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: LEPR

Gene summary for LEPR

Gene summary.

Gene information	Species	Human
	Gene symbol	LEPR
	Gene ID	3953
	Gene name	leptin receptor
	Gene Alias	CD295
	Cytomap	1p31.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P48357

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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
3953	LEPR	NAFLD1	Human	Liver	NAFLD	2.33e-17	1.48e+00	-0.04
3953	LEPR	S41	Human	Liver	Cirrhotic	1.87e-13	1.03e+00	-0.0343
3953	LEPR	HCC1_Meng	Human	Liver	HCC	1.65e-09	-1.91e-01	0.0246
3953	LEPR	HCC2_Meng	Human	Liver	HCC	4.30e-06	-1.66e-01	0.0107
3953	LEPR	cirrhotic1	Human	Liver	Cirrhotic	3.35e-02	-1.73e-01	0.0202
3953	LEPR	HCC1	Human	Liver	HCC	1.11e-25	4.83e+00	0.5336
3953	LEPR	HCC2	Human	Liver	HCC	5.25e-31	3.93e+00	0.5341
3953	LEPR	HCC5	Human	Liver	HCC	8.97e-06	3.05e+00	0.4932
3953	LEPR	S014	Human	Liver	HCC	5.56e-42	2.53e+00	0.2254
3953	LEPR	S015	Human	Liver	HCC	1.91e-36	2.88e+00	0.2375
3953	LEPR	S016	Human	Liver	HCC	3.35e-48	2.78e+00	0.2243
3953	LEPR	HTA12-15-2	Human	Pancreas	PDAC	5.43e-05	4.53e-01	0.2315
3953	LEPR	HTA12-23-1	Human	Pancreas	PDAC	6.72e-11	1.11e+00	0.3405
3953	LEPR	HTA12-25-1	Human	Pancreas	PDAC	4.27e-05	5.43e-01	0.313
3953	LEPR	HTA12-26-1	Human	Pancreas	PDAC	2.01e-28	1.18e+00	0.3728
3953	LEPR	HTA12-29-1	Human	Pancreas	PDAC	4.63e-52	1.17e+00	0.3722
3953	LEPR	male-WTA	Human	Thyroid	PTC	2.68e-09	1.35e-01	0.1037
3953	LEPR	PTC04	Human	Thyroid	PTC	1.34e-34	8.91e-01	0.1927
3953	LEPR	PTC06	Human	Thyroid	PTC	1.97e-05	2.95e-01	0.2057
3953	LEPR	PTC07	Human	Thyroid	PTC	2.37e-21	5.84e-01	0.2044

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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:00725949	Cervix	CC	establishment of protein localization to organelle	99/2311	422/18723	1.23e-10	2.11e-08	99
GO:190382910	Cervix	CC	positive regulation of cellular protein localization	72/2311	276/18723	3.20e-10	4.46e-08	72
GO:005122210	Cervix	CC	positive regulation of protein transport	72/2311	303/18723	2.36e-08	1.70e-06	72
GO:190495110	Cervix	CC	positive regulation of establishment of protein localization	73/2311	319/18723	9.69e-08	5.25e-06	73
GO:00068399	Cervix	CC	mitochondrial transport	60/2311	254/18723	4.21e-07	1.67e-05	60
GO:000660510	Cervix	CC	protein targeting	68/2311	314/18723	2.17e-06	6.55e-05	68
GO:00903167	Cervix	CC	positive regulation of intracellular protein transport	41/2311	160/18723	3.24e-06	8.80e-05	41
GO:00323868	Cervix	CC	regulation of intracellular transport	71/2311	337/18723	3.70e-06	9.74e-05	71
GO:00331579	Cervix	CC	regulation of intracellular protein transport	52/2311	229/18723	8.16e-06	1.88e-04	52
GO:00705859	Cervix	CC	protein localization to mitochondrion	33/2311	125/18723	1.46e-05	2.90e-04	33
GO:19016538	Cervix	CC	cellular response to peptide	72/2311	359/18723	1.89e-05	3.48e-04	72
GO:00323889	Cervix	CC	positive regulation of intracellular transport	46/2311	202/18723	2.45e-05	4.24e-04	46
GO:00726559	Cervix	CC	establishment of protein localization to mitochondrion	31/2311	120/18723	4.13e-05	6.36e-04	31
GO:00434349	Cervix	CC	response to peptide hormone	77/2311	414/18723	1.40e-04	1.70e-03	77
GO:00161977	Cervix	CC	endosomal transport	48/2311	230/18723	1.65e-04	1.97e-03	48
GO:00713757	Cervix	CC	cellular response to peptide hormone stimulus	57/2311	290/18723	2.32e-04	2.59e-03	57
GO:00066269	Cervix	CC	protein targeting to mitochondrion	25/2311	100/18723	3.80e-04	3.89e-03	25
GO:00070347	Cervix	CC	vacuolar transport	34/2311	157/18723	7.03e-04	6.40e-03	34
GO:19037475	Cervix	CC	regulation of establishment of protein localization to mitochondrion	15/2311	50/18723	7.36e-04	6.60e-03	15
GO:19032144	Cervix	CC	regulation of protein targeting to mitochondrion	13/2311	44/18723	1.90e-03	1.40e-02	13

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa041528	Liver	NAFLD	AMPK signaling pathway	28/1043	121/8465	6.26e-04	9.78e-03	7.88e-03	28
hsa0493214	Liver	NAFLD	Non-alcoholic fatty liver disease	33/1043	155/8465	1.04e-03	1.42e-02	1.14e-02	33
hsa04920	Liver	NAFLD	Adipocytokine signaling pathway	17/1043	69/8465	3.51e-03	3.38e-02	2.73e-02	17
hsa0415211	Liver	NAFLD	AMPK signaling pathway	28/1043	121/8465	6.26e-04	9.78e-03	7.88e-03	28
hsa0493215	Liver	NAFLD	Non-alcoholic fatty liver disease	33/1043	155/8465	1.04e-03	1.42e-02	1.14e-02	33
hsa049201	Liver	NAFLD	Adipocytokine signaling pathway	17/1043	69/8465	3.51e-03	3.38e-02	2.73e-02	17
hsa0493222	Liver	Cirrhotic	Non-alcoholic fatty liver disease	106/2530	155/8465	2.16e-23	2.40e-21	1.48e-21	106
hsa0415221	Liver	Cirrhotic	AMPK signaling pathway	49/2530	121/8465	7.90e-03	2.74e-02	1.69e-02	49
hsa0493232	Liver	Cirrhotic	Non-alcoholic fatty liver disease	106/2530	155/8465	2.16e-23	2.40e-21	1.48e-21	106
hsa0415231	Liver	Cirrhotic	AMPK signaling pathway	49/2530	121/8465	7.90e-03	2.74e-02	1.69e-02	49
hsa0493242	Liver	HCC	Non-alcoholic fatty liver disease	124/4020	155/8465	4.54e-17	2.54e-15	1.41e-15	124
hsa0415241	Liver	HCC	AMPK signaling pathway	77/4020	121/8465	2.32e-04	1.11e-03	6.18e-04	77
hsa049202	Liver	HCC	Adipocytokine signaling pathway	45/4020	69/8465	2.19e-03	7.55e-03	4.20e-03	45
hsa0493252	Liver	HCC	Non-alcoholic fatty liver disease	124/4020	155/8465	4.54e-17	2.54e-15	1.41e-15	124
hsa0415251	Liver	HCC	AMPK signaling pathway	77/4020	121/8465	2.32e-04	1.11e-03	6.18e-04	77
hsa049203	Liver	HCC	Adipocytokine signaling pathway	45/4020	69/8465	2.19e-03	7.55e-03	4.20e-03	45

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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

LEPR

SNV

Missense_Mutation

c.319G>A

p.Glu107Lys

p.E107K

P48357

protein_coding

deleterious(0.03)

benign(0.219)

TCGA-A2-A0CX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

LEPR

SNV

Missense_Mutation

c.2989N>A

p.Glu997Lys

p.E997K

P48357

protein_coding

tolerated(0.36)

benign(0.007)

TCGA-A2-A0EQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

LEPR

SNV

Missense_Mutation

c.290G>C

p.Arg97Thr

p.R97T

P48357

protein_coding

tolerated(0.59)

benign(0)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LEPR

SNV

Missense_Mutation

novel

c.511G>A

p.Asp171Asn

p.D171N

P48357

protein_coding

deleterious(0.04)

benign(0.02)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LEPR

SNV

Missense_Mutation

c.343N>A

p.Val115Ile

p.V115I

P48357

protein_coding

tolerated(0.75)

benign(0.003)

TCGA-AO-A124-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

LEPR

SNV

Missense_Mutation

c.1525N>C

p.Tyr509His

p.Y509H

P48357

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

LEPR

SNV

Missense_Mutation

rs758422493

c.2861N>T

p.Cys954Phe

p.C954F

P48357

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-B6-A0IA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

LEPR

SNV

Missense_Mutation

novel

c.232N>T

p.His78Tyr

p.H78Y

P48357

protein_coding

tolerated(1)

benign(0)

TCGA-LD-A7W5-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxotere

LEPR

SNV

Missense_Mutation

c.2015N>T

p.Ser672Leu

p.S672L

P48357

protein_coding

tolerated(0.06)

probably_damaging(0.999)

TCGA-LL-A5YL-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

LEPR

insertion

Frame_Shift_Ins

novel

c.3205_3206insGTATATATGTATATATGGATCCCTTATATTTAGATTTAACTCGT

p.Glu1069GlyfsTer27

p.E1069Gfs*27

P48357

protein_coding

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

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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
3953	LEPR	EXTERNAL SIDE OF PLASMA MEMBRANE, DRUGGABLE GENOME		antipsychotics		21510767
3953	LEPR	EXTERNAL SIDE OF PLASMA MEMBRANE, DRUGGABLE GENOME		valproic acid
3953	LEPR	EXTERNAL SIDE OF PLASMA MEMBRANE, DRUGGABLE GENOME		Metreleptin	METRELEPTIN
3953	LEPR	EXTERNAL SIDE OF PLASMA MEMBRANE, DRUGGABLE GENOME		atorvastatin	ATORVASTATIN	19023160
3953	LEPR	EXTERNAL SIDE OF PLASMA MEMBRANE, DRUGGABLE GENOME	agonist	CHEMBL2107857	METRELEPTIN
3953	LEPR	EXTERNAL SIDE OF PLASMA MEMBRANE, DRUGGABLE GENOME		simvastatin	SIMVASTATIN	18854995,14625131

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