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: F2R

Gene summary for F2R

Gene summary.

Gene information	Species	Human
	Gene symbol	F2R
	Gene ID	2149
	Gene name	coagulation factor II thrombin receptor
	Gene Alias	CF2R
	Cytomap	5q13.3
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P25116

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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
2149	F2R	LZE4T	Human	Esophagus	ESCC	6.58e-09	9.37e-02	0.0811
2149	F2R	LZE24T	Human	Esophagus	ESCC	8.04e-04	7.79e-02	0.0596
2149	F2R	P2T-E	Human	Esophagus	ESCC	4.63e-04	5.74e-02	0.1177
2149	F2R	P9T-E	Human	Esophagus	ESCC	5.05e-13	3.89e-01	0.1131
2149	F2R	P10T-E	Human	Esophagus	ESCC	4.05e-16	2.78e-01	0.116
2149	F2R	P11T-E	Human	Esophagus	ESCC	2.51e-04	4.12e-01	0.1426
2149	F2R	P12T-E	Human	Esophagus	ESCC	4.19e-09	2.64e-01	0.1122
2149	F2R	P15T-E	Human	Esophagus	ESCC	1.45e-03	2.26e-01	0.1149
2149	F2R	P19T-E	Human	Esophagus	ESCC	1.41e-05	7.12e-01	0.1662
2149	F2R	P20T-E	Human	Esophagus	ESCC	1.20e-02	1.42e-01	0.1124
2149	F2R	P21T-E	Human	Esophagus	ESCC	1.04e-19	4.74e-01	0.1617
2149	F2R	P22T-E	Human	Esophagus	ESCC	1.66e-10	1.63e-01	0.1236
2149	F2R	P26T-E	Human	Esophagus	ESCC	6.03e-03	4.83e-02	0.1276
2149	F2R	P28T-E	Human	Esophagus	ESCC	2.74e-09	1.37e-01	0.1149
2149	F2R	P30T-E	Human	Esophagus	ESCC	1.35e-02	3.82e-01	0.137
2149	F2R	P31T-E	Human	Esophagus	ESCC	2.35e-19	3.27e-01	0.1251
2149	F2R	P49T-E	Human	Esophagus	ESCC	2.52e-11	1.10e+00	0.1768
2149	F2R	P57T-E	Human	Esophagus	ESCC	1.92e-03	1.43e-01	0.0926
2149	F2R	P62T-E	Human	Esophagus	ESCC	1.33e-03	4.05e-02	0.1302
2149	F2R	P75T-E	Human	Esophagus	ESCC	5.92e-05	2.28e-02	0.1125

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
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:000703422	Oral cavity	EOLP	vacuolar transport	36/2218	157/18723	6.66e-05	8.27e-04	36
GO:004440325	Oral cavity	EOLP	biological process involved in symbiotic interaction	57/2218	290/18723	7.75e-05	9.39e-04	57
GO:004873224	Oral cavity	EOLP	gland development	77/2218	436/18723	2.05e-04	2.06e-03	77
GO:000704122	Oral cavity	EOLP	lysosomal transport	27/2218	114/18723	2.97e-04	2.79e-03	27
GO:001603233	Oral cavity	NEOLP	viral process	101/2005	415/18723	1.08e-15	5.85e-13	101
GO:004440333	Oral cavity	NEOLP	biological process involved in symbiotic interaction	64/2005	290/18723	1.28e-08	6.01e-07	64
GO:003109931	Oral cavity	NEOLP	regeneration	45/2005	198/18723	7.52e-07	2.10e-05	45
GO:000979131	Oral cavity	NEOLP	post-embryonic development	24/2005	80/18723	1.88e-06	4.50e-05	24
GO:000689831	Oral cavity	NEOLP	receptor-mediated endocytosis	51/2005	244/18723	2.08e-06	4.87e-05	51
GO:004873232	Oral cavity	NEOLP	gland development	76/2005	436/18723	1.25e-05	2.25e-04	76
GO:000703431	Oral cavity	NEOLP	vacuolar transport	30/2005	157/18723	1.18e-03	8.72e-03	30
GO:000704131	Oral cavity	NEOLP	lysosomal transport	22/2005	114/18723	4.42e-03	2.49e-02	22
GO:005170221	Oral cavity	NEOLP	biological process involved in interaction with symbiont	18/2005	94/18723	1.02e-02	4.77e-02	18
GO:001603218	Prostate	BPH	viral process	147/3107	415/18723	4.46e-21	5.52e-18	147
GO:004440318	Prostate	BPH	biological process involved in symbiotic interaction	90/3107	290/18723	6.98e-10	3.25e-08	90
GO:004873218	Prostate	BPH	gland development	122/3107	436/18723	1.13e-09	5.01e-08	122
GO:006100816	Prostate	BPH	hepaticobiliary system development	46/3107	150/18723	1.36e-05	1.78e-04	46
GO:000188916	Prostate	BPH	liver development	45/3107	147/18723	1.76e-05	2.18e-04	45
GO:00068989	Prostate	BPH	receptor-mediated endocytosis	66/3107	244/18723	2.34e-05	2.80e-04	66
GO:00447946	Prostate	BPH	positive regulation by host of viral process	9/3107	13/18723	3.55e-05	3.90e-04	9

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05130211	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142
hsa0481028	Esophagus	ESCC	Regulation of actin cytoskeleton	133/4205	229/8465	5.94e-03	1.48e-02	7.56e-03	133
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa05130310	Esophagus	ESCC	Pathogenic Escherichia coli infection	142/4205	197/8465	8.21e-11	1.06e-09	5.42e-10	142
hsa04810112	Esophagus	ESCC	Regulation of actin cytoskeleton	133/4205	229/8465	5.94e-03	1.48e-02	7.56e-03	133
hsa0415114	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0481021	Liver	Cirrhotic	Regulation of actin cytoskeleton	100/2530	229/8465	5.28e-06	5.50e-05	3.39e-05	100
hsa0513022	Liver	Cirrhotic	Pathogenic Escherichia coli infection	88/2530	197/8465	6.48e-06	6.24e-05	3.84e-05	88
hsa0481031	Liver	Cirrhotic	Regulation of actin cytoskeleton	100/2530	229/8465	5.28e-06	5.50e-05	3.39e-05	100
hsa0513032	Liver	Cirrhotic	Pathogenic Escherichia coli infection	88/2530	197/8465	6.48e-06	6.24e-05	3.84e-05	88
hsa0513042	Liver	HCC	Pathogenic Escherichia coli infection	129/4020	197/8465	2.02e-07	2.50e-06	1.39e-06	129
hsa046104	Liver	HCC	Complement and coagulation cascades	57/4020	86/8465	3.19e-04	1.45e-03	8.04e-04	57
hsa0481041	Liver	HCC	Regulation of actin cytoskeleton	134/4020	229/8465	4.48e-04	1.94e-03	1.08e-03	134
hsa046112	Liver	HCC	Platelet activation	71/4020	124/8465	1.77e-02	4.15e-02	2.31e-02	71
hsa0513052	Liver	HCC	Pathogenic Escherichia coli infection	129/4020	197/8465	2.02e-07	2.50e-06	1.39e-06	129
hsa046105	Liver	HCC	Complement and coagulation cascades	57/4020	86/8465	3.19e-04	1.45e-03	8.04e-04	57
hsa0481051	Liver	HCC	Regulation of actin cytoskeleton	134/4020	229/8465	4.48e-04	1.94e-03	1.08e-03	134
hsa0461111	Liver	HCC	Platelet activation	71/4020	124/8465	1.77e-02	4.15e-02	2.31e-02	71

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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
GZMA	F2R	GZMA_F2R	PARs	Breast	ADJ
GZMA	F2RL2	GZMA_F2RL2	PARs	Breast	ADJ
GZMA	F2R	GZMA_F2R	PARs	Breast	DCIS
CTSG	F2RL3	CTSG_F2RL3	PARs	Breast	Healthy
GZMA	F2RL3	GZMA_F2RL3	PARs	Breast	Healthy
GZMA	F2R	GZMA_F2R	PARs	Breast	IDC
CTSG	F2R	CTSG_F2R	PARs	Cervix	ADJ
GZMA	F2R	GZMA_F2R	PARs	Cervix	ADJ
PRSS3	F2R	PRSS3_F2R	PARs	Cervix	CC
CTSG	F2R	CTSG_F2R	PARs	Cervix	CC
GZMA	F2R	GZMA_F2R	PARs	Cervix	CC
GZMA	F2R	GZMA_F2R	PARs	Cervix	Healthy
CTSG	F2R	CTSG_F2R	PARs	Cervix	Precancer
GZMA	F2R	GZMA_F2R	PARs	Cervix	Precancer
PRSS3	F2R	PRSS3_F2R	PARs	CRC	AD
CTSG	F2R	CTSG_F2R	PARs	CRC	AD
GZMA	F2R	GZMA_F2R	PARs	CRC	AD
PRSS3	F2RL3	PRSS3_F2RL3	PARs	CRC	AD
CTSG	F2RL3	CTSG_F2RL3	PARs	CRC	AD
GZMA	F2RL3	GZMA_F2RL3	PARs	CRC	AD

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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

F2R

SNV

Missense_Mutation

c.978N>G

p.Phe326Leu

p.F326L

P25116

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A7-A13D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

F2R

SNV

Missense_Mutation

c.253N>A

p.Pro85Thr

p.P85T

P25116

protein_coding

tolerated(0.39)

benign(0.005)

TCGA-AO-A03R-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

F2R

SNV

Missense_Mutation

novel

c.1106N>C

p.Leu369Pro

p.L369P

P25116

protein_coding

deleterious(0)

probably_damaging(0.983)

TCGA-AO-A0JI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

F2R

SNV

Missense_Mutation

c.250N>T

p.Leu84Phe

p.L84F

P25116

protein_coding

tolerated(0.69)

benign(0.063)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

F2R

SNV

Missense_Mutation

c.238N>G

p.Leu80Val

p.L80V

P25116

protein_coding

tolerated(0.55)

benign(0.039)

TCGA-BH-A1FM-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

F2R

insertion

Frame_Shift_Ins

novel

c.391_392insACACTACCAGGCTCTGCTCTGCTGTCTCTGAGTTGGTACTACTC

p.Met131AsnfsTer16

p.M131Nfs*16

P25116

protein_coding

TCGA-BH-A0B1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

F2R

SNV

Missense_Mutation

c.299N>C

p.Trp100Ser

p.W100S

P25116

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-C5-A1BI-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

F2R

SNV

Missense_Mutation

novel

c.727N>C

p.Thr243Pro

p.T243P

P25116

protein_coding

deleterious(0)

probably_damaging(0.936)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

F2R

SNV

Missense_Mutation

novel

c.517N>A

p.Glu173Lys

p.E173K

P25116

protein_coding

tolerated(0.57)

benign(0.096)

TCGA-HM-A4S6-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

F2R

SNV

Missense_Mutation

c.1210N>G

p.Met404Val

p.M404V

P25116

protein_coding

tolerated(0.19)

benign(0)

TCGA-A6-6780-01

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
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE	inhibitor	CHEMBL2013119	RIGOSERTIB SODIUM
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE		TYROSINE KINASE INHIBITOR		15383630
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE		MORPHINE	MORPHINE	12373743
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE		ETHANOL	ALCOHOL	16930224
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE	antagonist	405560412
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE	antagonist	CHEMBL2103856	ATOPAXAR
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE	antagonist	CHEMBL2107386	VORAPAXAR SULFATE
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE		WORTMANNIN	WORTMANNIN	10318860,7559410,8955143
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE	antagonist	178100871	VORAPAXAR
2149	F2R	G PROTEIN COUPLED RECEPTOR, DRUGGABLE GENOME, CELL SURFACE	agonist	178100667

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