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: NOS2

Gene summary for NOS2

Gene summary.

Gene information	Species	Human
	Gene symbol	NOS2
	Gene ID	4843
	Gene name	nitric oxide synthase 2
	Gene Alias	HEP-NOS
	Cytomap	17q11.2
	Gene Type	protein-coding
	GO ID	GO:0001666
	UniProtAcc	P35228

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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
4843	NOS2	HTA11_1391_2000001011	Human	Colorectum	AD	1.87e-03	6.70e-01	-0.059
4843	NOS2	HTA11_7696_3000711011	Human	Colorectum	AD	7.81e-05	3.41e-01	0.0674
4843	NOS2	HTA11_99999971662_82457	Human	Colorectum	MSS	3.85e-03	-1.59e-01	0.3859
4843	NOS2	A002-C-114	Human	Colorectum	FAP	1.13e-03	-1.62e-01	-0.1561
4843	NOS2	A002-C-016	Human	Colorectum	FAP	3.85e-03	-1.55e-01	0.0521
4843	NOS2	F072B	Human	Colorectum	FAP	4.07e-04	-1.62e-01	0.257
4843	NOS2	CRC-3-11773	Human	Colorectum	CRC	1.71e-02	-1.62e-01	0.2564

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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

∗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:0006091	Colorectum	AD	generation of precursor metabolites and energy	209/3918	490/18723	3.17e-28	6.61e-25	209
GO:0045333	Colorectum	AD	cellular respiration	119/3918	230/18723	3.21e-25	4.02e-22	119
GO:0015980	Colorectum	AD	energy derivation by oxidation of organic compounds	143/3918	318/18723	2.78e-22	2.49e-19	143
GO:0042176	Colorectum	AD	regulation of protein catabolic process	160/3918	391/18723	1.06e-19	7.34e-17	160
GO:0006163	Colorectum	AD	purine nucleotide metabolic process	149/3918	396/18723	1.08e-14	2.80e-12	149
GO:0072521	Colorectum	AD	purine-containing compound metabolic process	153/3918	416/18723	4.34e-14	1.01e-11	153
GO:0009895	Colorectum	AD	negative regulation of catabolic process	124/3918	320/18723	1.66e-13	3.35e-11	124
GO:0009117	Colorectum	AD	nucleotide metabolic process	168/3918	489/18723	2.20e-12	3.36e-10	168
GO:0006753	Colorectum	AD	nucleoside phosphate metabolic process	169/3918	497/18723	4.99e-12	6.98e-10	169
GO:0042177	Colorectum	AD	negative regulation of protein catabolic process	55/3918	121/18723	1.19e-09	8.85e-08	55
GO:0044282	Colorectum	AD	small molecule catabolic process	118/3918	376/18723	1.05e-06	3.55e-05	118
GO:0007623	Colorectum	AD	circadian rhythm	72/3918	210/18723	4.50e-06	1.21e-04	72
GO:0006164	Colorectum	AD	purine nucleotide biosynthetic process	66/3918	191/18723	8.22e-06	1.97e-04	66
GO:0043467	Colorectum	AD	regulation of generation of precursor metabolites and energy	49/3918	130/18723	8.33e-06	1.99e-04	49
GO:0048511	Colorectum	AD	rhythmic process	94/3918	298/18723	1.00e-05	2.34e-04	94
GO:0072522	Colorectum	AD	purine-containing compound biosynthetic process	68/3918	200/18723	1.12e-05	2.55e-04	68
GO:1901293	Colorectum	AD	nucleoside phosphate biosynthetic process	80/3918	256/18723	6.31e-05	1.05e-03	80
GO:0050708	Colorectum	AD	regulation of protein secretion	83/3918	268/18723	6.59e-05	1.07e-03	83
GO:0009165	Colorectum	AD	nucleotide biosynthetic process	79/3918	254/18723	8.33e-05	1.30e-03	79
GO:0009306	Colorectum	AD	protein secretion	105/3918	359/18723	1.05e-04	1.57e-03	105

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05014	Colorectum	AD	Amyotrophic lateral sclerosis	164/2092	364/8465	4.28e-18	1.27e-16	8.09e-17	164
hsa05022	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa050141	Colorectum	AD	Amyotrophic lateral sclerosis	164/2092	364/8465	4.28e-18	1.27e-16	8.09e-17	164
hsa050221	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa050104	Colorectum	MSS	Alzheimer disease	169/1875	384/8465	1.21e-22	1.01e-20	6.21e-21	169
hsa050224	Colorectum	MSS	Pathways of neurodegeneration - multiple diseases	192/1875	476/8465	2.79e-20	1.04e-18	6.36e-19	192
hsa050144	Colorectum	MSS	Amyotrophic lateral sclerosis	156/1875	364/8465	1.43e-19	4.62e-18	2.83e-18	156
hsa040664	Colorectum	MSS	HIF-1 signaling pathway	39/1875	109/8465	7.61e-04	5.00e-03	3.06e-03	39
hsa04926	Colorectum	MSS	Relaxin signaling pathway	40/1875	129/8465	1.18e-02	3.99e-02	2.44e-02	40
hsa05222	Colorectum	MSS	Small cell lung cancer	30/1875	92/8465	1.31e-02	4.30e-02	2.64e-02	30
hsa050105	Colorectum	MSS	Alzheimer disease	169/1875	384/8465	1.21e-22	1.01e-20	6.21e-21	169
hsa050225	Colorectum	MSS	Pathways of neurodegeneration - multiple diseases	192/1875	476/8465	2.79e-20	1.04e-18	6.36e-19	192
hsa050145	Colorectum	MSS	Amyotrophic lateral sclerosis	156/1875	364/8465	1.43e-19	4.62e-18	2.83e-18	156
hsa040665	Colorectum	MSS	HIF-1 signaling pathway	39/1875	109/8465	7.61e-04	5.00e-03	3.06e-03	39
hsa049261	Colorectum	MSS	Relaxin signaling pathway	40/1875	129/8465	1.18e-02	3.99e-02	2.44e-02	40
hsa052221	Colorectum	MSS	Small cell lung cancer	30/1875	92/8465	1.31e-02	4.30e-02	2.64e-02	30
hsa050108	Colorectum	FAP	Alzheimer disease	105/1404	384/8465	3.74e-08	1.04e-06	6.33e-07	105
hsa040666	Colorectum	FAP	HIF-1 signaling pathway	38/1404	109/8465	2.43e-06	4.28e-05	2.60e-05	38
hsa050228	Colorectum	FAP	Pathways of neurodegeneration - multiple diseases	117/1404	476/8465	2.81e-06	4.47e-05	2.72e-05	117
hsa050148	Colorectum	FAP	Amyotrophic lateral sclerosis	91/1404	364/8465	1.84e-05	2.36e-04	1.44e-04	91

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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

NOS2

SNV

Missense_Mutation

c.1462N>G

p.Phe488Val

p.F488V

P35228

protein_coding

tolerated(0.17)

probably_damaging(1)

TCGA-A7-A13D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

NOS2

SNV

Missense_Mutation

novel

c.3189G>T

p.Gln1063His

p.Q1063H

P35228

protein_coding

deleterious(0.01)

possibly_damaging(0.663)

TCGA-A8-A0A1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

NOS2

SNV

Missense_Mutation

c.1672N>A

p.Gly558Arg

p.G558R

P35228

protein_coding

tolerated(0.69)

benign(0.056)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NOS2

SNV

Missense_Mutation

c.1536N>C

p.Glu512Asp

p.E512D

P35228

protein_coding

tolerated(0.06)

benign(0.075)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NOS2

SNV

Missense_Mutation

rs766602194

c.433N>A

p.Glu145Lys

p.E145K

P35228

protein_coding

deleterious(0.03)

benign(0.348)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NOS2

SNV

Missense_Mutation

c.1954N>G

p.Gln652Glu

p.Q652E

P35228

protein_coding

deleterious(0.01)

possibly_damaging(0.785)

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

NOS2

SNV

Missense_Mutation

novel

c.1564N>T

p.Val522Leu

p.V522L

P35228

protein_coding

deleterious(0.03)

possibly_damaging(0.459)

TCGA-AO-A0JM-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NOS2

SNV

Missense_Mutation

c.2968N>A

p.Arg990Ser

p.R990S

P35228

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C8-A12W-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NOS2

SNV

Missense_Mutation

rs201644791

c.874N>A

p.Asp292Asn

p.D292N

P35228

protein_coding

tolerated(0.12)

benign(0.419)

TCGA-D8-A1Y1-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

NOS2

SNV

Missense_Mutation

rs201165915

c.181G>A

p.Val61Met

p.V61M

P35228

protein_coding

tolerated(0.21)

benign(0.006)

TCGA-E2-A1IG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

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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
4843	NOS2	DRUGGABLE GENOME, ENZYME		GW274150	GW-274150
4843	NOS2	DRUGGABLE GENOME, ENZYME		TILARGININE	TILARGININE
4843	NOS2	DRUGGABLE GENOME, ENZYME		HP-228
4843	NOS2	DRUGGABLE GENOME, ENZYME		BENZODIAZEPINE	BENZODIAZEPINE	12106778
4843	NOS2	DRUGGABLE GENOME, ENZYME	inhibitor	363894143	GW-274150
4843	NOS2	DRUGGABLE GENOME, ENZYME		KD7040	KD7040
4843	NOS2	DRUGGABLE GENOME, ENZYME		ibuprofen	IBUPROFEN	25502615
4843	NOS2	DRUGGABLE GENOME, ENZYME		VEGF		10928051
4843	NOS2	DRUGGABLE GENOME, ENZYME		Curcumin	CURCUMIN
4843	NOS2	DRUGGABLE GENOME, ENZYME	inhibitor	178101915

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