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: TSC2

Gene summary for TSC2

Gene summary.

Gene information	Species	Human
	Gene symbol	TSC2
	Gene ID	7249
	Gene name	TSC complex subunit 2
	Gene Alias	LAM
	Cytomap	16p13.3
	Gene Type	protein-coding
	GO ID	GO:0000422
	UniProtAcc	P49815

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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
7249	TSC2	HTA11_2487_2000001011	Human	Colorectum	SER	3.22e-04	3.89e-01	-0.1808
7249	TSC2	HTA11_2951_2000001011	Human	Colorectum	AD	2.15e-02	5.45e-01	0.0216
7249	TSC2	HTA11_1938_2000001011	Human	Colorectum	AD	2.78e-08	5.31e-01	-0.0811
7249	TSC2	HTA11_78_2000001011	Human	Colorectum	AD	4.27e-02	2.95e-01	-0.1088
7249	TSC2	HTA11_347_2000001011	Human	Colorectum	AD	1.47e-14	4.67e-01	-0.1954
7249	TSC2	HTA11_3361_2000001011	Human	Colorectum	AD	6.02e-07	4.47e-01	-0.1207
7249	TSC2	HTA11_83_2000001011	Human	Colorectum	SER	7.62e-04	4.44e-01	-0.1526
7249	TSC2	HTA11_696_2000001011	Human	Colorectum	AD	3.16e-16	5.84e-01	-0.1464
7249	TSC2	HTA11_866_2000001011	Human	Colorectum	AD	6.11e-08	4.20e-01	-0.1001
7249	TSC2	HTA11_1391_2000001011	Human	Colorectum	AD	2.94e-04	3.36e-01	-0.059
7249	TSC2	HTA11_546_2000001011	Human	Colorectum	AD	8.29e-05	4.50e-01	-0.0842
7249	TSC2	HTA11_866_3004761011	Human	Colorectum	AD	1.09e-08	4.20e-01	0.096
7249	TSC2	HTA11_10711_2000001011	Human	Colorectum	AD	6.30e-08	5.13e-01	0.0338
7249	TSC2	HTA11_7696_3000711011	Human	Colorectum	AD	1.92e-12	4.93e-01	0.0674
7249	TSC2	HTA11_6818_2000001011	Human	Colorectum	AD	2.53e-02	4.43e-01	0.0112
7249	TSC2	HTA11_6818_2000001021	Human	Colorectum	AD	3.06e-02	3.43e-01	0.0588
7249	TSC2	HTA11_99999965062_69753	Human	Colorectum	MSI-H	2.84e-03	9.05e-01	0.3487
7249	TSC2	HTA11_99999965104_69814	Human	Colorectum	MSS	1.15e-04	3.48e-01	0.281
7249	TSC2	HTA11_99999971662_82457	Human	Colorectum	MSS	2.86e-06	4.01e-01	0.3859
7249	TSC2	A015-C-104	Human	Colorectum	FAP	3.31e-03	1.12e-01	-0.1899

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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
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:0001776	Oral cavity	OSCC	leukocyte homeostasis	48/7305	87/18723	1.60e-03	7.62e-03	48
GO:00466263	Oral cavity	OSCC	regulation of insulin receptor signaling pathway	38/7305	66/18723	1.70e-03	8.07e-03	38
GO:19000763	Oral cavity	OSCC	regulation of cellular response to insulin stimulus	37/7305	64/18723	1.76e-03	8.31e-03	37
GO:00004238	Oral cavity	OSCC	mitophagy	19/7305	28/18723	1.88e-03	8.84e-03	19
GO:00219158	Oral cavity	OSCC	neural tube development	77/7305	152/18723	2.26e-03	1.00e-02	77
GO:00434916	Oral cavity	OSCC	protein kinase B signaling	103/7305	211/18723	2.29e-03	1.02e-02	103
GO:0070227	Oral cavity	OSCC	lymphocyte apoptotic process	40/7305	72/18723	3.21e-03	1.38e-02	40
GO:20001061	Oral cavity	OSCC	regulation of leukocyte apoptotic process	44/7305	81/18723	3.66e-03	1.51e-02	44
GO:00605629	Oral cavity	OSCC	epithelial tube morphogenesis	149/7305	325/18723	6.73e-03	2.50e-02	149
GO:00518967	Oral cavity	OSCC	regulation of protein kinase B signaling	88/7305	185/18723	1.07e-02	3.64e-02	88
GO:007259419	Oral cavity	LP	establishment of protein localization to organelle	205/4623	422/18723	6.76e-27	3.85e-24	205
GO:001623615	Oral cavity	LP	macroautophagy	135/4623	291/18723	4.71e-16	6.70e-14	135
GO:003450416	Oral cavity	LP	protein localization to nucleus	133/4623	290/18723	2.41e-15	3.35e-13	133
GO:000691318	Oral cavity	LP	nucleocytoplasmic transport	130/4623	301/18723	1.19e-12	9.77e-11	130
GO:005116918	Oral cavity	LP	nuclear transport	130/4623	301/18723	1.19e-12	9.77e-11	130
GO:0022411110	Oral cavity	LP	cellular component disassembly	173/4623	443/18723	9.97e-12	7.44e-10	173
GO:001703816	Oral cavity	LP	protein import	95/4623	206/18723	1.55e-11	1.13e-09	95
GO:001050615	Oral cavity	LP	regulation of autophagy	132/4623	317/18723	1.82e-11	1.28e-09	132
GO:0009896110	Oral cavity	LP	positive regulation of catabolic process	187/4623	492/18723	2.30e-11	1.58e-09	187
GO:190300815	Oral cavity	LP	organelle disassembly	60/4623	114/18723	1.28e-10	7.30e-09	60

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04714	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa04152	Colorectum	AD	AMPK signaling pathway	47/2092	121/8465	3.74e-04	2.82e-03	1.80e-03	47
hsa05163	Colorectum	AD	Human cytomegalovirus infection	75/2092	225/8465	2.00e-03	1.10e-02	7.01e-03	75
hsa04140	Colorectum	AD	Autophagy - animal	49/2092	141/8465	4.58e-03	2.20e-02	1.40e-02	49
hsa04218	Colorectum	AD	Cellular senescence	53/2092	156/8465	5.55e-03	2.48e-02	1.58e-02	53
hsa04211	Colorectum	AD	Longevity regulating pathway	33/2092	89/8465	6.15e-03	2.68e-02	1.71e-02	33
hsa047141	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa049191	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa041521	Colorectum	AD	AMPK signaling pathway	47/2092	121/8465	3.74e-04	2.82e-03	1.80e-03	47
hsa051631	Colorectum	AD	Human cytomegalovirus infection	75/2092	225/8465	2.00e-03	1.10e-02	7.01e-03	75
hsa041401	Colorectum	AD	Autophagy - animal	49/2092	141/8465	4.58e-03	2.20e-02	1.40e-02	49
hsa042181	Colorectum	AD	Cellular senescence	53/2092	156/8465	5.55e-03	2.48e-02	1.58e-02	53
hsa042111	Colorectum	AD	Longevity regulating pathway	33/2092	89/8465	6.15e-03	2.68e-02	1.71e-02	33
hsa047142	Colorectum	SER	Thermogenesis	106/1580	232/8465	1.15e-21	6.34e-20	4.61e-20	106
hsa049192	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa041402	Colorectum	SER	Autophagy - animal	39/1580	141/8465	5.43e-03	3.28e-02	2.38e-02	39
hsa051632	Colorectum	SER	Human cytomegalovirus infection	57/1580	225/8465	7.40e-03	3.84e-02	2.79e-02	57
hsa047143	Colorectum	SER	Thermogenesis	106/1580	232/8465	1.15e-21	6.34e-20	4.61e-20	106
hsa049193	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40

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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

TSC2

SNV

Missense_Mutation

c.2106N>A

p.Asp702Glu

p.D702E

P49815

protein_coding

deleterious(0.01)

probably_damaging(0.992)

TCGA-A1-A0SO-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

TSC2

SNV

Missense_Mutation

c.4571N>T

p.Ser1524Leu

p.S1524L

P49815

protein_coding

tolerated(0.14)

benign(0)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TSC2

SNV

Missense_Mutation

c.2828N>A

p.Arg943Lys

p.R943K

P49815

protein_coding

tolerated(0.09)

possibly_damaging(0.867)

TCGA-AC-A2B8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

chemo

TSC2

SNV

Missense_Mutation

c.4346C>G

p.Ser1449Cys

p.S1449C

P49815

protein_coding

tolerated(0.12)

probably_damaging(0.987)

TCGA-B6-A0RQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TSC2

SNV

Missense_Mutation

c.1702N>G

p.Leu568Val

p.L568V

P49815

protein_coding

tolerated(0.17)

probably_damaging(0.987)

TCGA-C8-A1HM-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

TSC2

SNV

Missense_Mutation

c.1273N>T

p.Asn425Tyr

p.N425Y

P49815

protein_coding

deleterious(0.03)

probably_damaging(0.998)

TCGA-D8-A147-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

TSC2

SNV

Missense_Mutation

c.539N>C

p.Leu180Pro

p.L180P

P49815

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-E9-A1RB-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

methotrexate

TSC2

insertion

Frame_Shift_Ins

novel

c.2666_2667insATTGAAGAAATTAGACAAATTCAGGGAA

p.His890LeufsTer34

p.H890Lfs*34

P49815

protein_coding

TCGA-B6-A0I5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

TSC2

deletion

Frame_Shift_Del

novel

c.3113delT

p.Phe1038SerfsTer15

p.F1038Sfs*15

P49815

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

TSC2

SNV

Missense_Mutation

rs764925296

c.629C>T

p.Ala210Val

p.A210V

P49815

protein_coding

tolerated(0.46)

benign(0.003)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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
7249	TSC2	CLINICALLY ACTIONABLE, KINASE, TUMOR SUPPRESSOR		EVEROLIMUS	EVEROLIMUS	23158522,25295501
7249	TSC2	CLINICALLY ACTIONABLE, KINASE, TUMOR SUPPRESSOR		Everolimus	EVEROLIMUS
7249	TSC2	CLINICALLY ACTIONABLE, KINASE, TUMOR SUPPRESSOR		MTOR INHIBITOR		26831717

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