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: NTRK2

Gene summary for NTRK2

Gene summary.

Gene information	Species	Human
	Gene symbol	NTRK2
	Gene ID	4915
	Gene name	neurotrophic receptor tyrosine kinase 2
	Gene Alias	DEE58
	Cytomap	9q21.33
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q16620

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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
4915	NTRK2	GSM4909281	Human	Breast	IDC	7.11e-10	-3.33e-01	0.21
4915	NTRK2	GSM4909285	Human	Breast	IDC	1.62e-07	-2.65e-01	0.21
4915	NTRK2	GSM4909286	Human	Breast	IDC	3.60e-11	-3.34e-01	0.1081
4915	NTRK2	GSM4909290	Human	Breast	IDC	1.80e-10	-3.77e-01	0.2096
4915	NTRK2	GSM4909291	Human	Breast	IDC	1.24e-04	-3.53e-01	0.1753
4915	NTRK2	GSM4909293	Human	Breast	IDC	1.29e-13	-2.98e-01	0.1581
4915	NTRK2	GSM4909294	Human	Breast	IDC	7.50e-16	-3.52e-01	0.2022
4915	NTRK2	GSM4909296	Human	Breast	IDC	3.13e-15	-3.56e-01	0.1524
4915	NTRK2	GSM4909297	Human	Breast	IDC	3.01e-16	-3.71e-01	0.1517
4915	NTRK2	GSM4909298	Human	Breast	IDC	3.03e-12	-3.05e-01	0.1551
4915	NTRK2	GSM4909299	Human	Breast	IDC	3.64e-27	7.93e-01	0.035
4915	NTRK2	GSM4909301	Human	Breast	IDC	1.24e-19	-3.77e-01	0.1577
4915	NTRK2	GSM4909302	Human	Breast	IDC	5.84e-08	-3.45e-01	0.1545
4915	NTRK2	GSM4909304	Human	Breast	IDC	1.58e-16	-3.72e-01	0.1636
4915	NTRK2	GSM4909306	Human	Breast	IDC	1.51e-06	-2.78e-01	0.1564
4915	NTRK2	GSM4909311	Human	Breast	IDC	2.20e-19	-3.38e-01	0.1534
4915	NTRK2	GSM4909312	Human	Breast	IDC	2.86e-19	-3.77e-01	0.1552
4915	NTRK2	GSM4909315	Human	Breast	IDC	3.85e-17	-3.65e-01	0.21
4915	NTRK2	GSM4909316	Human	Breast	IDC	2.04e-03	-3.77e-01	0.21
4915	NTRK2	GSM4909319	Human	Breast	IDC	6.92e-19	-3.42e-01	0.1563

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
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:00709979	Breast	Precancer	neuron death	50/1080	361/18723	7.75e-09	5.70e-07	50
GO:00514029	Breast	Precancer	neuron apoptotic process	38/1080	246/18723	2.68e-08	1.75e-06	38
GO:19012149	Breast	Precancer	regulation of neuron death	41/1080	319/18723	1.27e-06	4.80e-05	41
GO:00435237	Breast	Precancer	regulation of neuron apoptotic process	31/1080	212/18723	1.69e-06	6.08e-05	31
GO:00420633	Breast	Precancer	gliogenesis	33/1080	301/18723	3.06e-04	4.40e-03	33
GO:00435243	Breast	Precancer	negative regulation of neuron apoptotic process	19/1080	145/18723	6.83e-04	8.34e-03	19
GO:19012157	Breast	Precancer	negative regulation of neuron death	24/1080	208/18723	9.50e-04	1.07e-02	24
GO:00100013	Breast	Precancer	glial cell differentiation	25/1080	225/18723	1.29e-03	1.37e-02	25
GO:00434912	Breast	Precancer	protein kinase B signaling	23/1080	211/18723	2.53e-03	2.30e-02	23
GO:00336749	Breast	Precancer	positive regulation of kinase activity	42/1080	467/18723	2.94e-03	2.54e-02	42
GO:19900908	Breast	Precancer	cellular response to nerve growth factor stimulus	9/1080	53/18723	3.05e-03	2.62e-02	9
GO:19900896	Breast	Precancer	response to nerve growth factor	9/1080	56/18723	4.47e-03	3.47e-02	9
GO:00011015	Breast	Precancer	response to acid chemical	16/1080	135/18723	4.85e-03	3.67e-02	16
GO:0021782	Breast	Precancer	glial cell development	14/1080	116/18723	6.92e-03	4.67e-02	14
GO:007099714	Breast	IDC	neuron death	57/1434	361/18723	1.31e-07	7.38e-06	57
GO:005140213	Breast	IDC	neuron apoptotic process	42/1434	246/18723	7.21e-07	3.35e-05	42
GO:190121414	Breast	IDC	regulation of neuron death	48/1434	319/18723	5.01e-06	1.69e-04	48
GO:004352313	Breast	IDC	regulation of neuron apoptotic process	35/1434	212/18723	1.26e-05	3.29e-04	35
GO:004352411	Breast	IDC	negative regulation of neuron apoptotic process	23/1434	145/18723	6.58e-04	8.11e-03	23
GO:004206311	Breast	IDC	gliogenesis	39/1434	301/18723	8.63e-04	1.00e-02	39

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0472214	Cervix	CC	Neurotrophin signaling pathway	32/1267	119/8465	5.01e-04	2.42e-03	1.43e-03	32
hsa040142	Cervix	CC	Ras signaling pathway	51/1267	236/8465	3.55e-03	1.34e-02	7.91e-03	51
hsa040109	Cervix	CC	MAPK signaling pathway	62/1267	302/8465	4.89e-03	1.67e-02	9.86e-03	62
hsa0472215	Cervix	CC	Neurotrophin signaling pathway	32/1267	119/8465	5.01e-04	2.42e-03	1.43e-03	32
hsa0401411	Cervix	CC	Ras signaling pathway	51/1267	236/8465	3.55e-03	1.34e-02	7.91e-03	51
hsa0401012	Cervix	CC	MAPK signaling pathway	62/1267	302/8465	4.89e-03	1.67e-02	9.86e-03	62
hsa04722	Colorectum	AD	Neurotrophin signaling pathway	50/2092	119/8465	2.28e-05	2.24e-04	1.43e-04	50
hsa047221	Colorectum	AD	Neurotrophin signaling pathway	50/2092	119/8465	2.28e-05	2.24e-04	1.43e-04	50
hsa0472225	Esophagus	ESCC	Neurotrophin signaling pathway	80/4205	119/8465	7.33e-05	3.07e-04	1.57e-04	80
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa04722111	Esophagus	ESCC	Neurotrophin signaling pathway	80/4205	119/8465	7.33e-05	3.07e-04	1.57e-04	80
hsa0415114	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0472220	Oral cavity	OSCC	Neurotrophin signaling pathway	74/3704	119/8465	3.55e-05	1.49e-04	7.58e-05	74
hsa0401014	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa041516	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa04722110	Oral cavity	OSCC	Neurotrophin signaling pathway	74/3704	119/8465	3.55e-05	1.49e-04	7.58e-05	74
hsa0401015	Oral cavity	OSCC	MAPK signaling pathway	165/3704	302/8465	7.11e-05	2.74e-04	1.40e-04	165
hsa0415113	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa0472224	Oral cavity	LP	Neurotrophin signaling pathway	46/2418	119/8465	1.07e-02	3.77e-02	2.43e-02	46
hsa0472234	Oral cavity	LP	Neurotrophin signaling pathway	46/2418	119/8465	1.07e-02	3.77e-02	2.43e-02	46

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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
NTF3	NTRK2	NTF3_NTRK2	NT	Endometrium	ADJ
BDNF	NTRK2	BDNF_NTRK2	NT	Esophagus	ESCC
NTF4	NTRK2	NTF5_NTRK2	NT	Esophagus	ESCC
NTF4	NTRK2	NTF5_NTRK2	NT	HNSCC	Precancer
NTF3	NTRK2	NTF3_NTRK2	NT	Liver	Healthy

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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

NTRK2

SNV

Missense_Mutation

rs144037140

c.407G>A

p.Arg136His

p.R136H

Q16620

protein_coding

tolerated(0.41)

benign(0.007)

TCGA-A8-A0A9-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

NTRK2

SNV

Missense_Mutation

rs200996090

c.1156N>A

p.Asp386Asn

p.D386N

Q16620

protein_coding

tolerated(0.75)

benign(0.001)

TCGA-AN-A0XW-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NTRK2

SNV

Missense_Mutation

novel

c.1869N>G

p.Cys623Trp

p.C623W

Q16620

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AR-A1AO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NTRK2

SNV

Missense_Mutation

rs778391314

c.157N>A

p.Val53Met

p.V53M

Q16620

protein_coding

tolerated(0.13)

benign(0.001)

TCGA-AR-A250-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NTRK2

SNV

Missense_Mutation

novel

c.2324N>G

p.Asn775Ser

p.N775S

Q16620

protein_coding

deleterious(0)

probably_damaging(0.992)

TCGA-B6-A0IK-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NTRK2

SNV

Missense_Mutation

c.724N>A

p.Glu242Lys

p.E242K

Q16620

protein_coding

tolerated(0.76)

benign(0.012)

TCGA-BH-A1F5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NTRK2

SNV

Missense_Mutation

c.1318N>A

p.Ala440Thr

p.A440T

Q16620

protein_coding

deleterious(0.02)

probably_damaging(0.983)

TCGA-E2-A1LS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Cyclophosphamide

NTRK2

SNV

Missense_Mutation

c.167N>T

p.Pro56Leu

p.P56L

Q16620

protein_coding

tolerated(0.1)

probably_damaging(1)

TCGA-E9-A22D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

NTRK2

insertion

In_Frame_Ins

novel

c.2322_2323insGGCATACTGTGT

p.Ser774_Asn775insGlyIleLeuCys

p.S774_N775insGILC

Q16620

protein_coding

TCGA-B6-A0IK-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NTRK2

deletion

Frame_Shift_Del

novel

c.50delG

p.Gly17AlafsTer47

p.G17Afs*47

Q16620

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

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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
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE		Macrocycle derivative 13
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE	inhibitor	249565751
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE	inhibitor	249565869	CEP-11981
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE		lithium	LITHIUM	21047205,24885933
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE	inhibitor	381744997	REPOTRECTINIB
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE		PILOCARPINE	PILOCARPINE	15183516
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE		AST-487	AST-487
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE	inhibitor	CHEMBL3545179	AZD-7451
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE	inhibitor	223366033
4915	NTRK2	KINASE, TYROSINE KINASE, ENZYME, DRUGGABLE GENOME, CLINICALLY ACTIONABLE		TCMDC-125758	CHEMBL546797

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