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: LRP6

Gene summary for LRP6

Gene summary.

Gene information	Species	Human
	Gene symbol	LRP6
	Gene ID	4040
	Gene name	LDL receptor related protein 6
	Gene Alias	ADCAD2
	Cytomap	12p13.2
	Gene Type	protein-coding
	GO ID	GO:0001756
	UniProtAcc	O75581

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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
4040	LRP6	CCI_2	Human	Cervix	CC	1.37e-08	1.05e+00	0.5249
4040	LRP6	CCI_3	Human	Cervix	CC	3.41e-20	1.04e+00	0.516
4040	LRP6	HTA11_3410_2000001011	Human	Colorectum	AD	1.04e-14	-5.65e-01	0.0155
4040	LRP6	HTA11_2487_2000001011	Human	Colorectum	SER	1.18e-02	-4.27e-01	-0.1808
4040	LRP6	HTA11_78_2000001011	Human	Colorectum	AD	2.90e-06	-4.88e-01	-0.1088
4040	LRP6	HTA11_347_2000001011	Human	Colorectum	AD	3.17e-02	-3.09e-01	-0.1954
4040	LRP6	HTA11_696_2000001011	Human	Colorectum	AD	6.93e-15	-4.78e-01	-0.1464
4040	LRP6	HTA11_866_2000001011	Human	Colorectum	AD	2.56e-11	-4.49e-01	-0.1001
4040	LRP6	HTA11_1391_2000001011	Human	Colorectum	AD	3.48e-04	-4.37e-01	-0.059
4040	LRP6	HTA11_866_3004761011	Human	Colorectum	AD	1.20e-07	-4.89e-01	0.096
4040	LRP6	HTA11_10711_2000001011	Human	Colorectum	AD	5.68e-03	-4.71e-01	0.0338
4040	LRP6	HTA11_7696_3000711011	Human	Colorectum	AD	6.33e-14	-5.03e-01	0.0674
4040	LRP6	HTA11_6818_2000001011	Human	Colorectum	AD	4.19e-03	-5.83e-01	0.0112
4040	LRP6	HTA11_99999970781_79442	Human	Colorectum	MSS	7.50e-07	-3.46e-01	0.294
4040	LRP6	HTA11_99999971662_82457	Human	Colorectum	MSS	1.24e-05	-3.88e-01	0.3859
4040	LRP6	HTA11_99999974143_84620	Human	Colorectum	MSS	5.29e-14	-4.79e-01	0.3005
4040	LRP6	A015-C-203	Human	Colorectum	FAP	4.07e-20	-2.09e-01	-0.1294
4040	LRP6	A015-C-204	Human	Colorectum	FAP	2.58e-03	-2.02e-01	-0.0228
4040	LRP6	A002-C-201	Human	Colorectum	FAP	7.11e-09	-2.55e-01	0.0324
4040	LRP6	A001-C-119	Human	Colorectum	FAP	1.23e-03	-2.91e-01	-0.1557

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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
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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
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:007265910	Cervix	CC	protein localization to plasma membrane	73/2311	284/18723	4.95e-10	6.73e-08	73
GO:00160557	Cervix	CC	Wnt signaling pathway	98/2311	444/18723	4.82e-09	4.65e-07	98
GO:01987387	Cervix	CC	cell-cell signaling by wnt	98/2311	446/18723	6.16e-09	5.58e-07	98
GO:19907788	Cervix	CC	protein localization to cell periphery	78/2311	333/18723	1.22e-08	9.73e-07	78
GO:00600707	Cervix	CC	canonical Wnt signaling pathway	66/2311	303/18723	2.47e-06	7.35e-05	66
GO:00719007	Cervix	CC	regulation of protein serine/threonine kinase activity	75/2311	359/18723	2.76e-06	8.02e-05	75
GO:005134810	Cervix	CC	negative regulation of transferase activity	60/2311	268/18723	2.77e-06	8.02e-05	60
GO:004593610	Cervix	CC	negative regulation of phosphate metabolic process	88/2311	441/18723	2.92e-06	8.27e-05	88
GO:001056310	Cervix	CC	negative regulation of phosphorus metabolic process	88/2311	442/18723	3.21e-06	8.77e-05	88
GO:00510904	Cervix	CC	regulation of DNA-binding transcription factor activity	87/2311	440/18723	4.85e-06	1.22e-04	87
GO:00457876	Cervix	CC	positive regulation of cell cycle	66/2311	313/18723	7.78e-06	1.81e-04	66
GO:004232610	Cervix	CC	negative regulation of phosphorylation	77/2311	385/18723	1.09e-05	2.38e-04	77
GO:00309019	Cervix	CC	midbrain development	26/2311	90/18723	2.12e-05	3.82e-04	26
GO:000193310	Cervix	CC	negative regulation of protein phosphorylation	69/2311	342/18723	2.29e-05	4.01e-04	69
GO:00068987	Cervix	CC	receptor-mediated endocytosis	53/2311	244/18723	2.52e-05	4.29e-04	53
GO:00488634	Cervix	CC	stem cell differentiation	46/2311	206/18723	4.11e-05	6.36e-04	46
GO:000646910	Cervix	CC	negative regulation of protein kinase activity	47/2311	212/18723	4.13e-05	6.36e-04	47
GO:00336739	Cervix	CC	negative regulation of kinase activity	50/2311	237/18723	9.22e-05	1.21e-03	50
GO:00434349	Cervix	CC	response to peptide hormone	77/2311	414/18723	1.40e-04	1.70e-03	77
GO:00510915	Cervix	CC	positive regulation of DNA-binding transcription factor activity	51/2311	260/18723	5.05e-04	4.92e-03	51

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501018	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0502218	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa043109	Cervix	CC	Wnt signaling pathway	43/1267	171/8465	3.03e-04	1.64e-03	9.68e-04	43
hsa0522510	Cervix	CC	Hepatocellular carcinoma	40/1267	168/8465	1.52e-03	6.39e-03	3.78e-03	40
hsa0492812	Cervix	CC	Parathyroid hormone synthesis, secretion and action	27/1267	106/8465	3.12e-03	1.19e-02	7.03e-03	27
hsa05224	Cervix	CC	Breast cancer	32/1267	147/8465	1.66e-02	4.88e-02	2.88e-02	32
hsa0501019	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0502219	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa0431012	Cervix	CC	Wnt signaling pathway	43/1267	171/8465	3.03e-04	1.64e-03	9.68e-04	43
hsa0522513	Cervix	CC	Hepatocellular carcinoma	40/1267	168/8465	1.52e-03	6.39e-03	3.78e-03	40
hsa0492813	Cervix	CC	Parathyroid hormone synthesis, secretion and action	27/1267	106/8465	3.12e-03	1.19e-02	7.03e-03	27
hsa052241	Cervix	CC	Breast cancer	32/1267	147/8465	1.66e-02	4.88e-02	2.88e-02	32
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

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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
WNT2B	FZD6_LRP6	WNT2B_FZD6_LRP6	WNT	Cervix	CC
WNT9A	FZD6_LRP6	WNT9A_FZD6_LRP6	WNT	Cervix	CC
WNT2	FZD4_LRP6	WNT2_FZD4_LRP6	WNT	Endometrium	ADJ
WNT2	FZD6_LRP6	WNT2_FZD6_LRP6	WNT	Endometrium	ADJ
WNT4	FZD4_LRP6	WNT4_FZD4_LRP6	WNT	Endometrium	ADJ
WNT4	FZD6_LRP6	WNT4_FZD6_LRP6	WNT	Endometrium	ADJ
WNT2	FZD4_LRP6	WNT2_FZD4_LRP6	WNT	Endometrium	AEH
WNT2B	FZD4_LRP6	WNT2B_FZD4_LRP6	WNT	Endometrium	AEH
WNT4	FZD4_LRP6	WNT4_FZD4_LRP6	WNT	Endometrium	AEH
WNT2	FZD4_LRP6	WNT2_FZD4_LRP6	WNT	Endometrium	EEC
WNT2	FZD6_LRP6	WNT2_FZD6_LRP6	WNT	Endometrium	EEC
WNT2B	FZD4_LRP6	WNT2B_FZD4_LRP6	WNT	Endometrium	EEC
WNT2B	FZD6_LRP6	WNT2B_FZD6_LRP6	WNT	Endometrium	EEC
WNT10A	FZD10_LRP6	WNT10A_FZD10_LRP6	WNT	Esophagus	ESCC
WNT10A	FZD3_LRP6	WNT10A_FZD3_LRP6	WNT	Esophagus	ESCC
WNT10A	FZD4_LRP6	WNT10A_FZD4_LRP6	WNT	Esophagus	ESCC
WNT10A	FZD5_LRP6	WNT10A_FZD5_LRP6	WNT	Esophagus	ESCC
WNT10A	FZD6_LRP6	WNT10A_FZD6_LRP6	WNT	Esophagus	ESCC
WNT10A	FZD8_LRP6	WNT10A_FZD8_LRP6	WNT	Esophagus	ESCC
WNT10B	FZD10_LRP6	WNT10B_FZD10_LRP6	WNT	Esophagus	ESCC

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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

LRP6

SNV

Missense_Mutation

c.2608N>A

p.Gln870Lys

p.Q870K

O75581

protein_coding

tolerated(0.11)

probably_damaging(0.933)

TCGA-A8-A07O-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

LRP6

SNV

Missense_Mutation

c.2527N>T

p.Asp843Tyr

p.D843Y

O75581

protein_coding

deleterious(0)

probably_damaging(0.976)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP6

SNV

Missense_Mutation

rs777840445

c.1244N>A

p.Arg415Gln

p.R415Q

O75581

protein_coding

deleterious(0.02)

possibly_damaging(0.842)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP6

SNV

Missense_Mutation

c.260N>T

p.Gln87Leu

p.Q87L

O75581

protein_coding

tolerated(0.09)

benign(0.03)

TCGA-AO-A03T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

LRP6

SNV

Missense_Mutation

c.778G>A

p.Glu260Lys

p.E260K

O75581

protein_coding

tolerated(0.33)

benign(0.003)

TCGA-BH-A0HX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adrimycin

LRP6

SNV

Missense_Mutation

c.2474N>A

p.Arg825His

p.R825H

O75581

protein_coding

deleterious(0.02)

benign(0.359)

TCGA-C8-A12M-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP6

SNV

Missense_Mutation

novel

c.721N>A

p.Asp241Asn

p.D241N

O75581

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-D8-A1J9-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

LRP6

SNV

Missense_Mutation

c.2119N>G

p.Pro707Ala

p.P707A

O75581

protein_coding

deleterious(0)

probably_damaging(0.945)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

LRP6

SNV

Missense_Mutation

rs143966208

c.3253C>T

p.Arg1085Trp

p.R1085W

O75581

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-GI-A2C8-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

Adriamycin

LRP6

SNV

Missense_Mutation

c.197A>G

p.Tyr66Cys

p.Y66C

O75581

protein_coding

tolerated(0.1)

benign(0.185)

TCGA-GM-A2DF-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxol

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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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