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: NCL

Gene summary for NCL

Gene summary.

Gene information	Species	Human
	Gene symbol	NCL
	Gene ID	4691
	Gene name	nucleolin
	Gene Alias	C23
	Cytomap	2q37.1
	Gene Type	protein-coding
	GO ID	GO:0000375
	UniProtAcc	A0A024R4A0

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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
4691	NCL	CA_HPV_1	Human	Cervix	CC	4.72e-16	6.24e-02	0.0264
4691	NCL	CA_HPV_3	Human	Cervix	CC	1.94e-02	2.23e-01	0.0414
4691	NCL	CCI_1	Human	Cervix	CC	1.52e-15	-9.54e-01	0.528
4691	NCL	CCI_3	Human	Cervix	CC	2.24e-02	-4.02e-01	0.516
4691	NCL	CCII_1	Human	Cervix	CC	2.21e-17	-8.02e-01	0.3249
4691	NCL	Tumor	Human	Cervix	CC	1.33e-11	-4.11e-01	0.1241
4691	NCL	sample3	Human	Cervix	CC	5.01e-17	-3.74e-01	0.1387
4691	NCL	L1	Human	Cervix	CC	3.17e-10	-5.94e-01	0.0802
4691	NCL	T1	Human	Cervix	CC	4.68e-03	-3.47e-01	0.0918
4691	NCL	T3	Human	Cervix	CC	1.71e-15	-3.70e-01	0.1389
4691	NCL	HTA11_3410_2000001011	Human	Colorectum	AD	1.81e-06	2.44e-01	0.0155
4691	NCL	HTA11_1938_2000001011	Human	Colorectum	AD	2.19e-09	6.93e-01	-0.0811
4691	NCL	HTA11_78_2000001011	Human	Colorectum	AD	3.71e-09	6.10e-01	-0.1088
4691	NCL	HTA11_347_2000001011	Human	Colorectum	AD	1.01e-22	8.11e-01	-0.1954
4691	NCL	HTA11_83_2000001011	Human	Colorectum	SER	1.63e-05	5.53e-01	-0.1526
4691	NCL	HTA11_696_2000001011	Human	Colorectum	AD	4.22e-09	5.12e-01	-0.1464
4691	NCL	HTA11_866_2000001011	Human	Colorectum	AD	1.96e-07	4.30e-01	-0.1001
4691	NCL	HTA11_1391_2000001011	Human	Colorectum	AD	4.45e-18	1.20e+00	-0.059
4691	NCL	HTA11_546_2000001011	Human	Colorectum	AD	3.76e-06	6.57e-01	-0.0842
4691	NCL	HTA11_7862_2000001011	Human	Colorectum	AD	1.71e-09	7.95e-01	-0.0179

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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
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:004348410	Cervix	CC	regulation of RNA splicing	42/2311	148/18723	1.25e-07	6.24e-06	42
GO:19033119	Cervix	CC	regulation of mRNA metabolic process	64/2311	288/18723	1.71e-06	5.64e-05	64
GO:000641710	Cervix	CC	regulation of translation	89/2311	468/18723	1.86e-05	3.46e-04	89
GO:004802410	Cervix	CC	regulation of mRNA splicing, via spliceosome	28/2311	101/18723	2.41e-05	4.19e-04	28
GO:00713648	Cervix	CC	cellular response to epidermal growth factor stimulus	16/2311	45/18723	5.24e-05	7.83e-04	16
GO:00506849	Cervix	CC	regulation of mRNA processing	33/2311	137/18723	1.06e-04	1.35e-03	33
GO:00708498	Cervix	CC	response to epidermal growth factor	16/2311	49/18723	1.67e-04	1.99e-03	16
GO:19033136	Cervix	CC	positive regulation of mRNA metabolic process	29/2311	118/18723	1.86e-04	2.18e-03	29
GO:00331208	Cervix	CC	positive regulation of RNA splicing	13/2311	37/18723	2.99e-04	3.21e-03	13
GO:000838010	Cervix	CC	RNA splicing	76/2311	434/18723	9.79e-04	8.19e-03	76
GO:19908234	Cervix	CC	response to leukemia inhibitory factor	22/2311	95/18723	2.40e-03	1.70e-02	22
GO:19908304	Cervix	CC	cellular response to leukemia inhibitory factor	21/2311	94/18723	4.68e-03	2.82e-02	21
GO:000037710	Cervix	CC	RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	55/2311	320/18723	6.71e-03	3.70e-02	55
GO:000039810	Cervix	CC	mRNA splicing, via spliceosome	55/2311	320/18723	6.71e-03	3.70e-02	55
GO:000037510	Cervix	CC	RNA splicing, via transesterification reactions	55/2311	324/18723	8.61e-03	4.44e-02	55
GO:0008380	Colorectum	AD	RNA splicing	169/3918	434/18723	3.59e-18	2.04e-15	169
GO:0000377	Colorectum	AD	RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	130/3918	320/18723	5.88e-16	2.16e-13	130
GO:0000398	Colorectum	AD	mRNA splicing, via spliceosome	130/3918	320/18723	5.88e-16	2.16e-13	130
GO:0000375	Colorectum	AD	RNA splicing, via transesterification reactions	131/3918	324/18723	7.11e-16	2.22e-13	131
GO:1903311	Colorectum	AD	regulation of mRNA metabolic process	117/3918	288/18723	1.69e-14	4.23e-12	117

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0513020	Cervix	CC	Pathogenic Escherichia coli infection	63/1267	197/8465	9.28e-10	2.00e-08	1.19e-08	63
hsa05130110	Cervix	CC	Pathogenic Escherichia coli infection	63/1267	197/8465	9.28e-10	2.00e-08	1.19e-08	63
hsa05130	Colorectum	AD	Pathogenic Escherichia coli infection	79/2092	197/8465	1.05e-06	1.36e-05	8.65e-06	79
hsa051301	Colorectum	AD	Pathogenic Escherichia coli infection	79/2092	197/8465	1.05e-06	1.36e-05	8.65e-06	79
hsa051302	Colorectum	SER	Pathogenic Escherichia coli infection	60/1580	197/8465	3.63e-05	4.31e-04	3.13e-04	60
hsa051303	Colorectum	SER	Pathogenic Escherichia coli infection	60/1580	197/8465	3.63e-05	4.31e-04	3.13e-04	60
hsa051304	Colorectum	MSS	Pathogenic Escherichia coli infection	73/1875	197/8465	1.10e-06	1.48e-05	9.06e-06	73
hsa051305	Colorectum	MSS	Pathogenic Escherichia coli infection	73/1875	197/8465	1.10e-06	1.48e-05	9.06e-06	73
hsa051306	Colorectum	MSI-H	Pathogenic Escherichia coli infection	31/797	197/8465	2.90e-03	2.93e-02	2.46e-02	31
hsa051307	Colorectum	MSI-H	Pathogenic Escherichia coli infection	31/797	197/8465	2.90e-03	2.93e-02	2.46e-02	31
hsa051308	Colorectum	FAP	Pathogenic Escherichia coli infection	62/1404	197/8465	1.37e-07	3.08e-06	1.87e-06	62
hsa051309	Colorectum	FAP	Pathogenic Escherichia coli infection	62/1404	197/8465	1.37e-07	3.08e-06	1.87e-06	62
hsa0513010	Colorectum	CRC	Pathogenic Escherichia coli infection	47/1091	197/8465	1.49e-05	3.84e-04	2.60e-04	47
hsa0513011	Colorectum	CRC	Pathogenic Escherichia coli infection	47/1091	197/8465	1.49e-05	3.84e-04	2.60e-04	47
hsa0513026	Endometrium	AEH	Pathogenic Escherichia coli infection	50/1197	197/8465	1.72e-05	1.86e-04	1.36e-04	50
hsa05130112	Endometrium	AEH	Pathogenic Escherichia coli infection	50/1197	197/8465	1.72e-05	1.86e-04	1.36e-04	50
hsa0513027	Endometrium	EEC	Pathogenic Escherichia coli infection	51/1237	197/8465	1.98e-05	2.28e-04	1.70e-04	51
hsa0513036	Endometrium	EEC	Pathogenic Escherichia coli infection	51/1237	197/8465	1.98e-05	2.28e-04	1.70e-04	51
hsa05130211	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142
hsa05130310	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142

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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
MDK	NCL	MDK_NCL	MK	Breast	ADJ
MDK	NCL	MDK_NCL	MK	Breast	DCIS
PTN	NCL	PTN_NCL	PTN	Breast	DCIS
MDK	NCL	MDK_NCL	MK	Breast	Healthy
PTN	NCL	PTN_NCL	PTN	Breast	Healthy
MDK	NCL	MDK_NCL	MK	Breast	IDC
MDK	NCL	MDK_NCL	MK	Breast	Precancer
MDK	NCL	MDK_NCL	MK	Cervix	ADJ
PTN	NCL	PTN_NCL	PTN	Cervix	ADJ
MDK	NCL	MDK_NCL	MK	Cervix	CC
PTN	NCL	PTN_NCL	PTN	Cervix	CC
MDK	NCL	MDK_NCL	MK	Cervix	Healthy
MDK	NCL	MDK_NCL	MK	Cervix	Precancer
PTN	NCL	PTN_NCL	PTN	Cervix	Precancer
MDK	NCL	MDK_NCL	MK	CRC	AD
PTN	NCL	PTN_NCL	PTN	CRC	AD
MDK	NCL	MDK_NCL	MK	CRC	ADJ
MDK	NCL	MDK_NCL	MK	CRC	MSI-H
MDK	NCL	MDK_NCL	MK	CRC	MSS
MDK	NCL	MDK_NCL	MK	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

NCL

SNV

Missense_Mutation

novel

c.581A>G

p.Asp194Gly

p.D194G

P19338

protein_coding

tolerated_low_confidence(0.07)

benign(0)

TCGA-A8-A083-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

rs769718813

c.511G>A

p.Glu171Lys

p.E171K

P19338

protein_coding

tolerated_low_confidence(0.21)

benign(0.003)

TCGA-A8-A095-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

NCL

SNV

Missense_Mutation

c.94N>A

p.Glu32Lys

p.E32K

P19338

protein_coding

deleterious_low_confidence(0.01)

benign(0.257)

TCGA-A8-A0A7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NCL

SNV

Missense_Mutation

c.2063N>A

p.Gly688Glu

p.G688E

P19338

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.999)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

c.2021N>T

p.Gly674Val

p.G674V

P19338

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.989)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

novel

c.700G>A

p.Glu234Lys

p.E234K

P19338

protein_coding

tolerated(0.37)

benign(0.005)

TCGA-BH-A18U-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

NCL

SNV

Missense_Mutation

c.1789N>T

p.Arg597Trp

p.R597W

P19338

protein_coding

deleterious(0.03)

probably_damaging(0.983)

TCGA-C8-A27A-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

NCL

SNV

Missense_Mutation

c.871N>G

p.Pro291Ala

p.P291A

P19338

protein_coding

tolerated(0.07)

benign(0.1)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

NCL

SNV

Missense_Mutation

c.368N>C

p.Gly123Ala

p.G123A

P19338

protein_coding

tolerated_low_confidence(0.13)

benign(0.175)

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NCL

SNV

Missense_Mutation

novel

c.790G>A

p.Glu264Lys

p.E264K

P19338

protein_coding

tolerated(0.05)

benign(0.19)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

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
4691	NCL	NA		AS1411
4691	NCL	NA		IPP-204106
4691	NCL	NA		Itarnafloxin	QUARFLOXIN	21455236
4691	NCL	NA		IPP-204106
4691	NCL	NA		ACT-GRO-777		25057429

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