylation	27/2622	115/18723	4.23e-03	2.90e-02	27
GO:0016571	Colorectum	FAP	histone methylation	31/2622	141/18723	6.47e-03	4.03e-02	31
GO:0046700	Colorectum	AD	heterocycle catabolic process	145/3918	445/18723	4.37e-09	2.84e-07	145
GO:00467005	Colorectum	CRC	heterocycle catabolic process	77/2078	445/18723	4.92e-05	1.14e-03	77

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

Cell Type

Tissue

Disease Stage

Target Gene

RSS

Regulon Activity

∗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

TET2

SNV

Missense_Mutation

rs116519313

c.5618T>C

p.Ile1873Thr

p.I1873T

Q6N021

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A0EQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

TET2

SNV

Missense_Mutation

novel

c.2253G>T

p.Lys751Asn

p.K751N

Q6N021

protein_coding

deleterious_low_confidence(0)

benign(0.299)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TET2

SNV

Missense_Mutation

c.4150N>C

p.Asp1384His

p.D1384H

Q6N021

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AR-A255-01

Breast

breast invasive carcinoma

Female

<65

I/II

Targeted Molecular therapy

trastuzumab

TET2

SNV

Missense_Mutation

c.2147C>T

p.Ser716Leu

p.S716L

Q6N021

protein_coding

deleterious(0)

possibly_damaging(0.469)

TCGA-AR-A2LE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

TET2

SNV

Missense_Mutation

c.1966N>T

p.Pro656Ser

p.P656S

Q6N021

protein_coding

tolerated(0.79)

benign(0.003)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

TET2

SNV

Missense_Mutation

c.4778G>A

p.Ser1593Asn

p.S1593N

Q6N021

protein_coding

tolerated(1)

benign(0.001)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TET2

SNV

Missense_Mutation

c.742N>G

p.His248Asp

p.H248D

Q6N021

protein_coding

deleterious(0)

possibly_damaging(0.795)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

TET2

SNV

Missense_Mutation

c.5081N>C

p.Leu1694Ser

p.L1694S

Q6N021

protein_coding

deleterious(0.02)

probably_damaging(0.977)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

TET2

SNV

Missense_Mutation

c.1276C>G

p.Leu426Val

p.L426V

Q6N021

protein_coding

deleterious_low_confidence(0)

possibly_damaging(0.647)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TET2

SNV

Missense_Mutation

novel

c.3952G>C

p.Glu1318Gln

p.E1318Q

Q6N021

protein_coding

deleterious(0.03)

probably_damaging(0.944)

TCGA-GM-A2DO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

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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
54790	TET2	CLINICALLY ACTIONABLE, ENZYME		Azacitidine	AZACITIDINE	25224413,21494260
54790	TET2	CLINICALLY ACTIONABLE, ENZYME		N/A		24507812,23099237,24994606,26769228,24524305,25224413,25412851,19666869
54790	TET2	CLINICALLY ACTIONABLE, ENZYME		hydrochlorothiazide	HYDROCHLOROTHIAZIDE
54790	TET2	CLINICALLY ACTIONABLE, ENZYME		Decitabine	DECITABINE	25224413

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