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: NRP1

Gene summary for NRP1

Gene summary.

Gene information	Species	Human
	Gene symbol	NRP1
	Gene ID	8829
	Gene name	neuropilin 1
	Gene Alias	BDCA4
	Cytomap	10p11.22
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	O14786

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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
8829	NRP1	LZE5T	Human	Esophagus	ESCC	2.25e-05	3.64e-01	0.0514
8829	NRP1	LZE24T	Human	Esophagus	ESCC	1.51e-10	3.03e-01	0.0596
8829	NRP1	P4T-E	Human	Esophagus	ESCC	3.26e-05	5.28e-02	0.1323
8829	NRP1	P8T-E	Human	Esophagus	ESCC	6.84e-15	3.84e-01	0.0889
8829	NRP1	P9T-E	Human	Esophagus	ESCC	3.07e-13	3.31e-01	0.1131
8829	NRP1	P10T-E	Human	Esophagus	ESCC	1.22e-06	6.30e-02	0.116
8829	NRP1	P11T-E	Human	Esophagus	ESCC	4.82e-14	5.65e-01	0.1426
8829	NRP1	P21T-E	Human	Esophagus	ESCC	1.19e-12	3.53e-01	0.1617
8829	NRP1	P23T-E	Human	Esophagus	ESCC	3.67e-03	1.87e-01	0.108
8829	NRP1	P24T-E	Human	Esophagus	ESCC	3.08e-07	2.96e-01	0.1287
8829	NRP1	P27T-E	Human	Esophagus	ESCC	5.89e-04	3.26e-02	0.1055
8829	NRP1	P30T-E	Human	Esophagus	ESCC	1.52e-14	5.34e-01	0.137
8829	NRP1	P31T-E	Human	Esophagus	ESCC	2.14e-28	5.21e-01	0.1251
8829	NRP1	P32T-E	Human	Esophagus	ESCC	2.86e-12	3.91e-01	0.1666
8829	NRP1	P36T-E	Human	Esophagus	ESCC	5.97e-11	6.40e-01	0.1187
8829	NRP1	P37T-E	Human	Esophagus	ESCC	2.89e-09	2.17e-01	0.1371
8829	NRP1	P40T-E	Human	Esophagus	ESCC	4.11e-05	3.04e-01	0.109
8829	NRP1	P42T-E	Human	Esophagus	ESCC	7.60e-04	1.34e-01	0.1175
8829	NRP1	P44T-E	Human	Esophagus	ESCC	3.11e-05	2.51e-01	0.1096
8829	NRP1	P47T-E	Human	Esophagus	ESCC	4.52e-05	1.31e-01	0.1067

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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:0016032111	Esophagus	ESCC	viral process	301/8552	415/18723	3.34e-29	1.32e-26	301
GO:2001233111	Esophagus	ESCC	regulation of apoptotic signaling pathway	256/8552	356/18723	4.11e-24	1.04e-21	256
GO:0019058111	Esophagus	ESCC	viral life cycle	226/8552	317/18723	1.17e-20	1.76e-18	226
GO:0051098111	Esophagus	ESCC	regulation of binding	251/8552	363/18723	6.73e-20	8.46e-18	251
GO:0097191111	Esophagus	ESCC	extrinsic apoptotic signaling pathway	159/8552	219/18723	4.12e-16	2.94e-14	159
GO:2001234111	Esophagus	ESCC	negative regulation of apoptotic signaling pathway	161/8552	224/18723	1.24e-15	8.09e-14	161
GO:2001236111	Esophagus	ESCC	regulation of extrinsic apoptotic signaling pathway	111/8552	151/18723	2.97e-12	1.18e-10	111
GO:0048732111	Esophagus	ESCC	gland development	269/8552	436/18723	7.81e-12	2.95e-10	269
GO:0051099111	Esophagus	ESCC	positive regulation of binding	122/8552	173/18723	2.79e-11	9.45e-10	122
GO:004339320	Esophagus	ESCC	regulation of protein binding	135/8552	196/18723	3.69e-11	1.22e-09	135
GO:1902905111	Esophagus	ESCC	positive regulation of supramolecular fiber organization	142/8552	209/18723	5.51e-11	1.76e-09	142
GO:1902903111	Esophagus	ESCC	regulation of supramolecular fiber organization	237/8552	383/18723	9.06e-11	2.75e-09	237
GO:0016049110	Esophagus	ESCC	cell growth	289/8552	482/18723	1.29e-10	3.77e-09	289
GO:0044403111	Esophagus	ESCC	biological process involved in symbiotic interaction	186/8552	290/18723	1.43e-10	4.16e-09	186
GO:0150115110	Esophagus	ESCC	cell-substrate junction organization	77/8552	101/18723	3.46e-10	9.57e-09	77
GO:000704418	Esophagus	ESCC	cell-substrate junction assembly	73/8552	95/18723	5.27e-10	1.35e-08	73
GO:0051701111	Esophagus	ESCC	biological process involved in interaction with host	135/8552	203/18723	1.49e-09	3.49e-08	135
GO:005149520	Esophagus	ESCC	positive regulation of cytoskeleton organization	147/8552	226/18723	2.93e-09	6.38e-08	147
GO:000155819	Esophagus	ESCC	regulation of cell growth	248/8552	414/18723	2.97e-09	6.45e-08	248
GO:003158919	Esophagus	ESCC	cell-substrate adhesion	221/8552	363/18723	3.06e-09	6.62e-08	221

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05166211	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa05171211	Esophagus	ESCC	Coronavirus disease - COVID-19	156/4205	232/8465	3.18e-08	2.68e-07	1.37e-07	156
hsa0436016	Esophagus	ESCC	Axon guidance	108/4205	182/8465	5.13e-03	1.30e-02	6.67e-03	108
hsa05166310	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa05171310	Esophagus	ESCC	Coronavirus disease - COVID-19	156/4205	232/8465	3.18e-08	2.68e-07	1.37e-07	156
hsa0436017	Esophagus	ESCC	Axon guidance	108/4205	182/8465	5.13e-03	1.30e-02	6.67e-03	108
hsa0517122	Liver	Cirrhotic	Coronavirus disease - COVID-19	136/2530	232/8465	3.28e-20	1.82e-18	1.12e-18	136
hsa0516614	Liver	Cirrhotic	Human T-cell leukemia virus 1 infection	87/2530	222/8465	1.69e-03	8.01e-03	4.94e-03	87
hsa0517132	Liver	Cirrhotic	Coronavirus disease - COVID-19	136/2530	232/8465	3.28e-20	1.82e-18	1.12e-18	136
hsa0516615	Liver	Cirrhotic	Human T-cell leukemia virus 1 infection	87/2530	222/8465	1.69e-03	8.01e-03	4.94e-03	87
hsa0517142	Liver	HCC	Coronavirus disease - COVID-19	167/4020	232/8465	1.50e-14	4.19e-13	2.33e-13	167
hsa0516622	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0517152	Liver	HCC	Coronavirus disease - COVID-19	167/4020	232/8465	1.50e-14	4.19e-13	2.33e-13	167
hsa0516632	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0517116	Lung	IAC	Coronavirus disease - COVID-19	102/1053	232/8465	5.89e-34	1.91e-31	1.27e-31	102
hsa0516616	Lung	IAC	Human T-cell leukemia virus 1 infection	49/1053	222/8465	3.44e-05	6.38e-04	4.24e-04	49
hsa043608	Lung	IAC	Axon guidance	34/1053	182/8465	9.31e-03	3.62e-02	2.41e-02	34
hsa0517117	Lung	IAC	Coronavirus disease - COVID-19	102/1053	232/8465	5.89e-34	1.91e-31	1.27e-31	102
hsa0516617	Lung	IAC	Human T-cell leukemia virus 1 infection	49/1053	222/8465	3.44e-05	6.38e-04	4.24e-04	49
hsa0436011	Lung	IAC	Axon guidance	34/1053	182/8465	9.31e-03	3.62e-02	2.41e-02	34

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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
SEMA3D	NRP1_PLXNA2	SEMA3D_NRP1_PLXNA2	SEMA3	Breast	ADJ
SEMA4A	NRP1_PLXNA4	SEMA4A_NRP1_PLXNA4	SEMA4	Breast	DCIS
SEMA3C	NRP1_PLXNA4	SEMA3C_NRP1_PLXNA4	SEMA3	Breast	DCIS
SEMA3D	NRP1_PLXNA4	SEMA3D_NRP1_PLXNA4	SEMA3	Breast	DCIS
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Breast	DCIS
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	Breast	Healthy
SEMA3D	NRP1_PLXNA2	SEMA3D_NRP1_PLXNA2	SEMA3	Breast	Healthy
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Breast	Healthy
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Cervix	ADJ
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	Cervix	CC
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Cervix	CC
SEMA4A	NRP1_PLXNA2	SEMA4A_NRP1_PLXNA2	SEMA4	Cervix	CC
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Cervix	Precancer
SEMA3A	NRP1_PLXNA2	SEMA3A_NRP1_PLXNA2	SEMA3	CRC	AD
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	CRC	AD
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	CRC	AD
SEMA4A	NRP1_PLXNA2	SEMA4A_NRP1_PLXNA2	SEMA4	CRC	AD
SEMA4A	NRP1_PLXNA2	SEMA4A_NRP1_PLXNA2	SEMA4	CRC	ADJ
SEMA4A	NRP1_PLXNA4	SEMA4A_NRP1_PLXNA4	SEMA4	CRC	ADJ
SEMA3A	NRP1_PLXNA2	SEMA3A_NRP1_PLXNA2	SEMA3	CRC	ADJ

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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

NRP1

SNV

Missense_Mutation

c.1447N>A

p.Glu483Lys

p.E483K

O14786

protein_coding

deleterious(0.02)

probably_damaging(0.933)

TCGA-A2-A0SY-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

arimidex

NRP1

SNV

Missense_Mutation

c.1591N>A

p.Asp531Asn

p.D531N

O14786

protein_coding

deleterious(0.03)

probably_damaging(0.947)

TCGA-A8-A075-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

epirubicin

NRP1

SNV

Missense_Mutation

c.1756G>A

p.Glu586Lys

p.E586K

O14786

protein_coding

tolerated(0.41)

possibly_damaging(0.458)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NRP1

SNV

Missense_Mutation

c.878C>T

p.Ala293Val

p.A293V

O14786

protein_coding

tolerated(0.06)

benign(0.02)

TCGA-AO-A0J3-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cyclophosphamide

NRP1

SNV

Missense_Mutation

c.2588N>T

p.Ala863Val

p.A863V

O14786

protein_coding

tolerated(0.5)

possibly_damaging(0.841)

TCGA-E9-A1R7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

fareston

NRP1

insertion

Nonsense_Mutation

novel

c.1004_1005insCTAATCAAAAGATTTCGGAGAATTCATACTCACCATCTCCCAGAA

p.Phe335_Val336insTer

p.F335_V336ins*

O14786

protein_coding

TCGA-A8-A06X-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NRP1

insertion

In_Frame_Ins

novel

c.2660_2661insAAAGCCCTGCTCTTTAATCAAACTCTGGTGGCC

p.Gly887_Met888insLysProCysSerLeuIleLysLeuTrpTrpPro

p.G887_M888insKPCSLIKLWWP

O14786

protein_coding

TCGA-AN-A0FX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NRP1

insertion

In_Frame_Ins

novel

c.2083_2084insTTTGTAATACACAGGGCACAGTCTCTTGCCTCAAAG

p.Ser695delinsPheCysAsnThrGlnGlyThrValSerCysLeuLysAla

p.S695delinsFCNTQGTVSCLKA

O14786

protein_coding

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

NRP1

insertion

Frame_Shift_Ins

novel

c.724_725insCAGTGGTTTGGTTGTGGAAGATGCTGGGGGAAGCCAGTATGTTT

p.Ile242ThrfsTer27

p.I242Tfs*27

O14786

protein_coding

TCGA-AQ-A04J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

NRP1

SNV

Missense_Mutation

novel

c.2522A>C

p.Lys841Thr

p.K841T

O14786

protein_coding

tolerated(0.62)

benign(0.109)

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
8829	NRP1	DRUGGABLE GENOME		PEGAPTANIB	PEGAPTANIB SODIUM
8829	NRP1	DRUGGABLE GENOME		ranibizumab	RANIBIZUMAB	26426212
8829	NRP1	DRUGGABLE GENOME		ANTI-NRP1 MAB
8829	NRP1	DRUGGABLE GENOME	antagonist	363894198
8829	NRP1	DRUGGABLE GENOME		Pegaptanib	PEGAPTANIB SODIUM
8829	NRP1	DRUGGABLE GENOME		PALIFERMIN	PALIFERMIN
8829	NRP1	DRUGGABLE GENOME		RG7347		26090340

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