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: LDLR

Gene summary for LDLR

Gene summary.

Gene information	Species	Human
	Gene symbol	LDLR
	Gene ID	3949
	Gene name	low density lipoprotein receptor
	Gene Alias	FH
	Cytomap	19p13.2
	Gene Type	protein-coding
	GO ID	GO:0001568
	UniProtAcc	A0A024R7D5

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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
3949	LDLR	P57T-E	Human	Esophagus	ESCC	1.91e-04	3.45e-01	0.0926
3949	LDLR	P62T-E	Human	Esophagus	ESCC	5.11e-32	1.42e+00	0.1302
3949	LDLR	P74T-E	Human	Esophagus	ESCC	9.45e-05	6.61e-01	0.1479
3949	LDLR	P75T-E	Human	Esophagus	ESCC	4.11e-28	9.60e-01	0.1125
3949	LDLR	P76T-E	Human	Esophagus	ESCC	3.25e-03	3.26e-01	0.1207
3949	LDLR	P79T-E	Human	Esophagus	ESCC	1.51e-06	2.17e-01	0.1154
3949	LDLR	P80T-E	Human	Esophagus	ESCC	8.95e-40	2.15e+00	0.155
3949	LDLR	P83T-E	Human	Esophagus	ESCC	3.44e-24	1.31e+00	0.1738
3949	LDLR	P91T-E	Human	Esophagus	ESCC	1.34e-10	1.73e+00	0.1828
3949	LDLR	P104T-E	Human	Esophagus	ESCC	5.59e-03	7.76e-01	0.0931
3949	LDLR	P107T-E	Human	Esophagus	ESCC	5.65e-24	1.54e+00	0.171
3949	LDLR	P127T-E	Human	Esophagus	ESCC	3.65e-12	9.09e-01	0.0826
3949	LDLR	P128T-E	Human	Esophagus	ESCC	9.34e-27	2.33e+00	0.1241
3949	LDLR	P130T-E	Human	Esophagus	ESCC	1.75e-28	1.08e+00	0.1676
3949	LDLR	S43	Human	Liver	Cirrhotic	1.08e-16	-3.18e-01	-0.0187
3949	LDLR	HCC1_Meng	Human	Liver	HCC	4.29e-64	-4.52e-01	0.0246
3949	LDLR	HCC2_Meng	Human	Liver	HCC	3.04e-35	1.79e-01	0.0107
3949	LDLR	cirrhotic1	Human	Liver	Cirrhotic	1.05e-04	-9.75e-03	0.0202
3949	LDLR	cirrhotic2	Human	Liver	Cirrhotic	7.27e-11	-2.86e-01	0.0201
3949	LDLR	cirrhotic3	Human	Liver	Cirrhotic	3.98e-10	-1.65e-01	0.0215

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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:004325414	Breast	IDC	regulation of protein-containing complex assembly	61/1434	428/18723	1.77e-06	7.31e-05	61
GO:00512712	Breast	IDC	negative regulation of cellular component movement	48/1434	367/18723	1.88e-04	3.12e-03	48
GO:20001462	Breast	IDC	negative regulation of cell motility	46/1434	359/18723	4.01e-04	5.60e-03	46
GO:00459369	Breast	IDC	negative regulation of phosphate metabolic process	53/1434	441/18723	7.21e-04	8.79e-03	53
GO:00105639	Breast	IDC	negative regulation of phosphorus metabolic process	53/1434	442/18723	7.60e-04	9.25e-03	53
GO:00303362	Breast	IDC	negative regulation of cell migration	43/1434	344/18723	1.01e-03	1.13e-02	43
GO:003133313	Breast	IDC	negative regulation of protein-containing complex assembly	22/1434	141/18723	1.07e-03	1.17e-02	22
GO:00400132	Breast	IDC	negative regulation of locomotion	47/1434	391/18723	1.39e-03	1.43e-02	47
GO:000183711	Breast	IDC	epithelial to mesenchymal transition	23/1434	157/18723	1.97e-03	1.88e-02	23
GO:004325424	Breast	DCIS	regulation of protein-containing complex assembly	61/1390	428/18723	6.32e-07	2.71e-05	61
GO:005127111	Breast	DCIS	negative regulation of cellular component movement	48/1390	367/18723	8.97e-05	1.69e-03	48
GO:200014611	Breast	DCIS	negative regulation of cell motility	46/1390	359/18723	2.01e-04	3.23e-03	46
GO:004593614	Breast	DCIS	negative regulation of phosphate metabolic process	53/1390	441/18723	3.48e-04	4.96e-03	53
GO:001056314	Breast	DCIS	negative regulation of phosphorus metabolic process	53/1390	442/18723	3.68e-04	5.18e-03	53
GO:003033611	Breast	DCIS	negative regulation of cell migration	43/1390	344/18723	5.41e-04	6.96e-03	43
GO:003133322	Breast	DCIS	negative regulation of protein-containing complex assembly	22/1390	141/18723	7.08e-04	8.51e-03	22
GO:004001311	Breast	DCIS	negative regulation of locomotion	47/1390	391/18723	7.30e-04	8.69e-03	47
GO:000183721	Breast	DCIS	epithelial to mesenchymal transition	22/1390	157/18723	2.92e-03	2.50e-02	22
GO:00423269	Breast	DCIS	negative regulation of phosphorylation	43/1390	385/18723	4.78e-03	3.62e-02	43
GO:00019339	Breast	DCIS	negative regulation of protein phosphorylation	39/1390	342/18723	4.94e-03	3.71e-02	39

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0414418	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0514514	Cervix	CC	Toxoplasmosis	34/1267	112/8465	2.42e-05	1.82e-04	1.08e-04	34
hsa05417110	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0414419	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0514515	Cervix	CC	Toxoplasmosis	34/1267	112/8465	2.42e-05	1.82e-04	1.08e-04	34
hsa0514522	Cervix	HSIL_HPV	Toxoplasmosis	22/459	112/8465	1.07e-07	3.14e-06	2.54e-06	22
hsa0541725	Cervix	HSIL_HPV	Lipid and atherosclerosis	21/459	215/8465	6.30e-03	3.69e-02	2.99e-02	21
hsa0514532	Cervix	HSIL_HPV	Toxoplasmosis	22/459	112/8465	1.07e-07	3.14e-06	2.54e-06	22
hsa0541735	Cervix	HSIL_HPV	Lipid and atherosclerosis	21/459	215/8465	6.30e-03	3.69e-02	2.99e-02	21
hsa0541745	Cervix	N_HPV	Lipid and atherosclerosis	22/349	215/8465	7.28e-05	7.92e-04	6.19e-04	22
hsa0514541	Cervix	N_HPV	Toxoplasmosis	11/349	112/8465	6.32e-03	3.24e-02	2.54e-02	11
hsa0541755	Cervix	N_HPV	Lipid and atherosclerosis	22/349	215/8465	7.28e-05	7.92e-04	6.19e-04	22
hsa0514551	Cervix	N_HPV	Toxoplasmosis	11/349	112/8465	6.32e-03	3.24e-02	2.54e-02	11
hsa04144	Colorectum	AD	Endocytosis	111/2092	251/8465	5.95e-12	1.42e-10	9.08e-11	111
hsa05417	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73
hsa05160	Colorectum	AD	Hepatitis C	54/2092	157/8465	3.87e-03	1.96e-02	1.25e-02	54
hsa041441	Colorectum	AD	Endocytosis	111/2092	251/8465	5.95e-12	1.42e-10	9.08e-11	111
hsa054171	Colorectum	AD	Lipid and atherosclerosis	73/2092	215/8465	1.31e-03	8.27e-03	5.27e-03	73
hsa051601	Colorectum	AD	Hepatitis C	54/2092	157/8465	3.87e-03	1.96e-02	1.25e-02	54

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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

LDLR

SNV

Missense_Mutation

c.617N>T

p.Ser206Ile

p.S206I

P01130

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-A7-A0DA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

LDLR

SNV

Missense_Mutation

rs376459828

c.590N>A

p.Cys197Tyr

p.C197Y

P01130

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-AR-A2LE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

LDLR

insertion

Frame_Shift_Ins

c.241_242insA

p.Arg81GlnfsTer49

p.R81Qfs*49

P01130

protein_coding

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LDLR

insertion

Frame_Shift_Ins

novel

c.242_243insTCTCACT

p.Cys82LeufsTer50

p.C82Lfs*50

P01130

protein_coding

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LDLR

insertion

Frame_Shift_Ins

novel

c.866_867insGAAGTTGGCTGCGTTAATGGTGAGCGCTGGCCATCTGGTTTTC

p.Cys289TrpfsTer26

p.C289Wfs*26

P01130

protein_coding

TCGA-BH-A0BD-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

LDLR

insertion

Frame_Shift_Ins

novel

c.2350_2351insG

p.Pro784ArgfsTer3

p.P784Rfs*3

P01130

protein_coding

TCGA-BH-A0BR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

LDLR

insertion

Frame_Shift_Ins

novel

c.2352_2353insCACCGCCACGGCTGGCTAATTTTTGTATTTTT

p.Ser785HisfsTer14

p.S785Hfs*14

P01130

protein_coding

TCGA-BH-A0BR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

LDLR

deletion

Frame_Shift_Del

novel

c.1931delN

p.Asn645ThrfsTer20

p.N645Tfs*20

P01130

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

LDLR

SNV

Missense_Mutation

rs121908029

c.682N>A

p.Glu228Lys

p.E228K

P01130

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-FU-A40J-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

carboplatin

LDLR

SNV

Missense_Mutation

rs750126678

c.323N>T

p.Thr108Met

p.T108M

P01130

protein_coding

deleterious(0.01)

possibly_damaging(0.807)

TCGA-A6-5661-01

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
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		Porfimer Sodium
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		GEMFIBROZIL	GEMFIBROZIL	9409246
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		evolocumab	EVOLOCUMAB
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		ANTIVIRAL		8211145
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		lovastatin	LOVASTATIN	16103896
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		HEPARIN CALCIUM		17322644
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		RETINOL	RETINOL	2920014
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		ANTIBIOTICS		9470171
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		PF-429242	CHEMBL233611	17583500
3949	LDLR	ENZYME, CLINICALLY ACTIONABLE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, DRUGGABLE GENOME		mipomersen	MIPOMERSEN

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