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: NOTCH2

Gene summary for NOTCH2

Gene summary.

Gene information	Species	Human
	Gene symbol	NOTCH2
	Gene ID	4853
	Gene name	notch receptor 2
	Gene Alias	AGS2
	Cytomap	1p12
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	Q04721

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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
4853	NOTCH2	HTA11_347_2000001011	Human	Colorectum	AD	3.75e-09	7.12e-01	-0.1954
4853	NOTCH2	HTA11_99999965104_69814	Human	Colorectum	MSS	2.86e-08	6.05e-01	0.281
4853	NOTCH2	A015-C-203	Human	Colorectum	FAP	2.15e-07	-2.31e-01	-0.1294
4853	NOTCH2	A002-C-201	Human	Colorectum	FAP	1.19e-08	-2.87e-01	0.0324
4853	NOTCH2	A001-C-119	Human	Colorectum	FAP	8.48e-06	-3.11e-01	-0.1557
4853	NOTCH2	A001-C-108	Human	Colorectum	FAP	3.71e-05	-2.38e-01	-0.0272
4853	NOTCH2	A002-C-205	Human	Colorectum	FAP	6.75e-10	-3.09e-01	-0.1236
4853	NOTCH2	A015-C-006	Human	Colorectum	FAP	3.30e-05	-2.81e-01	-0.0994
4853	NOTCH2	A002-C-114	Human	Colorectum	FAP	7.02e-09	-3.29e-01	-0.1561
4853	NOTCH2	A015-C-104	Human	Colorectum	FAP	2.61e-10	-3.20e-01	-0.1899
4853	NOTCH2	A001-C-014	Human	Colorectum	FAP	7.25e-04	-2.45e-01	0.0135
4853	NOTCH2	A002-C-016	Human	Colorectum	FAP	1.69e-08	-2.78e-01	0.0521
4853	NOTCH2	A015-C-002	Human	Colorectum	FAP	6.88e-04	-2.91e-01	-0.0763
4853	NOTCH2	A001-C-007	Human	Colorectum	CRC	4.04e-03	-3.32e-01	0.1899
4853	NOTCH2	A001-C-203	Human	Colorectum	FAP	2.84e-03	-1.89e-01	-0.0481
4853	NOTCH2	A002-C-116	Human	Colorectum	FAP	3.62e-07	-2.80e-01	-0.0452
4853	NOTCH2	A014-C-008	Human	Colorectum	FAP	4.18e-04	-2.53e-01	-0.191
4853	NOTCH2	A018-E-020	Human	Colorectum	FAP	1.72e-07	-2.70e-01	-0.2034
4853	NOTCH2	F034	Human	Colorectum	FAP	2.53e-06	-2.44e-01	-0.0665
4853	NOTCH2	F072B	Human	Colorectum	FAP	7.16e-08	-2.96e-01	0.257

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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
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:0032970	Colorectum	AD	regulation of actin filament-based process	142/3918	397/18723	4.05e-12	5.90e-10	142
GO:0002064	Colorectum	AD	epithelial cell development	89/3918	220/18723	2.98e-11	3.52e-09	89
GO:0048732	Colorectum	AD	gland development	149/3918	436/18723	6.07e-11	6.33e-09	149
GO:0032956	Colorectum	AD	regulation of actin cytoskeleton organization	127/3918	358/18723	1.03e-10	1.04e-08	127
GO:0030099	Colorectum	AD	myeloid cell differentiation	119/3918	381/18723	1.24e-06	4.01e-05	119
GO:0042060	Colorectum	AD	wound healing	128/3918	422/18723	2.73e-06	7.89e-05	128
GO:0061008	Colorectum	AD	hepaticobiliary system development	55/3918	150/18723	6.34e-06	1.59e-04	55
GO:0001889	Colorectum	AD	liver development	54/3918	147/18723	7.20e-06	1.77e-04	54
GO:0007265	Colorectum	AD	Ras protein signal transduction	104/3918	337/18723	1.01e-05	2.35e-04	104
GO:0051056	Colorectum	AD	regulation of small GTPase mediated signal transduction	94/3918	302/18723	1.81e-05	3.76e-04	94
GO:0001701	Colorectum	AD	in utero embryonic development	110/3918	367/18723	2.36e-05	4.62e-04	110
GO:0031532	Colorectum	AD	actin cytoskeleton reorganization	41/3918	107/18723	2.81e-05	5.28e-04	41
GO:0007409	Colorectum	AD	axonogenesis	122/3918	418/18723	3.36e-05	6.15e-04	122
GO:0001890	Colorectum	AD	placenta development	51/3918	144/18723	3.99e-05	7.16e-04	51
GO:0061564	Colorectum	AD	axon development	132/3918	467/18723	8.40e-05	1.31e-03	132
GO:0022612	Colorectum	AD	gland morphogenesis	42/3918	118/18723	1.62e-04	2.23e-03	42
GO:0060562	Colorectum	AD	epithelial tube morphogenesis	93/3918	325/18723	5.65e-04	6.00e-03	93
GO:0050673	Colorectum	AD	epithelial cell proliferation	119/3918	437/18723	8.75e-04	8.51e-03	119
GO:0007178	Colorectum	AD	transmembrane receptor protein serine/threonine kinase signaling pathway	99/3918	355/18723	9.92e-04	9.28e-03	99
GO:0061458	Colorectum	AD	reproductive system development	116/3918	427/18723	1.11e-03	1.01e-02	116

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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
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
hsa049198	Colorectum	FAP	Thyroid hormone signaling pathway	41/1404	121/8465	2.28e-06	4.28e-05	2.60e-05	41
hsa049199	Colorectum	FAP	Thyroid hormone signaling pathway	41/1404	121/8465	2.28e-06	4.28e-05	2.60e-05	41
hsa0491910	Colorectum	CRC	Thyroid hormone signaling pathway	35/1091	121/8465	2.05e-06	6.85e-05	4.64e-05	35
hsa05207	Colorectum	CRC	Chemical carcinogenesis - receptor activation	42/1091	212/8465	2.62e-03	1.75e-02	1.19e-02	42
hsa0491911	Colorectum	CRC	Thyroid hormone signaling pathway	35/1091	121/8465	2.05e-06	6.85e-05	4.64e-05	35
hsa052071	Colorectum	CRC	Chemical carcinogenesis - receptor activation	42/1091	212/8465	2.62e-03	1.75e-02	1.19e-02	42
hsa0516510	Esophagus	ESCC	Human papillomavirus infection	215/4205	331/8465	7.86e-09	7.12e-08	3.65e-08	215
hsa0491928	Esophagus	ESCC	Thyroid hormone signaling pathway	78/4205	121/8465	6.79e-04	2.23e-03	1.14e-03	78
hsa015227	Esophagus	ESCC	Endocrine resistance	63/4205	98/8465	2.38e-03	6.58e-03	3.37e-03	63
hsa043306	Esophagus	ESCC	Notch signaling pathway	42/4205	62/8465	2.97e-03	7.97e-03	4.08e-03	42
hsa046585	Esophagus	ESCC	Th1 and Th2 cell differentiation	58/4205	92/8465	6.49e-03	1.60e-02	8.19e-03	58
hsa0516515	Esophagus	ESCC	Human papillomavirus infection	215/4205	331/8465	7.86e-09	7.12e-08	3.65e-08	215
hsa04919113	Esophagus	ESCC	Thyroid hormone signaling pathway	78/4205	121/8465	6.79e-04	2.23e-03	1.14e-03	78
hsa0152215	Esophagus	ESCC	Endocrine resistance	63/4205	98/8465	2.38e-03	6.58e-03	3.37e-03	63
hsa0433013	Esophagus	ESCC	Notch signaling pathway	42/4205	62/8465	2.97e-03	7.97e-03	4.08e-03	42
hsa0465812	Esophagus	ESCC	Th1 and Th2 cell differentiation	58/4205	92/8465	6.49e-03	1.60e-02	8.19e-03	58

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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
DLK1	NOTCH2	DLK1_NOTCH2	NOTCH	Breast	ADJ
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	Breast	ADJ
DLL1	NOTCH2	DLL1_NOTCH2	NOTCH	Breast	ADJ
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	Breast	DCIS
DLK1	NOTCH2	DLK1_NOTCH2	NOTCH	Breast	Healthy
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	Breast	Healthy
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	Breast	IDC
DLL4	NOTCH2	DLL4_NOTCH2	NOTCH	Cervix	ADJ
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	Cervix	CC
JAG2	NOTCH2	JAG2_NOTCH2	NOTCH	Cervix	CC
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	Cervix	Precancer
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	CRC	ADJ
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	CRC	CRC
DLL1	NOTCH2	DLL1_NOTCH2	NOTCH	CRC	CRC
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	CRC	FAP
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	CRC	Healthy
DLL4	NOTCH2	DLL4_NOTCH2	NOTCH	CRC	MSI-H
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	CRC	MSI-H
JAG2	NOTCH2	JAG2_NOTCH2	NOTCH	CRC	MSI-H
JAG1	NOTCH2	JAG1_NOTCH2	NOTCH	CRC	SER

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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

NOTCH2

SNV

Missense_Mutation

c.4888C>G

p.Arg1630Gly

p.R1630G

Q04721

protein_coding

deleterious(0.03)

probably_damaging(0.95)

TCGA-A7-A4SC-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

NOTCH2

SNV

Missense_Mutation

novel

c.4163N>C

p.Ser1388Thr

p.S1388T

Q04721

protein_coding

tolerated(1)

benign(0)

TCGA-A7-A6VY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

NOTCH2

SNV

Missense_Mutation

c.6991G>T

p.Ala2331Ser

p.A2331S

Q04721

protein_coding

tolerated(0.78)

benign(0.003)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NOTCH2

SNV

Missense_Mutation

c.3044N>C

p.Val1015Ala

p.V1015A

Q04721

protein_coding

tolerated(0.27)

benign(0.015)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NOTCH2

SNV

Missense_Mutation

c.804N>T

p.Arg268Ser

p.R268S

Q04721

protein_coding

tolerated(0.65)

benign(0.037)

TCGA-AO-A03T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

NOTCH2

SNV

Missense_Mutation

novel

c.290N>G

p.Thr97Arg

p.T97R

Q04721

protein_coding

tolerated(0.1)

probably_damaging(0.979)

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

NOTCH2

SNV

Missense_Mutation

rs376783592

c.1698G>T

p.Leu566Phe

p.L566F

Q04721

protein_coding

tolerated(0.7)

possibly_damaging(0.77)

TCGA-AR-A24Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NOTCH2

SNV

Missense_Mutation

c.4996N>T

p.Val1666Phe

p.V1666F

Q04721

protein_coding

deleterious(0.01)

probably_damaging(0.969)

TCGA-B6-A0X0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NOTCH2

SNV

Missense_Mutation

c.4812N>T

p.Arg1604Ser

p.R1604S

Q04721

protein_coding

tolerated(0.57)

benign(0.007)

TCGA-BH-A0AW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

NOTCH2

SNV

Missense_Mutation

novel

c.2864G>A

p.Ser955Asn

p.S955N

Q04721

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-BH-A0B8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

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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
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE	inhibitor	MK0752
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE	antibody	252166663	TAREXTUMAB
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE	inhibitor	RO4929097	RG-4733
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE	inhibitor	PF-03084014	NIROGACESTAT
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE	antibody	REGN421
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE		Tarextumab	TAREXTUMAB
4853	NOTCH2	DRUGGABLE GENOME, CELL SURFACE, CLINICALLY ACTIONABLE		OMP-59R5	TAREXTUMAB

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