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: NF1

Gene summary for NF1

Gene summary.

Gene information	Species	Human
	Gene symbol	NF1
	Gene ID	4763
	Gene name	neurofibromin 1
	Gene Alias	NFNS
	Cytomap	17q11.2
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P21359

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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
4763	NF1	CCI_2	Human	Cervix	CC	2.42e-06	1.15e+00	0.5249
4763	NF1	CCI_3	Human	Cervix	CC	1.70e-12	1.10e+00	0.516
4763	NF1	L1	Human	Cervix	CC	4.58e-03	-2.05e-01	0.0802
4763	NF1	HTA11_3410_2000001011	Human	Colorectum	AD	4.06e-24	-5.45e-01	0.0155
4763	NF1	HTA11_2951_2000001011	Human	Colorectum	AD	2.91e-06	-4.45e-01	0.0216
4763	NF1	HTA11_3361_2000001011	Human	Colorectum	AD	8.50e-04	-5.39e-01	-0.1207
4763	NF1	HTA11_83_2000001011	Human	Colorectum	SER	1.42e-02	-4.88e-01	-0.1526
4763	NF1	HTA11_696_2000001011	Human	Colorectum	AD	3.57e-02	-3.12e-01	-0.1464
4763	NF1	HTA11_866_2000001011	Human	Colorectum	AD	9.78e-03	-2.37e-01	-0.1001
4763	NF1	HTA11_2992_2000001011	Human	Colorectum	SER	4.35e-02	-4.54e-01	-0.1706
4763	NF1	HTA11_5212_2000001011	Human	Colorectum	AD	2.54e-04	-6.00e-01	-0.2061
4763	NF1	HTA11_5216_2000001011	Human	Colorectum	SER	1.21e-08	-7.37e-01	-0.1462
4763	NF1	HTA11_9341_2000001011	Human	Colorectum	SER	4.42e-02	-4.02e-01	-0.00410000000000005
4763	NF1	HTA11_7862_2000001011	Human	Colorectum	AD	8.48e-09	-5.76e-01	-0.0179
4763	NF1	HTA11_866_3004761011	Human	Colorectum	AD	1.21e-12	-4.97e-01	0.096
4763	NF1	HTA11_7696_3000711011	Human	Colorectum	AD	4.09e-14	-4.28e-01	0.0674
4763	NF1	HTA11_7469_2000001011	Human	Colorectum	AD	7.92e-04	-4.98e-01	-0.0124
4763	NF1	HTA11_99999970781_79442	Human	Colorectum	MSS	6.44e-07	-3.50e-01	0.294
4763	NF1	HTA11_99999965104_69814	Human	Colorectum	MSS	2.24e-03	-1.90e-01	0.281
4763	NF1	HTA11_99999973899_84307	Human	Colorectum	MSS	2.94e-03	-5.74e-01	0.2585

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
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:00104989	Breast	Precancer	proteasomal protein catabolic process	58/1080	490/18723	1.54e-07	8.05e-06	58
GO:00431619	Breast	Precancer	proteasome-mediated ubiquitin-dependent protein catabolic process	42/1080	412/18723	2.49e-04	3.72e-03	42
GO:004586214	Breast	IDC	positive regulation of proteolysis	66/1434	372/18723	9.76e-11	1.29e-08	66
GO:001049814	Breast	IDC	proteasomal protein catabolic process	75/1434	490/18723	5.59e-09	4.41e-07	75
GO:004217614	Breast	IDC	regulation of protein catabolic process	63/1434	391/18723	1.32e-08	9.61e-07	63
GO:190336214	Breast	IDC	regulation of cellular protein catabolic process	46/1434	255/18723	4.00e-08	2.68e-06	46
GO:190305014	Breast	IDC	regulation of proteolysis involved in cellular protein catabolic process	41/1434	221/18723	9.77e-08	5.84e-06	41
GO:006113614	Breast	IDC	regulation of proteasomal protein catabolic process	33/1434	187/18723	5.24e-06	1.75e-04	33
GO:190336414	Breast	IDC	positive regulation of cellular protein catabolic process	29/1434	155/18723	5.93e-06	1.90e-04	29
GO:200005814	Breast	IDC	regulation of ubiquitin-dependent protein catabolic process	30/1434	164/18723	6.62e-06	2.05e-04	30
GO:004316114	Breast	IDC	proteasome-mediated ubiquitin-dependent protein catabolic process	57/1434	412/18723	9.55e-06	2.68e-04	57
GO:004573214	Breast	IDC	positive regulation of protein catabolic process	37/1434	231/18723	1.46e-05	3.71e-04	37
GO:190305213	Breast	IDC	positive regulation of proteolysis involved in cellular protein catabolic process	25/1434	133/18723	2.34e-05	5.59e-04	25
GO:190180014	Breast	IDC	positive regulation of proteasomal protein catabolic process	22/1434	114/18723	4.68e-05	1.04e-03	22
GO:000989614	Breast	IDC	positive regulation of catabolic process	62/1434	492/18723	7.06e-05	1.42e-03	62
GO:003243414	Breast	IDC	regulation of proteasomal ubiquitin-dependent protein catabolic process	24/1434	134/18723	7.59e-05	1.50e-03	24
GO:00324368	Breast	IDC	positive regulation of proteasomal ubiquitin-dependent protein catabolic process	18/1434	90/18723	1.39e-04	2.48e-03	18
GO:20000609	Breast	IDC	positive regulation of ubiquitin-dependent protein catabolic process	20/1434	107/18723	1.61e-04	2.76e-03	20
GO:003133114	Breast	IDC	positive regulation of cellular catabolic process	54/1434	427/18723	1.85e-04	3.07e-03	54
GO:004586224	Breast	DCIS	positive regulation of proteolysis	65/1390	372/18723	7.13e-11	9.17e-09	65

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
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
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
hsa01521	Colorectum	AD	EGFR tyrosine kinase inhibitor resistance	29/2092	79/8465	1.15e-02	4.24e-02	2.71e-02	29
hsa015211	Colorectum	AD	EGFR tyrosine kinase inhibitor resistance	29/2092	79/8465	1.15e-02	4.24e-02	2.71e-02	29
hsa015212	Colorectum	FAP	EGFR tyrosine kinase inhibitor resistance	26/1404	79/8465	2.69e-04	2.19e-03	1.33e-03	26
hsa04010	Colorectum	FAP	MAPK signaling pathway	68/1404	302/8465	4.00e-03	1.67e-02	1.02e-02	68
hsa015213	Colorectum	FAP	EGFR tyrosine kinase inhibitor resistance	26/1404	79/8465	2.69e-04	2.19e-03	1.33e-03	26
hsa040101	Colorectum	FAP	MAPK signaling pathway	68/1404	302/8465	4.00e-03	1.67e-02	1.02e-02	68
hsa015214	Colorectum	CRC	EGFR tyrosine kinase inhibitor resistance	22/1091	79/8465	2.89e-04	3.45e-03	2.34e-03	22
hsa04014	Colorectum	CRC	Ras signaling pathway	49/1091	236/8465	4.04e-04	4.50e-03	3.05e-03	49
hsa040102	Colorectum	CRC	MAPK signaling pathway	56/1091	302/8465	2.76e-03	1.77e-02	1.20e-02	56
hsa015215	Colorectum	CRC	EGFR tyrosine kinase inhibitor resistance	22/1091	79/8465	2.89e-04	3.45e-03	2.34e-03	22
hsa040141	Colorectum	CRC	Ras signaling pathway	49/1091	236/8465	4.04e-04	4.50e-03	3.05e-03	49
hsa040103	Colorectum	CRC	MAPK signaling pathway	56/1091	302/8465	2.76e-03	1.77e-02	1.20e-02	56
hsa0152110	Esophagus	ESCC	EGFR tyrosine kinase inhibitor resistance	55/4205	79/8465	2.44e-04	8.78e-04	4.50e-04	55
hsa0152115	Esophagus	ESCC	EGFR tyrosine kinase inhibitor resistance	55/4205	79/8465	2.44e-04	8.78e-04	4.50e-04	55
hsa015216	Liver	Cirrhotic	EGFR tyrosine kinase inhibitor resistance	35/2530	79/8465	4.50e-03	1.70e-02	1.05e-02	35
hsa0152111	Liver	Cirrhotic	EGFR tyrosine kinase inhibitor resistance	35/2530	79/8465	4.50e-03	1.70e-02	1.05e-02	35

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
NF1	ISLET	Pancreas	Healthy	PWRN1,TMEM260,LRIG3, etc.	2.22e-02
NF1	MSC	Prostate	ADJ	CCDC102B,NARS2,CADPS, etc.	4.55e-02
NF1	MSC	Prostate	BPH	CCDC102B,NARS2,CADPS, etc.	2.75e-03
NF1	FIB	Prostate	Healthy	CCDC102B,NARS2,CADPS, etc.	7.69e-03
NF1	MSC	Prostate	Tumor	CCDC102B,NARS2,CADPS, etc.	1.59e-02

∗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

NF1

SNV

Missense_Mutation

c.1570N>C

p.Glu524Gln

p.E524Q

P21359

protein_coding

tolerated(0.1)

possibly_damaging(0.732)

TCGA-A2-A0YK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

NF1

SNV

Missense_Mutation

novel

c.374N>C

p.Arg125Pro

p.R125P

P21359

protein_coding

tolerated(0.21)

possibly_damaging(0.567)

TCGA-A7-A6VY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

NF1

SNV

Missense_Mutation

c.4054N>G

p.Ser1352Gly

p.S1352G

P21359

protein_coding

tolerated(0.21)

benign(0.012)

TCGA-A8-A06X-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NF1

SNV

Missense_Mutation

c.3917G>A

p.Arg1306Gln

p.R1306Q

P21359

protein_coding

tolerated(0.65)

benign(0.19)

TCGA-A8-A083-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NF1

SNV

Missense_Mutation

c.2147A>T

p.Glu716Val

p.E716V

P21359

protein_coding

deleterious(0)

probably_damaging(0.983)

TCGA-AC-A23C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

chemo

NF1

SNV

Missense_Mutation

c.7053N>G

p.Phe2351Leu

p.F2351L

P21359

protein_coding

tolerated(0.08)

benign(0.063)

TCGA-AN-A0XW-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NF1

SNV

Missense_Mutation

c.3748C>T

p.Arg1250Trp

p.R1250W

P21359

protein_coding

deleterious(0)

probably_damaging(0.973)

TCGA-AO-A12H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

NF1

SNV

Missense_Mutation

rs876660206

c.4341G>C

p.Gln1447His

p.Q1447H

P21359

protein_coding

deleterious(0.01)

possibly_damaging(0.905)

TCGA-AR-A1AW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

NF1

SNV

Missense_Mutation

novel

c.5713A>C

p.Thr1905Pro

p.T1905P

P21359

protein_coding

deleterious(0)

probably_damaging(0.961)

TCGA-AR-A1AY-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unspecific

Doxorubicin

NF1

SNV

Missense_Mutation

rs774893767

c.5680G>C

p.Glu1894Gln

p.E1894Q

P21359

protein_coding

deleterious(0.02)

possibly_damaging(0.867)

TCGA-B6-A0IB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

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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
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		MEK162	BINIMETINIB
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		VEMURAFENIB	VEMURAFENIB	23288408
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		PD-325901
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		SELUMETINIB	SELUMETINIB
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		MEK INHIBITOR PD0325901		23171796
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		JQ1 COMPOUND		24373973
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		SIROLIMUS	SIROLIMUS	23171796
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		TRAMETINIB	TRAMETINIB	29127119
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		Trametinib	TRAMETINIB
4763	NF1	CLINICALLY ACTIONABLE, DRUG RESISTANCE		Cobimetinib	COBIMETINIB

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