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: FLT1

Gene summary for FLT1

Gene summary.

Gene information	Species	Human
	Gene symbol	FLT1
	Gene ID	2321
	Gene name	fms related receptor tyrosine kinase 1
	Gene Alias	FLT
	Cytomap	13q12.3
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P17948

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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
2321	FLT1	HTA11_3410_2000001011	Human	Colorectum	AD	5.67e-04	1.32e-01	0.0155
2321	FLT1	HTA11_2487_2000001011	Human	Colorectum	SER	2.72e-07	3.21e-01	-0.1808
2321	FLT1	HTA11_1938_2000001011	Human	Colorectum	AD	2.70e-16	6.30e-01	-0.0811
2321	FLT1	HTA11_78_2000001011	Human	Colorectum	AD	6.12e-09	2.59e-01	-0.1088
2321	FLT1	HTA11_347_2000001011	Human	Colorectum	AD	1.22e-04	1.62e-01	-0.1954
2321	FLT1	HTA11_3361_2000001011	Human	Colorectum	AD	6.26e-04	2.24e-01	-0.1207
2321	FLT1	HTA11_83_2000001011	Human	Colorectum	SER	2.02e-04	2.47e-01	-0.1526
2321	FLT1	HTA11_696_2000001011	Human	Colorectum	AD	3.19e-14	2.72e-01	-0.1464
2321	FLT1	HTA11_866_2000001011	Human	Colorectum	AD	2.05e-06	1.53e-01	-0.1001
2321	FLT1	HTA11_1391_2000001011	Human	Colorectum	AD	6.18e-07	2.26e-01	-0.059
2321	FLT1	HTA11_9408_2000001011	Human	Colorectum	AD	2.77e-05	3.61e-01	0.0451
2321	FLT1	HTA11_7663_2000001011	Human	Colorectum	SER	4.47e-02	2.47e-01	0.0131
2321	FLT1	HTA11_6818_2000001011	Human	Colorectum	AD	1.89e-09	4.93e-01	0.0112
2321	FLT1	HTA11_6818_2000001021	Human	Colorectum	AD	1.11e-05	2.54e-01	0.0588
2321	FLT1	HTA11_99999970781_79442	Human	Colorectum	MSS	2.30e-41	7.06e-01	0.294
2321	FLT1	HTA11_99999965062_69753	Human	Colorectum	MSI-H	7.69e-08	7.11e-01	0.3487
2321	FLT1	HTA11_99999974143_84620	Human	Colorectum	MSS	8.44e-12	2.29e-01	0.3005
2321	FLT1	HCC1	Human	Liver	HCC	1.08e-08	4.46e+00	0.5336
2321	FLT1	HCC2	Human	Liver	HCC	1.66e-14	1.27e+00	0.5341
2321	FLT1	HCC5	Human	Liver	HCC	3.89e-10	1.16e+00	0.4932

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease

∗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:0046777	Colorectum	AD	protein autophosphorylation	74/3918	227/18723	2.48e-05	4.76e-04	74
GO:0033674	Colorectum	AD	positive regulation of kinase activity	131/3918	467/18723	1.28e-04	1.85e-03	131
GO:0045860	Colorectum	AD	positive regulation of protein kinase activity	107/3918	386/18723	8.01e-04	7.92e-03	107
GO:0050673	Colorectum	AD	epithelial cell proliferation	119/3918	437/18723	8.75e-04	8.51e-03	119
GO:0071900	Colorectum	AD	regulation of protein serine/threonine kinase activity	98/3918	359/18723	2.18e-03	1.73e-02	98
GO:0071902	Colorectum	AD	positive regulation of protein serine/threonine kinase activity	58/3918	200/18723	4.09e-03	2.84e-02	58
GO:0048017	Colorectum	AD	inositol lipid-mediated signaling	53/3918	182/18723	5.35e-03	3.52e-02	53
GO:0048015	Colorectum	AD	phosphatidylinositol-mediated signaling	52/3918	178/18723	5.37e-03	3.54e-02	52
GO:00467771	Colorectum	SER	protein autophosphorylation	60/2897	227/18723	1.36e-05	4.25e-04	60
GO:00336741	Colorectum	SER	positive regulation of kinase activity	95/2897	467/18723	2.62e-03	2.41e-02	95
GO:00480171	Colorectum	SER	inositol lipid-mediated signaling	42/2897	182/18723	4.36e-03	3.49e-02	42
GO:00458601	Colorectum	SER	positive regulation of protein kinase activity	79/2897	386/18723	4.85e-03	3.79e-02	79
GO:00480151	Colorectum	SER	phosphatidylinositol-mediated signaling	41/2897	178/18723	4.97e-03	3.86e-02	41
GO:00719001	Colorectum	SER	regulation of protein serine/threonine kinase activity	74/2897	359/18723	5.22e-03	3.96e-02	74
GO:00336742	Colorectum	MSS	positive regulation of kinase activity	122/3467	467/18723	2.50e-05	5.21e-04	122
GO:00458602	Colorectum	MSS	positive regulation of protein kinase activity	102/3467	386/18723	6.93e-05	1.20e-03	102
GO:00719002	Colorectum	MSS	regulation of protein serine/threonine kinase activity	93/3467	359/18723	2.98e-04	3.91e-03	93
GO:00467772	Colorectum	MSS	protein autophosphorylation	63/3467	227/18723	3.96e-04	4.91e-03	63
GO:00506731	Colorectum	MSS	epithelial cell proliferation	108/3467	437/18723	6.76e-04	7.30e-03	108
GO:00719021	Colorectum	MSS	positive regulation of protein serine/threonine kinase activity	55/3467	200/18723	1.12e-03	1.11e-02	55

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04066	Colorectum	AD	HIF-1 signaling pathway	48/2092	109/8465	7.25e-06	7.84e-05	5.00e-05	48
hsa04015	Colorectum	AD	Rap1 signaling pathway	71/2092	210/8465	1.72e-03	9.68e-03	6.18e-03	71
hsa04510	Colorectum	AD	Focal adhesion	67/2092	203/8465	4.40e-03	2.17e-02	1.38e-02	67
hsa040661	Colorectum	AD	HIF-1 signaling pathway	48/2092	109/8465	7.25e-06	7.84e-05	5.00e-05	48
hsa040151	Colorectum	AD	Rap1 signaling pathway	71/2092	210/8465	1.72e-03	9.68e-03	6.18e-03	71
hsa045101	Colorectum	AD	Focal adhesion	67/2092	203/8465	4.40e-03	2.17e-02	1.38e-02	67
hsa040662	Colorectum	SER	HIF-1 signaling pathway	36/1580	109/8465	2.27e-04	2.15e-03	1.56e-03	36
hsa040152	Colorectum	SER	Rap1 signaling pathway	54/1580	210/8465	6.55e-03	3.68e-02	2.67e-02	54
hsa040663	Colorectum	SER	HIF-1 signaling pathway	36/1580	109/8465	2.27e-04	2.15e-03	1.56e-03	36
hsa040153	Colorectum	SER	Rap1 signaling pathway	54/1580	210/8465	6.55e-03	3.68e-02	2.67e-02	54
hsa040664	Colorectum	MSS	HIF-1 signaling pathway	39/1875	109/8465	7.61e-04	5.00e-03	3.06e-03	39
hsa040154	Colorectum	MSS	Rap1 signaling pathway	66/1875	210/8465	1.03e-03	5.94e-03	3.64e-03	66
hsa040665	Colorectum	MSS	HIF-1 signaling pathway	39/1875	109/8465	7.61e-04	5.00e-03	3.06e-03	39
hsa040155	Colorectum	MSS	Rap1 signaling pathway	66/1875	210/8465	1.03e-03	5.94e-03	3.64e-03	66
hsa0451041	Liver	HCC	Focal adhesion	125/4020	203/8465	3.12e-05	1.88e-04	1.04e-04	125
hsa0406622	Liver	HCC	HIF-1 signaling pathway	70/4020	109/8465	2.96e-04	1.36e-03	7.57e-04	70
hsa0451051	Liver	HCC	Focal adhesion	125/4020	203/8465	3.12e-05	1.88e-04	1.04e-04	125
hsa0406632	Liver	HCC	HIF-1 signaling pathway	70/4020	109/8465	2.96e-04	1.36e-03	7.57e-04	70

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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
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Breast	ADJ
PGF	FLT1	PGF_VEGFR1	VEGF	Breast	ADJ
VEGFA	FLT1_KDR	VEGFA_VEGFR1R2	VEGF	Breast	ADJ
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Breast	DCIS
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Breast	DCIS
PGF	FLT1	PGF_VEGFR1	VEGF	Breast	DCIS
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Breast	Healthy
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Breast	Healthy
PGF	FLT1	PGF_VEGFR1	VEGF	Breast	Healthy
VEGFA	FLT1_KDR	VEGFA_VEGFR1R2	VEGF	Breast	Healthy
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Breast	IDC
PGF	FLT1	PGF_VEGFR1	VEGF	Breast	IDC
VEGFA	FLT1_KDR	VEGFA_VEGFR1R2	VEGF	Breast	IDC
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Breast	Precancer
PGF	FLT1	PGF_VEGFR1	VEGF	Breast	Precancer
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Cervix	ADJ
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Cervix	ADJ
VEGFA	FLT1_KDR	VEGFA_VEGFR1R2	VEGF	Cervix	ADJ
VEGFA	FLT1	VEGFA_VEGFR1	VEGF	Cervix	CC
VEGFB	FLT1	VEGFB_VEGFR1	VEGF	Cervix	CC

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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

FLT1

SNV

Missense_Mutation

c.1596N>G

p.Ile532Met

p.I532M

P17948

protein_coding

tolerated(0.98)

possibly_damaging(0.882)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

FLT1

SNV

Missense_Mutation

c.3929A>G

p.Asp1310Gly

p.D1310G

P17948

protein_coding

tolerated(0.15)

benign(0.001)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

FLT1

SNV

Missense_Mutation

novel

c.1982C>A

p.Pro661Gln

p.P661Q

P17948

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

FLT1

SNV

Missense_Mutation

c.3040N>C

p.Ser1014Pro

p.S1014P

P17948

protein_coding

deleterious(0)

probably_damaging(0.959)

TCGA-AR-A1AQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

FLT1

SNV

Missense_Mutation

c.876C>G

p.Phe292Leu

p.F292L

P17948

protein_coding

tolerated(0.41)

probably_damaging(0.999)

TCGA-BH-A18P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

FLT1

SNV

Missense_Mutation

c.277N>T

p.Thr93Ser

p.T93S

P17948

protein_coding

tolerated(0.28)

probably_damaging(0.978)

TCGA-C8-A12K-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

FLT1

insertion

Frame_Shift_Ins

novel

c.1979_1980insCAGGTGTTCCAAGTTCT

p.Pro661ArgfsTer26

p.P661Rfs*26

P17948

protein_coding

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

FLT1

SNV

Missense_Mutation

rs759739030

c.3914G>A

p.Arg1305His

p.R1305H

P17948

protein_coding

tolerated(0.2)

possibly_damaging(0.613)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

FLT1

SNV

Missense_Mutation

c.1596C>G

p.Ile532Met

p.I532M

P17948

protein_coding

tolerated(0.98)

possibly_damaging(0.882)

TCGA-4J-AA1J-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

FLT1

SNV

Missense_Mutation

rs373801409

c.406G>A

p.Val136Ile

p.V136I

P17948

protein_coding

tolerated(0.91)

benign(0.006)

TCGA-C5-A1MK-01

Cervix

cervical & endocervical cancer

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
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE	inhibitor	VANDETANIB	VANDETANIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE		TABERMINOGENE VADENOVEC
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE		NINTEDANIB	NINTEDANIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE		VANDETANIB	VANDETANIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE	inhibitor	178102585	DOVITINIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE	inhibitor	CHEMBL522892	DOVITINIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE	inhibitor	AXITINIB	AXITINIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE	inhibitor	CHEMBL3544927	L-21649
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE	inhibitor	363894211	PEXMETINIB
2321	FLT1	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, KINASE, TYROSINE KINASE		PAZOPANIB	PAZOPANIB

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