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: F2RL1

Gene summary for F2RL1

Gene summary.

Gene information	Species	Human
	Gene symbol	F2RL1
	Gene ID	2150
	Gene name	F2R like trypsin receptor 1
	Gene Alias	GPR11
	Cytomap	5q13.3
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P55085

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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
2150	F2RL1	LZE4T	Human	Esophagus	ESCC	1.16e-06	-6.47e-02	0.0811
2150	F2RL1	LZE8T	Human	Esophagus	ESCC	2.76e-02	-9.72e-02	0.067
2150	F2RL1	LZE20T	Human	Esophagus	ESCC	9.79e-03	-2.53e-01	0.0662
2150	F2RL1	LZE24T	Human	Esophagus	ESCC	5.02e-13	1.09e+00	0.0596
2150	F2RL1	P2T-E	Human	Esophagus	ESCC	2.99e-04	-5.82e-02	0.1177
2150	F2RL1	P5T-E	Human	Esophagus	ESCC	3.33e-10	-7.32e-02	0.1327
2150	F2RL1	P8T-E	Human	Esophagus	ESCC	9.25e-06	1.52e-01	0.0889
2150	F2RL1	P9T-E	Human	Esophagus	ESCC	6.24e-03	1.95e-01	0.1131
2150	F2RL1	P10T-E	Human	Esophagus	ESCC	4.85e-09	-1.74e-01	0.116
2150	F2RL1	P11T-E	Human	Esophagus	ESCC	2.79e-02	-1.36e-01	0.1426
2150	F2RL1	P12T-E	Human	Esophagus	ESCC	2.84e-02	1.35e-01	0.1122
2150	F2RL1	P15T-E	Human	Esophagus	ESCC	1.29e-13	5.18e-02	0.1149
2150	F2RL1	P16T-E	Human	Esophagus	ESCC	1.28e-08	-1.89e-01	0.1153
2150	F2RL1	P20T-E	Human	Esophagus	ESCC	1.13e-05	-1.49e-02	0.1124
2150	F2RL1	P21T-E	Human	Esophagus	ESCC	1.57e-20	3.40e-02	0.1617
2150	F2RL1	P22T-E	Human	Esophagus	ESCC	1.35e-05	-1.95e-01	0.1236
2150	F2RL1	P24T-E	Human	Esophagus	ESCC	4.13e-08	-2.57e-01	0.1287
2150	F2RL1	P26T-E	Human	Esophagus	ESCC	1.67e-07	4.22e-01	0.1276
2150	F2RL1	P27T-E	Human	Esophagus	ESCC	1.02e-08	-8.17e-02	0.1055
2150	F2RL1	P28T-E	Human	Esophagus	ESCC	2.91e-10	3.28e-01	0.1149

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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
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:00603261	Stomach	CAG with IM	cell chemotaxis	31/1050	310/18723	1.33e-03	1.57e-02	31
GO:000315811	Stomach	CAG with IM	endothelium development	17/1050	136/18723	1.59e-03	1.76e-02	17
GO:00019061	Stomach	CAG with IM	cell killing	21/1050	188/18723	2.04e-03	2.11e-02	21
GO:19004261	Stomach	CAG with IM	positive regulation of defense response to bacterium	4/1050	11/18723	2.36e-03	2.35e-02	4
GO:19004241	Stomach	CAG with IM	regulation of defense response to bacterium	5/1050	18/18723	2.55e-03	2.49e-02	5
GO:000188511	Stomach	CAG with IM	endothelial cell development	10/1050	64/18723	2.82e-03	2.69e-02	10
GO:003083411	Stomach	CAG with IM	regulation of actin filament depolymerization	9/1050	54/18723	2.88e-03	2.73e-02	9
GO:003433111	Stomach	CAG with IM	cell junction maintenance	7/1050	35/18723	2.89e-03	2.73e-02	7
GO:00103241	Stomach	CAG with IM	membrane invagination	17/1050	144/18723	2.94e-03	2.77e-02	17
GO:00463282	Stomach	CAG with IM	regulation of JNK cascade	16/1050	133/18723	3.19e-03	2.96e-02	16
GO:00313411	Stomach	CAG with IM	regulation of cell killing	13/1050	99/18723	3.52e-03	3.16e-02	13
GO:01200325	Stomach	CAG with IM	regulation of plasma membrane bounded cell projection assembly	20/1050	186/18723	3.99e-03	3.46e-02	20
GO:00030441	Stomach	CAG with IM	regulation of systemic arterial blood pressure mediated by a chemical signal	8/1050	47/18723	4.25e-03	3.60e-02	8
GO:00604914	Stomach	CAG with IM	regulation of cell projection assembly	20/1050	188/18723	4.50e-03	3.77e-02	20
GO:00341351	Stomach	CAG with IM	regulation of toll-like receptor 2 signaling pathway	4/1050	13/18723	4.68e-03	3.84e-02	4
GO:00300425	Stomach	CAG with IM	actin filament depolymerization	9/1050	59/18723	5.31e-03	4.22e-02	9
GO:0062207	Stomach	CAG with IM	regulation of pattern recognition receptor signaling pathway	13/1050	105/18723	5.85e-03	4.55e-02	13
GO:01200343	Stomach	CAG with IM	positive regulation of plasma membrane bounded cell projection assembly	13/1050	105/18723	5.85e-03	4.55e-02	13
GO:00072542	Stomach	CAG with IM	JNK cascade	18/1050	167/18723	5.96e-03	4.62e-02	18
GO:004340911	Stomach	CAG with IM	negative regulation of MAPK cascade	19/1050	180/18723	6.02e-03	4.63e-02	19

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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
GZMA	F2RL1	GZMA_F2RL1	PARs	Endometrium	Healthy
CTSG	F2RL1	CTSG_F2RL1	PARs	GC	Healthy
PRSS2	F2RL1	PRSS2_F2RL1	PARs	GC	Healthy
GZMA	F2RL1	GZMA_F2RL1	PARs	GC	Precancer
GZMA	F2RL1	GZMA_F2RL1	PARs	Prostate	BPH
GZMA	F2RL1	GZMA_F2RL1	PARs	Prostate	Healthy
PRSS3	F2RL1	PRSS3_F2RL1	PARs	Skin	ADJ
CTSG	F2RL1	CTSG_F2RL1	PARs	Skin	ADJ
GZMA	F2RL1	GZMA_F2RL1	PARs	Skin	ADJ
CTSG	F2RL1	CTSG_F2RL1	PARs	Skin	AK
GZMA	F2RL1	GZMA_F2RL1	PARs	Skin	AK
CTSG	F2RL1	CTSG_F2RL1	PARs	Skin	Healthy
GZMA	F2RL1	GZMA_F2RL1	PARs	Skin	Healthy
GZMA	F2RL1	GZMA_F2RL1	PARs	THCA	Cancer

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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

F2RL1

SNV

Missense_Mutation

rs185549069

c.308N>A

p.Arg103Gln

p.R103Q

P55085

protein_coding

deleterious(0.04)

benign(0.103)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

F2RL1

SNV

Missense_Mutation

novel

c.946A>T

p.Ser316Cys

p.S316C

P55085

protein_coding

tolerated(0.05)

possibly_damaging(0.882)

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

F2RL1

insertion

Nonsense_Mutation

novel

c.703_704insCACATAAGTTAGCATAACATGCTAA

p.Leu235SerfsTer6

p.L235Sfs*6

P55085

protein_coding

TCGA-AN-A0FF-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

F2RL1

insertion

Frame_Shift_Ins

novel

c.947_948insAAATATTGATCTCTACATCCCCCAACACTCCA

p.Ser316ArgfsTer24

p.S316Rfs*24

P55085

protein_coding

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

F2RL1

SNV

Missense_Mutation

novel

c.1076T>C

p.Leu359Pro

p.L359P

P55085

protein_coding

deleterious(0)

probably_damaging(0.956)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

F2RL1

SNV

Missense_Mutation

novel

c.998N>G

p.Ser333Cys

p.S333C

P55085

protein_coding

deleterious(0.03)

probably_damaging(0.967)

TCGA-C5-A8YQ-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

cisplatin

F2RL1

SNV

Missense_Mutation

novel

c.945N>C

p.Lys315Asn

p.K315N

P55085

protein_coding

tolerated(0.26)

probably_damaging(0.913)

TCGA-EA-A97N-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

F2RL1

SNV

Missense_Mutation

novel

c.1018N>A

p.Asp340Asn

p.D340N

P55085

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-EI-6917-01

Colorectum

rectum adenocarcinoma

Male

<65

III/IV

Chemotherapy

5fluorouracil+oxaciplatina+l-folinian

F2RL1

SNV

Missense_Mutation

novel

c.1019N>G

p.Asp340Gly

p.D340G

P55085

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AJ-A23O-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

F2RL1

SNV

Missense_Mutation

c.376N>G

p.Ile126Val

p.I126V

P55085

protein_coding

tolerated(0.34)

benign(0.012)

TCGA-AP-A054-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

carboplatin

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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
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME		ERYTHROMYCIN	ERYTHROMYCIN	18212111
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME		AC-55541	CHEMBL493076	18720984
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	agonist	178100874
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME		ROXITHROMYCIN	ROXITHROMYCIN	18212111
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	antagonist	381744949
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	agonist	178103272
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	antagonist	178103271
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	agonist	178100746
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	agonist	178103269
2150	F2RL1	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR, KINASE, ENZYME	antagonist	178103270

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