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	LN46	Human	Oral cavity	OSCC	1.79e-27	9.30e-01	0.1666
7249	TSC2	LP15	Human	Oral cavity	LP	1.28e-02	7.99e-01	0.2174
7249	TSC2	SYSMH2	Human	Oral cavity	OSCC	4.52e-06	1.80e-01	0.2326
7249	TSC2	SYSMH3	Human	Oral cavity	OSCC	2.28e-09	3.48e-01	0.2442
7249	TSC2	SYSMH5	Human	Oral cavity	OSCC	5.51e-03	1.92e-01	0.0647
7249	TSC2	SYSMH6	Human	Oral cavity	OSCC	7.79e-03	1.51e-01	0.1275
7249	TSC2	male-WTA	Human	Thyroid	PTC	7.27e-27	2.76e-01	0.1037
7249	TSC2	PTC01	Human	Thyroid	PTC	1.71e-13	3.32e-01	0.1899
7249	TSC2	PTC03	Human	Thyroid	PTC	1.75e-07	4.49e-01	0.1784
7249	TSC2	PTC04	Human	Thyroid	PTC	3.44e-20	4.45e-01	0.1927
7249	TSC2	PTC05	Human	Thyroid	PTC	1.07e-26	8.64e-01	0.2065
7249	TSC2	PTC06	Human	Thyroid	PTC	1.92e-39	8.03e-01	0.2057
7249	TSC2	PTC07	Human	Thyroid	PTC	2.92e-39	6.09e-01	0.2044
7249	TSC2	ATC09	Human	Thyroid	ATC	2.73e-14	4.76e-01	0.2871
7249	TSC2	ATC11	Human	Thyroid	ATC	7.04e-07	3.76e-01	0.3386
7249	TSC2	ATC12	Human	Thyroid	ATC	4.56e-32	5.76e-01	0.34
7249	TSC2	ATC13	Human	Thyroid	ATC	4.11e-32	5.23e-01	0.34
7249	TSC2	ATC1	Human	Thyroid	ATC	5.30e-14	4.67e-01	0.2878
7249	TSC2	ATC2	Human	Thyroid	ATC	8.80e-06	7.65e-01	0.34
7249	TSC2	ATC3	Human	Thyroid	ATC	9.55e-11	5.87e-01	0.338

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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:000268311	Breast	IDC	negative regulation of immune system process	55/1434	434/18723	1.53e-04	2.67e-03	55
GO:004887214	Breast	IDC	homeostasis of number of cells	36/1434	272/18723	9.10e-04	1.04e-02	36
GO:0070229	Breast	IDC	negative regulation of lymphocyte apoptotic process	7/1434	30/18723	6.48e-03	4.56e-02	7
GO:000268321	Breast	DCIS	negative regulation of immune system process	57/1390	434/18723	1.81e-05	4.35e-04	57
GO:004887224	Breast	DCIS	homeostasis of number of cells	36/1390	272/18723	5.17e-04	6.73e-03	36
GO:0009896	Colorectum	AD	positive regulation of catabolic process	180/3918	492/18723	4.33e-16	1.94e-13	180
GO:0031331	Colorectum	AD	positive regulation of cellular catabolic process	156/3918	427/18723	4.68e-14	1.05e-11	156
GO:0009895	Colorectum	AD	negative regulation of catabolic process	124/3918	320/18723	1.66e-13	3.35e-11	124
GO:0031330	Colorectum	AD	negative regulation of cellular catabolic process	104/3918	262/18723	2.66e-12	3.96e-10	104
GO:0072594	Colorectum	AD	establishment of protein localization to organelle	148/3918	422/18723	7.95e-12	1.04e-09	148
GO:0022411	Colorectum	AD	cellular component disassembly	147/3918	443/18723	8.53e-10	6.76e-08	147
GO:0010506	Colorectum	AD	regulation of autophagy	111/3918	317/18723	3.57e-09	2.35e-07	111
GO:0016236	Colorectum	AD	macroautophagy	103/3918	291/18723	6.76e-09	4.15e-07	103
GO:0006913	Colorectum	AD	nucleocytoplasmic transport	102/3918	301/18723	1.00e-07	4.85e-06	102
GO:0051169	Colorectum	AD	nuclear transport	102/3918	301/18723	1.00e-07	4.85e-06	102
GO:0010639	Colorectum	AD	negative regulation of organelle organization	114/3918	348/18723	1.41e-07	6.49e-06	114
GO:0032868	Colorectum	AD	response to insulin	91/3918	264/18723	2.02e-07	8.48e-06	91
GO:0010821	Colorectum	AD	regulation of mitochondrion organization	57/3918	144/18723	2.43e-07	9.92e-06	57
GO:1901653	Colorectum	AD	cellular response to peptide	114/3918	359/18723	8.32e-07	2.88e-05	114
GO:0032869	Colorectum	AD	cellular response to insulin stimulus	72/3918	203/18723	1.10e-06	3.68e-05	72

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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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