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: RBFOX2

Gene summary for RBFOX2

Gene summary.

Gene information	Species	Human
	Gene symbol	RBFOX2
	Gene ID	23543
	Gene name	RNA binding fox-1 homolog 2
	Gene Alias	FOX2
	Cytomap	22q12.3
	Gene Type	protein-coding
	GO ID	GO:0000375
	UniProtAcc	O43251

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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
23543	RBFOX2	CA_HPV_3	Human	Cervix	CC	4.95e-04	1.70e-01	0.0414
23543	RBFOX2	CCI_1	Human	Cervix	CC	7.99e-16	1.70e+00	0.528
23543	RBFOX2	CCI_2	Human	Cervix	CC	2.32e-10	1.25e+00	0.5249
23543	RBFOX2	CCI_3	Human	Cervix	CC	1.03e-24	1.37e+00	0.516
23543	RBFOX2	sample3	Human	Cervix	CC	4.63e-06	2.08e-01	0.1387
23543	RBFOX2	T3	Human	Cervix	CC	4.77e-04	1.92e-01	0.1389
23543	RBFOX2	HTA11_3410_2000001011	Human	Colorectum	AD	1.28e-41	1.22e+00	0.0155
23543	RBFOX2	HTA11_2487_2000001011	Human	Colorectum	SER	8.55e-37	2.23e+00	-0.1808
23543	RBFOX2	HTA11_2951_2000001011	Human	Colorectum	AD	1.23e-32	2.85e+00	0.0216
23543	RBFOX2	HTA11_1938_2000001011	Human	Colorectum	AD	5.35e-37	2.30e+00	-0.0811
23543	RBFOX2	HTA11_78_2000001011	Human	Colorectum	AD	8.14e-11	7.39e-01	-0.1088
23543	RBFOX2	HTA11_347_2000001011	Human	Colorectum	AD	9.79e-43	2.28e+00	-0.1954
23543	RBFOX2	HTA11_411_2000001011	Human	Colorectum	SER	3.88e-34	2.91e+00	-0.2602
23543	RBFOX2	HTA11_2112_2000001011	Human	Colorectum	SER	4.42e-20	2.32e+00	-0.2196
23543	RBFOX2	HTA11_3361_2000001011	Human	Colorectum	AD	2.94e-33	2.64e+00	-0.1207
23543	RBFOX2	HTA11_83_2000001011	Human	Colorectum	SER	5.46e-33	2.16e+00	-0.1526
23543	RBFOX2	HTA11_696_2000001011	Human	Colorectum	AD	1.85e-67	2.73e+00	-0.1464
23543	RBFOX2	HTA11_866_2000001011	Human	Colorectum	AD	9.98e-51	2.51e+00	-0.1001
23543	RBFOX2	HTA11_1391_2000001011	Human	Colorectum	AD	2.30e-47	2.97e+00	-0.059
23543	RBFOX2	HTA11_2992_2000001011	Human	Colorectum	SER	1.28e-35	2.51e+00	-0.1706

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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
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
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:00305204	Lung	IAC	intracellular estrogen receptor signaling pathway	13/2061	54/18723	4.89e-03	3.78e-02	13
GO:19037068	Lung	IAC	regulation of hemopoiesis	56/2061	367/18723	7.23e-03	4.94e-02	56
GO:004348413	Lung	AIS	regulation of RNA splicing	45/1849	148/18723	2.75e-12	2.67e-09	45
GO:004802413	Lung	AIS	regulation of mRNA splicing, via spliceosome	32/1849	101/18723	1.20e-09	2.42e-07	32
GO:190331112	Lung	AIS	regulation of mRNA metabolic process	60/1849	288/18723	1.74e-08	2.47e-06	60
GO:005068412	Lung	AIS	regulation of mRNA processing	36/1849	137/18723	3.06e-08	3.79e-06	36
GO:003052213	Lung	AIS	intracellular receptor signaling pathway	53/1849	265/18723	4.57e-07	3.55e-05	53
GO:001635812	Lung	AIS	dendrite development	49/1849	243/18723	9.53e-07	6.69e-05	49
GO:000038112	Lung	AIS	regulation of alternative mRNA splicing, via spliceosome	19/1849	60/18723	2.77e-06	1.52e-04	19
GO:003051812	Lung	AIS	intracellular steroid hormone receptor signaling pathway	28/1849	116/18723	6.14e-06	2.82e-04	28
GO:003410113	Lung	AIS	erythrocyte homeostasis	30/1849	129/18723	6.51e-06	2.92e-04	30
GO:007138313	Lung	AIS	cellular response to steroid hormone stimulus	41/1849	204/18723	7.76e-06	3.35e-04	41
GO:004854513	Lung	AIS	response to steroid hormone	59/1849	339/18723	1.15e-05	4.65e-04	59
GO:000038012	Lung	AIS	alternative mRNA splicing, via spliceosome	21/1849	77/18723	1.19e-05	4.71e-04	21
GO:003021813	Lung	AIS	erythrocyte differentiation	28/1849	120/18723	1.22e-05	4.71e-04	28
GO:003009913	Lung	AIS	myeloid cell differentiation	63/1849	381/18723	3.05e-05	9.70e-04	63
GO:000226213	Lung	AIS	myeloid cell homeostasis	32/1849	157/18723	5.57e-05	1.57e-03	32
GO:004881311	Lung	AIS	dendrite morphogenesis	30/1849	146/18723	8.03e-05	2.02e-03	30
GO:000838013	Lung	AIS	RNA splicing	68/1849	434/18723	8.50e-05	2.11e-03	68
GO:004887213	Lung	AIS	homeostasis of number of cells	47/1849	272/18723	1.03e-04	2.50e-03	47

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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
RBFOX2	NUER	Prostate	ADJ	PPP1R12B,CHD9,DHX8, etc.	0.00e+00
RBFOX2	BAS	Prostate	ADJ	PPP1R12B,CHD9,DHX8, etc.	0.00e+00
RBFOX2	BAS	Prostate	Tumor	PPP1R12B,CHD9,DHX8, etc.	8.56e-03
RBFOX2	NUER	Prostate	Tumor	PPP1R12B,CHD9,DHX8, etc.	7.36e-03

∗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

RBFOX2

SNV

Missense_Mutation

c.964A>G

p.Ser322Gly

p.S322G

O43251

protein_coding

tolerated_low_confidence(0.31)

benign(0.015)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

RBFOX2

SNV

Missense_Mutation

novel

c.383N>C

p.Asn128Thr

p.N128T

O43251

protein_coding

tolerated(0.93)

benign(0.019)

TCGA-D8-A1XG-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

RBFOX2

SNV

Missense_Mutation

c.434N>T

p.Ser145Leu

p.S145L

O43251

protein_coding

deleterious(0.04)

benign(0.015)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

RBFOX2

SNV

Missense_Mutation

novel

c.383N>C

p.Asn128Thr

p.N128T

O43251

protein_coding

tolerated(0.93)

benign(0.019)

TCGA-E9-A1RE-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

RBFOX2

insertion

Frame_Shift_Ins

novel

c.547_548insTTTAT

p.Arg183LeufsTer29

p.R183Lfs*29

O43251

protein_coding

TCGA-A8-A079-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

RBFOX2

insertion

Nonsense_Mutation

novel

c.546_547insGCATTACGATGATAGGATTGCAGATTAT

p.Arg183AlafsTer4

p.R183Afs*4

O43251

protein_coding

TCGA-A8-A079-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

RBFOX2

SNV

Missense_Mutation

c.1073G>A

p.Arg358Gln

p.R358Q

O43251

protein_coding

deleterious(0.02)

probably_damaging(0.996)

TCGA-C5-A1MH-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

cisplatin

RBFOX2

SNV

Missense_Mutation

novel

c.511N>C

p.Ser171Arg

p.S171R

O43251

protein_coding

tolerated(0.3)

benign(0.147)

TCGA-5M-AAT6-01

Colorectum

colon adenocarcinoma

Female

<65

III/IV

Unknown

RBFOX2

SNV

Missense_Mutation

c.1018N>A

p.Ala340Thr

p.A340T

O43251

protein_coding

tolerated(0.06)

benign(0.154)

TCGA-AA-3877-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

RBFOX2

SNV

Missense_Mutation

novel

c.292N>T

p.Ile98Phe

p.I98F

O43251

protein_coding

tolerated_low_confidence(0.09)

possibly_damaging(0.791)

TCGA-AM-5820-01

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

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