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: CBL

Gene summary for CBL

Gene summary.

Gene information	Species	Human
	Gene symbol	CBL
	Gene ID	867
	Gene name	Cbl proto-oncogene
	Gene Alias	C-CBL
	Cytomap	11q23.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P22681

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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
867	CBL	LZE4T	Human	Esophagus	ESCC	1.29e-06	1.76e-01	0.0811
867	CBL	LZE20T	Human	Esophagus	ESCC	4.46e-02	5.96e-02	0.0662
867	CBL	LZE22D1	Human	Esophagus	HGIN	4.11e-03	2.19e-01	0.0595
867	CBL	LZE22T	Human	Esophagus	ESCC	1.71e-12	7.21e-01	0.068
867	CBL	LZE24T	Human	Esophagus	ESCC	6.27e-15	2.81e-01	0.0596
867	CBL	P2T-E	Human	Esophagus	ESCC	1.06e-05	9.22e-02	0.1177
867	CBL	P4T-E	Human	Esophagus	ESCC	4.16e-16	3.61e-01	0.1323
867	CBL	P5T-E	Human	Esophagus	ESCC	5.82e-08	1.64e-01	0.1327
867	CBL	P8T-E	Human	Esophagus	ESCC	3.13e-07	1.16e-01	0.0889
867	CBL	P9T-E	Human	Esophagus	ESCC	9.93e-13	1.12e-01	0.1131
867	CBL	P10T-E	Human	Esophagus	ESCC	2.10e-07	1.34e-01	0.116
867	CBL	P11T-E	Human	Esophagus	ESCC	4.70e-10	2.85e-01	0.1426
867	CBL	P12T-E	Human	Esophagus	ESCC	5.27e-08	2.15e-01	0.1122
867	CBL	P15T-E	Human	Esophagus	ESCC	3.88e-05	6.25e-02	0.1149
867	CBL	P16T-E	Human	Esophagus	ESCC	1.64e-04	1.40e-01	0.1153
867	CBL	P17T-E	Human	Esophagus	ESCC	3.31e-05	1.70e-01	0.1278
867	CBL	P19T-E	Human	Esophagus	ESCC	5.34e-03	1.80e-01	0.1662
867	CBL	P20T-E	Human	Esophagus	ESCC	2.61e-03	5.17e-02	0.1124
867	CBL	P21T-E	Human	Esophagus	ESCC	5.98e-20	4.15e-01	0.1617
867	CBL	P22T-E	Human	Esophagus	ESCC	2.50e-06	7.85e-02	0.1236

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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
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:004205915	Thyroid	PTC	negative regulation of epidermal growth factor receptor signaling pathway	20/5968	28/18723	2.01e-05	2.04e-04	20
GO:190118514	Thyroid	PTC	negative regulation of ERBB signaling pathway	22/5968	32/18723	2.03e-05	2.05e-04	22
GO:0044409113	Thyroid	PTC	entry into host	72/5968	151/18723	3.48e-05	3.29e-04	72
GO:004825918	Thyroid	PTC	regulation of receptor-mediated endocytosis	55/5968	110/18723	5.64e-05	4.99e-04	55
GO:00103329	Thyroid	PTC	response to gamma radiation	32/5968	56/18723	8.16e-05	6.94e-04	32
GO:1990089110	Thyroid	PTC	response to nerve growth factor	32/5968	56/18723	8.16e-05	6.94e-04	32
GO:0061458112	Thyroid	PTC	reproductive system development	173/5968	427/18723	8.70e-05	7.23e-04	173
GO:004826017	Thyroid	PTC	positive regulation of receptor-mediated endocytosis	30/5968	52/18723	1.06e-04	8.56e-04	30
GO:0036294112	Thyroid	PTC	cellular response to decreased oxygen levels	74/5968	161/18723	1.23e-04	9.75e-04	74
GO:190118410	Thyroid	PTC	regulation of ERBB signaling pathway	41/5968	79/18723	1.70e-04	1.31e-03	41
GO:0048608111	Thyroid	PTC	reproductive structure development	170/5968	424/18723	1.86e-04	1.41e-03	170
GO:00610974	Thyroid	PTC	regulation of protein tyrosine kinase activity	45/5968	90/18723	2.57e-04	1.84e-03	45
GO:004205810	Thyroid	PTC	regulation of epidermal growth factor receptor signaling pathway	38/5968	73/18723	2.69e-04	1.91e-03	38
GO:0097305113	Thyroid	PTC	response to alcohol	107/5968	253/18723	2.92e-04	2.07e-03	107
GO:004592614	Thyroid	PTC	negative regulation of growth	105/5968	249/18723	3.76e-04	2.54e-03	105
GO:00610999	Thyroid	PTC	negative regulation of protein tyrosine kinase activity	19/5968	31/18723	7.02e-04	4.39e-03	19
GO:00466776	Thyroid	PTC	response to antibiotic	26/5968	47/18723	7.38e-04	4.59e-03	26
GO:00065138	Thyroid	PTC	protein monoubiquitination	34/5968	67/18723	1.00e-03	5.98e-03	34
GO:00303087	Thyroid	PTC	negative regulation of cell growth	80/5968	188/18723	1.28e-03	7.31e-03	80
GO:00071764	Thyroid	PTC	regulation of epidermal growth factor-activated receptor activity	18/5968	30/18723	1.38e-03	7.74e-03	18

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0414429	Esophagus	HGIN	Endocytosis	76/1383	251/8465	1.74e-08	3.34e-07	2.65e-07	76
hsa0412026	Esophagus	HGIN	Ubiquitin mediated proteolysis	49/1383	142/8465	7.78e-08	1.33e-06	1.06e-06	49
hsa0510039	Esophagus	HGIN	Bacterial invasion of epithelial cells	30/1383	77/8465	1.49e-06	2.31e-05	1.84e-05	30
hsa0520528	Esophagus	HGIN	Proteoglycans in cancer	47/1383	205/8465	8.23e-03	4.71e-02	3.74e-02	47
hsa04144113	Esophagus	HGIN	Endocytosis	76/1383	251/8465	1.74e-08	3.34e-07	2.65e-07	76
hsa04120111	Esophagus	HGIN	Ubiquitin mediated proteolysis	49/1383	142/8465	7.78e-08	1.33e-06	1.06e-06	49
hsa05100114	Esophagus	HGIN	Bacterial invasion of epithelial cells	30/1383	77/8465	1.49e-06	2.31e-05	1.84e-05	30
hsa05205112	Esophagus	HGIN	Proteoglycans in cancer	47/1383	205/8465	8.23e-03	4.71e-02	3.74e-02	47
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
hsa0522020	Esophagus	ESCC	Chronic myeloid leukemia	61/4205	76/8465	3.20e-08	2.68e-07	1.37e-07	61
hsa0520529	Esophagus	ESCC	Proteoglycans in cancer	138/4205	205/8465	1.79e-07	1.40e-06	7.15e-07	138
hsa05100211	Esophagus	ESCC	Bacterial invasion of epithelial cells	59/4205	77/8465	1.05e-06	6.76e-06	3.46e-06	59
hsa049109	Esophagus	ESCC	Insulin signaling pathway	89/4205	137/8465	1.97e-04	7.32e-04	3.75e-04	89
hsa0401218	Esophagus	ESCC	ErbB signaling pathway	56/4205	85/8465	1.78e-03	5.24e-03	2.68e-03	56
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
hsa05220110	Esophagus	ESCC	Chronic myeloid leukemia	61/4205	76/8465	3.20e-08	2.68e-07	1.37e-07	61
hsa0520537	Esophagus	ESCC	Proteoglycans in cancer	138/4205	205/8465	1.79e-07	1.40e-06	7.15e-07	138
hsa05100310	Esophagus	ESCC	Bacterial invasion of epithelial cells	59/4205	77/8465	1.05e-06	6.76e-06	3.46e-06	59

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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

CBL

SNV

Missense_Mutation

rs759585425

c.1028N>A

p.Arg343Gln

p.R343Q

P22681

protein_coding

tolerated(0.07)

possibly_damaging(0.68)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CBL

SNV

Missense_Mutation

c.397N>C

p.Phe133Leu

p.F133L

P22681

protein_coding

tolerated(0.22)

probably_damaging(1)

TCGA-AN-A0FT-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CBL

SNV

Missense_Mutation

c.293N>C

p.Ile98Thr

p.I98T

P22681

protein_coding

deleterious(0.02)

benign(0.422)

TCGA-AR-A24S-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

anastrozole

CBL

SNV

Missense_Mutation

novel

c.1501N>C

p.Asp501His

p.D501H

P22681

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-E2-A1LG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CBL

SNV

Missense_Mutation

c.1619N>C

p.Arg540Pro

p.R540P

P22681

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.997)

TCGA-E2-A1LG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CBL

deletion

Frame_Shift_Del

novel

c.2287delN

p.Gly763ValfsTer103

p.G763Vfs*103

P22681

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

CBL

SNV

Missense_Mutation

novel

c.570N>C

p.Trp190Cys

p.W190C

P22681

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C5-A8YR-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CBL

SNV

Missense_Mutation

c.1366N>A

p.Asp456Asn

p.D456N

P22681

protein_coding

deleterious(0)

benign(0.439)

TCGA-LP-A4AV-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CBL

SNV

Missense_Mutation

c.416N>T

p.Arg139Ile

p.R139I

P22681

protein_coding

deleterious(0)

probably_damaging(0.975)

TCGA-AA-3510-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

CBL

SNV

Missense_Mutation

c.617N>A

p.Arg206Gln

p.R206Q

P22681

protein_coding

tolerated(0.09)

probably_damaging(0.978)

TCGA-AA-3510-01

Colorectum

colon adenocarcinoma

Male

>=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
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		Fasudil	FASUDIL	26177294
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		ANTISENSE OLIGONUCLEOTIDES		8849724
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		Gemcitabine	GEMCITABINE	25348515
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		DASATINIB	DASATINIB	23696637
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		SU11274		28835699
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		N/A		26230957,23690417,19901108
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		Quizartinib	QUIZARTINIB	22990016
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		IL-2	ALDESLEUKIN	9461587
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		Erlotinib	ERLOTINIB	25348515
867	CBL	KINASE, ENZYME, CLINICALLY ACTIONABLE		FLT3-LIGAND		17446348

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