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:0044270	Colorectum	AD	cellular nitrogen compound catabolic process	147/3918	451/18723	3.35e-09	2.23e-07	147
GO:0046700	Colorectum	AD	heterocycle catabolic process	145/3918	445/18723	4.37e-09	2.84e-07	145
GO:0019439	Colorectum	AD	aromatic compound catabolic process	146/3918	467/18723	7.48e-08	3.84e-06	146
GO:1901361	Colorectum	AD	organic cyclic compound catabolic process	153/3918	495/18723	8.23e-08	4.18e-06	153
GO:0030099	Colorectum	AD	myeloid cell differentiation	119/3918	381/18723	1.24e-06	4.01e-05	119
GO:0006486	Colorectum	AD	protein glycosylation	64/3918	226/18723	4.86e-03	3.27e-02	64
GO:0043413	Colorectum	AD	macromolecule glycosylation	64/3918	226/18723	4.86e-03	3.27e-02	64
GO:0070085	Colorectum	AD	glycosylation	67/3918	240/18723	5.78e-03	3.67e-02	67
GO:00442701	Colorectum	SER	cellular nitrogen compound catabolic process	99/2897	451/18723	1.46e-04	2.86e-03	99
GO:00467001	Colorectum	SER	heterocycle catabolic process	97/2897	445/18723	2.20e-04	3.89e-03	97
GO:19013611	Colorectum	SER	organic cyclic compound catabolic process	104/2897	495/18723	5.46e-04	7.63e-03	104
GO:00194391	Colorectum	SER	aromatic compound catabolic process	98/2897	467/18723	8.09e-04	1.01e-02	98
GO:00300991	Colorectum	SER	myeloid cell differentiation	80/2897	381/18723	2.28e-03	2.18e-02	80
GO:00442702	Colorectum	MSS	cellular nitrogen compound catabolic process	141/3467	451/18723	2.95e-11	3.83e-09	141
GO:00467002	Colorectum	MSS	heterocycle catabolic process	139/3467	445/18723	4.37e-11	5.05e-09	139
GO:19013612	Colorectum	MSS	organic cyclic compound catabolic process	148/3467	495/18723	3.47e-10	3.18e-08	148
GO:00194392	Colorectum	MSS	aromatic compound catabolic process	140/3467	467/18723	8.56e-10	6.85e-08	140
GO:00300992	Colorectum	MSS	myeloid cell differentiation	110/3467	381/18723	4.48e-07	1.75e-05	110
GO:0016570	Colorectum	MSS	histone modification	113/3467	463/18723	8.37e-04	8.68e-03	113
GO:00442704	Colorectum	FAP	cellular nitrogen compound catabolic process	101/2622	451/18723	7.42e-07	3.44e-05	101

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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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