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: LRP5

Gene summary for LRP5

Gene summary.

Gene information	Species	Human
	Gene symbol	LRP5
	Gene ID	4041
	Gene name	LDL receptor related protein 5
	Gene Alias	BMND1
	Cytomap	11q13.2
	Gene Type	protein-coding
	GO ID	GO:0000278
	UniProtAcc	O75197

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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
4041	LRP5	HTA11_3410_2000001011	Human	Colorectum	AD	4.25e-02	2.23e-01	0.0155
4041	LRP5	HTA11_2487_2000001011	Human	Colorectum	SER	3.19e-02	3.05e-01	-0.1808
4041	LRP5	HTA11_1938_2000001011	Human	Colorectum	AD	1.46e-04	4.35e-01	-0.0811
4041	LRP5	HTA11_78_2000001011	Human	Colorectum	AD	1.61e-03	3.07e-01	-0.1088
4041	LRP5	HTA11_347_2000001011	Human	Colorectum	AD	1.61e-12	5.14e-01	-0.1954
4041	LRP5	HTA11_83_2000001011	Human	Colorectum	SER	9.33e-05	5.17e-01	-0.1526
4041	LRP5	HTA11_696_2000001011	Human	Colorectum	AD	4.01e-14	6.69e-01	-0.1464
4041	LRP5	HTA11_866_2000001011	Human	Colorectum	AD	1.75e-04	4.27e-01	-0.1001
4041	LRP5	HTA11_1391_2000001011	Human	Colorectum	AD	1.13e-13	7.54e-01	-0.059
4041	LRP5	HTA11_546_2000001011	Human	Colorectum	AD	2.07e-04	5.25e-01	-0.0842
4041	LRP5	HTA11_866_3004761011	Human	Colorectum	AD	1.44e-02	2.88e-01	0.096
4041	LRP5	HTA11_7696_3000711011	Human	Colorectum	AD	6.19e-03	4.54e-01	0.0674
4041	LRP5	HTA11_6818_2000001011	Human	Colorectum	AD	1.32e-02	5.17e-01	0.0112
4041	LRP5	HTA11_6818_2000001021	Human	Colorectum	AD	4.22e-03	4.01e-01	0.0588
4041	LRP5	HTA11_99999971662_82457	Human	Colorectum	MSS	2.36e-02	5.05e-01	0.3859
4041	LRP5	HTA11_99999973899_84307	Human	Colorectum	MSS	1.63e-07	7.44e-01	0.2585
4041	LRP5	A015-C-203	Human	Colorectum	FAP	3.77e-14	-1.75e-01	-0.1294
4041	LRP5	A002-C-201	Human	Colorectum	FAP	3.94e-03	-2.04e-02	0.0324
4041	LRP5	A001-C-108	Human	Colorectum	FAP	1.00e-06	7.70e-02	-0.0272
4041	LRP5	A002-C-205	Human	Colorectum	FAP	1.85e-09	-5.00e-02	-0.1236

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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
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:00434342	Colorectum	MSS	response to peptide hormone	104/3467	414/18723	4.58e-04	5.43e-03	104
GO:00158332	Colorectum	MSS	peptide transport	71/3467	264/18723	4.79e-04	5.60e-03	71
GO:00017631	Colorectum	MSS	morphogenesis of a branching structure	55/3467	196/18723	6.70e-04	7.25e-03	55
GO:00160522	Colorectum	MSS	carbohydrate catabolic process	45/3467	154/18723	7.93e-04	8.36e-03	45
GO:00510912	Colorectum	MSS	positive regulation of DNA-binding transcription factor activity	69/3467	260/18723	8.44e-04	8.71e-03	69
GO:00442822	Colorectum	MSS	small molecule catabolic process	94/3467	376/18723	9.85e-04	9.86e-03	94
GO:0061138	Colorectum	MSS	morphogenesis of a branching epithelium	51/3467	182/18723	1.06e-03	1.05e-02	51
GO:00457871	Colorectum	MSS	positive regulation of cell cycle	80/3467	313/18723	1.15e-03	1.12e-02	80
GO:00193182	Colorectum	MSS	hexose metabolic process	63/3467	237/18723	1.32e-03	1.25e-02	63
GO:00900872	Colorectum	MSS	regulation of peptide transport	55/3467	202/18723	1.44e-03	1.34e-02	55
GO:00487362	Colorectum	MSS	appendage development	48/3467	172/18723	1.61e-03	1.46e-02	48
GO:00601732	Colorectum	MSS	limb development	48/3467	172/18723	1.61e-03	1.46e-02	48
GO:0051090	Colorectum	MSS	regulation of DNA-binding transcription factor activity	106/3467	440/18723	1.88e-03	1.65e-02	106
GO:00027912	Colorectum	MSS	regulation of peptide secretion	54/3467	200/18723	1.94e-03	1.67e-02	54
GO:00300721	Colorectum	MSS	peptide hormone secretion	62/3467	236/18723	1.95e-03	1.68e-02	62
GO:00902762	Colorectum	MSS	regulation of peptide hormone secretion	53/3467	196/18723	2.04e-03	1.75e-02	53
GO:00428861	Colorectum	MSS	amide transport	76/3467	301/18723	2.14e-03	1.80e-02	76
GO:00027901	Colorectum	MSS	peptide secretion	63/3467	242/18723	2.28e-03	1.87e-02	63
GO:00104641	Colorectum	MSS	regulation of mesenchymal cell proliferation	12/3467	28/18723	2.53e-03	2.02e-02	12
GO:00059962	Colorectum	MSS	monosaccharide metabolic process	66/3467	257/18723	2.61e-03	2.06e-02	66

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05010	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa05022	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa05225	Colorectum	AD	Hepatocellular carcinoma	59/2092	168/8465	1.50e-03	8.69e-03	5.54e-03	59
hsa04928	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38
hsa04310	Colorectum	AD	Wnt signaling pathway	56/2092	171/8465	1.03e-02	3.93e-02	2.51e-02	56
hsa050101	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa050221	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa052251	Colorectum	AD	Hepatocellular carcinoma	59/2092	168/8465	1.50e-03	8.69e-03	5.54e-03	59
hsa049281	Colorectum	AD	Parathyroid hormone synthesis, secretion and action	38/2092	106/8465	6.60e-03	2.77e-02	1.76e-02	38
hsa043101	Colorectum	AD	Wnt signaling pathway	56/2092	171/8465	1.03e-02	3.93e-02	2.51e-02	56
hsa050102	Colorectum	SER	Alzheimer disease	146/1580	384/8465	6.52e-20	2.40e-18	1.75e-18	146
hsa050222	Colorectum	SER	Pathways of neurodegeneration - multiple diseases	168/1580	476/8465	6.23e-19	2.07e-17	1.50e-17	168
hsa049282	Colorectum	SER	Parathyroid hormone synthesis, secretion and action	31/1580	106/8465	5.20e-03	3.28e-02	2.38e-02	31
hsa050103	Colorectum	SER	Alzheimer disease	146/1580	384/8465	6.52e-20	2.40e-18	1.75e-18	146
hsa050223	Colorectum	SER	Pathways of neurodegeneration - multiple diseases	168/1580	476/8465	6.23e-19	2.07e-17	1.50e-17	168
hsa049283	Colorectum	SER	Parathyroid hormone synthesis, secretion and action	31/1580	106/8465	5.20e-03	3.28e-02	2.38e-02	31
hsa050104	Colorectum	MSS	Alzheimer disease	169/1875	384/8465	1.21e-22	1.01e-20	6.21e-21	169
hsa050224	Colorectum	MSS	Pathways of neurodegeneration - multiple diseases	192/1875	476/8465	2.79e-20	1.04e-18	6.36e-19	192
hsa052252	Colorectum	MSS	Hepatocellular carcinoma	56/1875	168/8465	5.04e-04	3.45e-03	2.11e-03	56
hsa049284	Colorectum	MSS	Parathyroid hormone synthesis, secretion and action	37/1875	106/8465	1.72e-03	9.13e-03	5.59e-03	37

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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
WNT7B	FZD4_LRP5	WNT7B_FZD4_LRP5	WNT	Cervix	ADJ
WNT7B	FZD6_LRP5	WNT7B_FZD6_LRP5	WNT	Cervix	ADJ
WNT2B	FZD6_LRP5	WNT2B_FZD6_LRP5	WNT	Cervix	CC
WNT9A	FZD6_LRP5	WNT9A_FZD6_LRP5	WNT	Cervix	CC
WNT4	FZD5_LRP5	WNT4_FZD5_LRP5	WNT	CRC	AD
WNT2	FZD6_LRP5	WNT2_FZD6_LRP5	WNT	Endometrium	ADJ
WNT4	FZD6_LRP5	WNT4_FZD6_LRP5	WNT	Endometrium	ADJ
WNT10A	FZD4_LRP5	WNT10A_FZD4_LRP5	WNT	HNSCC	OSCC
WNT10A	FZD6_LRP5	WNT10A_FZD6_LRP5	WNT	HNSCC	OSCC
WNT2	FZD4_LRP5	WNT2_FZD4_LRP5	WNT	HNSCC	OSCC
WNT2	FZD6_LRP5	WNT2_FZD6_LRP5	WNT	HNSCC	OSCC
WNT4	FZD4_LRP5	WNT4_FZD4_LRP5	WNT	HNSCC	OSCC
WNT4	FZD6_LRP5	WNT4_FZD6_LRP5	WNT	HNSCC	OSCC
WNT7B	FZD4_LRP5	WNT7B_FZD4_LRP5	WNT	HNSCC	OSCC
WNT7B	FZD6_LRP5	WNT7B_FZD6_LRP5	WNT	HNSCC	OSCC
WNT10A	FZD6_LRP5	WNT10A_FZD6_LRP5	WNT	HNSCC	Precancer
WNT2	FZD6_LRP5	WNT2_FZD6_LRP5	WNT	HNSCC	Precancer
WNT2B	FZD6_LRP5	WNT2B_FZD6_LRP5	WNT	HNSCC	Precancer
WNT4	FZD6_LRP5	WNT4_FZD6_LRP5	WNT	HNSCC	Precancer
WNT7B	FZD6_LRP5	WNT7B_FZD6_LRP5	WNT	HNSCC	Precancer

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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

LRP5

SNV

Missense_Mutation

rs750390421

c.2600N>A

p.Ser867Asn

p.S867N

O75197

protein_coding

deleterious(0.05)

probably_damaging(0.985)

TCGA-A1-A0SO-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

LRP5

SNV

Missense_Mutation

novel

c.1730G>A

p.Ser577Asn

p.S577N

O75197

protein_coding

tolerated(0.6)

benign(0)

TCGA-A8-A07G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

5-fluorouracil

LRP5

SNV

Missense_Mutation

novel

c.139G>A

p.Asp47Asn

p.D47N

O75197

protein_coding

tolerated(0.58)

benign(0.36)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP5

SNV

Missense_Mutation

c.326C>T

p.Ser109Phe

p.S109F

O75197

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP5

SNV

Missense_Mutation

rs751683687

c.1117N>T

p.Arg373Trp

p.R373W

O75197

protein_coding

deleterious(0)

probably_damaging(0.982)

TCGA-AN-A0FN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

LRP5

SNV

Missense_Mutation

novel

c.1752G>C

p.Gln584His

p.Q584H

O75197

protein_coding

deleterious(0)

probably_damaging(0.971)

TCGA-BH-A0C0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

LRP5

SNV

Missense_Mutation

rs376914943

c.3220N>A

p.Val1074Ile

p.V1074I

O75197

protein_coding

tolerated(0.25)

possibly_damaging(0.518)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP5

SNV

Missense_Mutation

c.2242N>T

p.Asp748Tyr

p.D748Y

O75197

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-BH-A18L-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

LRP5

SNV

Missense_Mutation

c.1480N>T

p.Arg494Trp

p.R494W

O75197

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-D8-A1JA-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

LRP5

SNV

Missense_Mutation

c.1924N>T

p.Val642Leu

p.V642L

O75197

protein_coding

tolerated(0.09)

benign(0.14)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

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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

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