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: CBLC

Gene summary for CBLC

Gene summary.

Gene information	Species	Human
	Gene symbol	CBLC
	Gene ID	23624
	Gene name	Cbl proto-oncogene C
	Gene Alias	CBL-3
	Cytomap	19q13.32
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q9ULV8

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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
23624	CBLC	HTA11_3410_2000001011	Human	Colorectum	AD	1.03e-02	-3.22e-01	0.0155
23624	CBLC	HTA11_347_2000001011	Human	Colorectum	AD	1.06e-04	3.61e-01	-0.1954
23624	CBLC	HTA11_99999970781_79442	Human	Colorectum	MSS	9.28e-06	-3.60e-01	0.294
23624	CBLC	A002-C-010	Human	Colorectum	FAP	2.81e-05	-3.07e-01	0.242
23624	CBLC	A015-C-203	Human	Colorectum	FAP	2.26e-18	-2.73e-01	-0.1294
23624	CBLC	A015-C-204	Human	Colorectum	FAP	6.79e-03	3.51e-02	-0.0228
23624	CBLC	A014-C-040	Human	Colorectum	FAP	1.88e-02	-3.00e-01	-0.1184
23624	CBLC	A002-C-201	Human	Colorectum	FAP	1.24e-07	-2.05e-01	0.0324
23624	CBLC	A002-C-203	Human	Colorectum	FAP	1.92e-04	-1.39e-01	0.2786
23624	CBLC	A001-C-119	Human	Colorectum	FAP	6.05e-06	-3.93e-01	-0.1557
23624	CBLC	A001-C-108	Human	Colorectum	FAP	2.87e-11	-2.25e-01	-0.0272
23624	CBLC	A002-C-205	Human	Colorectum	FAP	3.38e-16	-4.05e-01	-0.1236
23624	CBLC	A015-C-005	Human	Colorectum	FAP	4.82e-04	-2.64e-01	-0.0336
23624	CBLC	A015-C-006	Human	Colorectum	FAP	8.29e-08	-2.52e-01	-0.0994
23624	CBLC	A015-C-106	Human	Colorectum	FAP	2.72e-08	-1.97e-01	-0.0511
23624	CBLC	A002-C-114	Human	Colorectum	FAP	1.44e-13	-4.01e-01	-0.1561
23624	CBLC	A015-C-104	Human	Colorectum	FAP	1.04e-21	-3.83e-01	-0.1899
23624	CBLC	A001-C-014	Human	Colorectum	FAP	5.61e-11	-3.01e-01	0.0135
23624	CBLC	A002-C-016	Human	Colorectum	FAP	1.30e-15	-3.66e-01	0.0521
23624	CBLC	A015-C-002	Human	Colorectum	FAP	2.78e-05	-2.18e-01	-0.0763

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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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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

∗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:0038127	Colorectum	AD	ERBB signaling pathway	55/3918	121/18723	1.19e-09	8.85e-08	55
GO:0007173	Colorectum	AD	epidermal growth factor receptor signaling pathway	50/3918	108/18723	3.08e-09	2.07e-07	50
GO:1901185	Colorectum	AD	negative regulation of ERBB signaling pathway	19/3918	32/18723	2.39e-06	6.98e-05	19
GO:1901184	Colorectum	AD	regulation of ERBB signaling pathway	34/3918	79/18723	7.46e-06	1.82e-04	34
GO:0010563	Colorectum	AD	negative regulation of phosphorus metabolic process	130/3918	442/18723	1.26e-05	2.76e-04	130
GO:0045936	Colorectum	AD	negative regulation of phosphate metabolic process	129/3918	441/18723	1.81e-05	3.76e-04	129
GO:0051348	Colorectum	AD	negative regulation of transferase activity	85/3918	268/18723	2.07e-05	4.19e-04	85
GO:0042058	Colorectum	AD	regulation of epidermal growth factor receptor signaling pathway	31/3918	73/18723	2.56e-05	4.89e-04	31
GO:0042059	Colorectum	AD	negative regulation of epidermal growth factor receptor signaling pathway	16/3918	28/18723	2.96e-05	5.46e-04	16
GO:0042326	Colorectum	AD	negative regulation of phosphorylation	112/3918	385/18723	8.02e-05	1.27e-03	112
GO:0001933	Colorectum	AD	negative regulation of protein phosphorylation	101/3918	342/18723	9.39e-05	1.42e-03	101
GO:0043409	Colorectum	AD	negative regulation of MAPK cascade	57/3918	180/18723	4.61e-04	5.14e-03	57
GO:0006469	Colorectum	AD	negative regulation of protein kinase activity	65/3918	212/18723	5.21e-04	5.62e-03	65
GO:0033673	Colorectum	AD	negative regulation of kinase activity	71/3918	237/18723	6.18e-04	6.47e-03	71
GO:0071900	Colorectum	AD	regulation of protein serine/threonine kinase activity	98/3918	359/18723	2.18e-03	1.73e-02	98
GO:0061099	Colorectum	AD	negative regulation of protein tyrosine kinase activity	13/3918	31/18723	6.53e-03	4.06e-02	13
GO:00071732	Colorectum	MSS	epidermal growth factor receptor signaling pathway	43/3467	108/18723	1.92e-07	8.31e-06	43
GO:00381272	Colorectum	MSS	ERBB signaling pathway	46/3467	121/18723	3.63e-07	1.45e-05	46
GO:00513482	Colorectum	MSS	negative regulation of transferase activity	80/3467	268/18723	4.06e-06	1.17e-04	80
GO:00105632	Colorectum	MSS	negative regulation of phosphorus metabolic process	118/3467	442/18723	1.18e-05	2.77e-04	118

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04144	Colorectum	AD	Endocytosis	111/2092	251/8465	5.95e-12	1.42e-10	9.08e-11	111
hsa04120	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa041441	Colorectum	AD	Endocytosis	111/2092	251/8465	5.95e-12	1.42e-10	9.08e-11	111
hsa041201	Colorectum	AD	Ubiquitin mediated proteolysis	58/2092	142/8465	1.46e-05	1.53e-04	9.76e-05	58
hsa041444	Colorectum	MSS	Endocytosis	102/1875	251/8465	1.85e-11	4.43e-10	2.71e-10	102
hsa041204	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa041445	Colorectum	MSS	Endocytosis	102/1875	251/8465	1.85e-11	4.43e-10	2.71e-10	102
hsa041205	Colorectum	MSS	Ubiquitin mediated proteolysis	55/1875	142/8465	5.02e-06	6.00e-05	3.68e-05	55
hsa041446	Colorectum	FAP	Endocytosis	78/1404	251/8465	6.20e-09	2.96e-07	1.80e-07	78
hsa041206	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa041447	Colorectum	FAP	Endocytosis	78/1404	251/8465	6.20e-09	2.96e-07	1.80e-07	78
hsa041207	Colorectum	FAP	Ubiquitin mediated proteolysis	51/1404	142/8465	1.55e-08	5.84e-07	3.55e-07	51
hsa041448	Colorectum	CRC	Endocytosis	65/1091	251/8465	1.27e-08	1.06e-06	7.19e-07	65
hsa041208	Colorectum	CRC	Ubiquitin mediated proteolysis	42/1091	142/8465	9.98e-08	6.67e-06	4.52e-06	42
hsa041449	Colorectum	CRC	Endocytosis	65/1091	251/8465	1.27e-08	1.06e-06	7.19e-07	65
hsa041209	Colorectum	CRC	Ubiquitin mediated proteolysis	42/1091	142/8465	9.98e-08	6.67e-06	4.52e-06	42
hsa0412027	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa04144210	Esophagus	ESCC	Endocytosis	186/4205	251/8465	9.74e-16	4.66e-14	2.39e-14	186
hsa0412036	Esophagus	ESCC	Ubiquitin mediated proteolysis	122/4205	142/8465	6.53e-20	7.29e-18	3.74e-18	122
hsa0414437	Esophagus	ESCC	Endocytosis	186/4205	251/8465	9.74e-16	4.66e-14	2.39e-14	186

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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

CBLC

SNV

Missense_Mutation

novel

c.740N>C

p.Val247Ala

p.V247A

Q9ULV8

protein_coding

deleterious(0.02)

probably_damaging(0.999)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CBLC

SNV

Missense_Mutation

c.1387C>G

p.Pro463Ala

p.P463A

Q9ULV8

protein_coding

tolerated_low_confidence(0.15)

benign(0.003)

TCGA-AR-A1AY-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unspecific

Doxorubicin

CBLC

SNV

Missense_Mutation

rs752145860

c.499N>G

p.Arg167Gly

p.R167G

Q9ULV8

protein_coding

deleterious(0.01)

probably_damaging(0.985)

TCGA-B6-A400-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

CBLC

insertion

Nonsense_Mutation

novel

c.860_861insACCCAGGACCCCAGAGAGTTGATAACTCAGAGG

p.Thr287_Ile288insProArgThrProGluSerTerTerLeuArgGly

p.T287_I288insPRTPES**LRG

Q9ULV8

protein_coding

TCGA-A8-A09Q-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

CBLC

deletion

Frame_Shift_Del

novel

c.1407delN

p.Asp470ThrfsTer?

p.D470Tfs*?

Q9ULV8

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

CBLC

SNV

Missense_Mutation

rs770372319

c.40N>A

p.Glu14Lys

p.E14K

Q9ULV8

protein_coding

deleterious(0.03)

benign(0.003)

TCGA-C5-A1MK-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

carboplatin

CBLC

SNV

Missense_Mutation

rs763654909

c.1066G>A

p.Glu356Lys

p.E356K

Q9ULV8

protein_coding

deleterious(0)

probably_damaging(0.96)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CBLC

SNV

Missense_Mutation

novel

c.1186N>C

p.Trp396Arg

p.W396R

Q9ULV8

protein_coding

tolerated(0.37)

benign(0)

TCGA-AD-A5EJ-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

CBLC

SNV

Missense_Mutation

c.706N>T

p.Pro236Ser

p.P236S

Q9ULV8

protein_coding

deleterious(0.02)

probably_damaging(0.998)

TCGA-AU-6004-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

CBLC

SNV

Missense_Mutation

rs745556828

c.1295N>T

p.Ser432Leu

p.S432L

Q9ULV8

protein_coding

deleterious(0.04)

benign(0)

TCGA-AZ-6598-01

Colorectum

colon adenocarcinoma

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
23624	CBLC	CLINICALLY ACTIONABLE, KINASE, ENZYME		Olaparib	OLAPARIB	25883215
23624	CBLC	CLINICALLY ACTIONABLE, KINASE, ENZYME		N/A		17671213

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