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: APP

Gene summary for APP

Gene summary.

Gene information	Species	Human
	Gene symbol	APP
	Gene ID	351
	Gene name	amyloid beta precursor protein
	Gene Alias	AAA
	Cytomap	21q21.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A140VJC8

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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
351	APP	GSM4909280	Human	Breast	Precancer	3.75e-05	-6.94e-01	0.0305
351	APP	GSM4909285	Human	Breast	IDC	6.71e-04	2.00e-01	0.21
351	APP	GSM4909286	Human	Breast	IDC	1.88e-11	-1.49e-01	0.1081
351	APP	GSM4909287	Human	Breast	IDC	2.66e-03	-2.56e-01	0.2057
351	APP	GSM4909288	Human	Breast	IDC	6.20e-06	-5.47e-01	0.0988
351	APP	GSM4909290	Human	Breast	IDC	4.51e-06	-3.59e-01	0.2096
351	APP	GSM4909293	Human	Breast	IDC	2.76e-12	-4.57e-01	0.1581
351	APP	GSM4909294	Human	Breast	IDC	4.82e-16	-5.04e-01	0.2022
351	APP	GSM4909296	Human	Breast	IDC	3.53e-32	-7.44e-01	0.1524
351	APP	GSM4909297	Human	Breast	IDC	1.60e-24	-5.27e-01	0.1517
351	APP	GSM4909298	Human	Breast	IDC	2.90e-04	2.05e-01	0.1551
351	APP	GSM4909299	Human	Breast	IDC	2.15e-15	4.12e-01	0.035
351	APP	GSM4909301	Human	Breast	IDC	1.23e-29	-7.29e-01	0.1577
351	APP	GSM4909304	Human	Breast	IDC	3.58e-34	-8.21e-01	0.1636
351	APP	GSM4909306	Human	Breast	IDC	6.59e-16	-5.71e-01	0.1564
351	APP	GSM4909308	Human	Breast	IDC	2.13e-13	-3.25e-01	0.158
351	APP	GSM4909309	Human	Breast	IDC	9.43e-04	1.60e-03	0.0483
351	APP	GSM4909311	Human	Breast	IDC	5.75e-46	-5.06e-01	0.1534
351	APP	GSM4909312	Human	Breast	IDC	2.32e-16	-4.22e-01	0.1552
351	APP	GSM4909313	Human	Breast	IDC	5.19e-10	1.64e-01	0.0391

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
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:00460349	Breast	Precancer	ATP metabolic process	82/1080	277/18723	1.94e-36	5.19e-33	82
GO:00060918	Breast	Precancer	generation of precursor metabolites and energy	94/1080	490/18723	1.54e-25	1.64e-22	94
GO:00069799	Breast	Precancer	response to oxidative stress	70/1080	446/18723	1.59e-14	4.26e-12	70
GO:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:00064179	Breast	Precancer	regulation of translation	67/1080	468/18723	4.71e-12	7.64e-10	67
GO:00458619	Breast	Precancer	negative regulation of proteolysis	50/1080	351/18723	2.99e-09	2.39e-07	50
GO:00709979	Breast	Precancer	neuron death	50/1080	361/18723	7.75e-09	5.70e-07	50
GO:00458629	Breast	Precancer	positive regulation of proteolysis	51/1080	372/18723	7.77e-09	5.70e-07	51
GO:00514029	Breast	Precancer	neuron apoptotic process	38/1080	246/18723	2.68e-08	1.75e-06	38
GO:00109529	Breast	Precancer	positive regulation of peptidase activity	33/1080	197/18723	3.01e-08	1.89e-06	33
GO:00513468	Breast	Precancer	negative regulation of hydrolase activity	50/1080	379/18723	3.85e-08	2.34e-06	50
GO:00104668	Breast	Precancer	negative regulation of peptidase activity	38/1080	262/18723	1.46e-07	7.82e-06	38
GO:00109519	Breast	Precancer	negative regulation of endopeptidase activity	37/1080	252/18723	1.55e-07	8.05e-06	37
GO:00509006	Breast	Precancer	leukocyte migration	47/1080	369/18723	2.82e-07	1.39e-05	47
GO:00196938	Breast	Precancer	ribose phosphate metabolic process	49/1080	396/18723	3.81e-07	1.78e-05	49
GO:00100389	Breast	Precancer	response to metal ion	47/1080	373/18723	3.88e-07	1.79e-05	47
GO:00091509	Breast	Precancer	purine ribonucleotide metabolic process	46/1080	368/18723	6.47e-07	2.71e-05	46
GO:00091179	Breast	Precancer	nucleotide metabolic process	56/1080	489/18723	7.40e-07	3.00e-05	56
GO:00092598	Breast	Precancer	ribonucleotide metabolic process	47/1080	385/18723	9.69e-07	3.84e-05	47

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501016	Breast	Precancer	Alzheimer disease	103/684	384/8465	1.03e-29	4.66e-28	3.57e-28	103
hsa0502216	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0501017	Breast	Precancer	Alzheimer disease	103/684	384/8465	1.03e-29	4.66e-28	3.57e-28	103
hsa0502217	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0501023	Breast	IDC	Alzheimer disease	107/867	384/8465	1.70e-23	7.88e-22	5.90e-22	107
hsa0502223	Breast	IDC	Pathways of neurodegeneration - multiple diseases	116/867	476/8465	3.63e-20	1.18e-18	8.82e-19	116
hsa0501033	Breast	IDC	Alzheimer disease	107/867	384/8465	1.70e-23	7.88e-22	5.90e-22	107
hsa0502233	Breast	IDC	Pathways of neurodegeneration - multiple diseases	116/867	476/8465	3.63e-20	1.18e-18	8.82e-19	116
hsa0501044	Cervix	N_HPV	Alzheimer disease	41/349	384/8465	1.50e-08	3.13e-07	2.45e-07	41
hsa0501054	Cervix	N_HPV	Alzheimer disease	41/349	384/8465	1.50e-08	3.13e-07	2.45e-07	41
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
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
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
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
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

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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
APP	CD74	APP_CD74	APP	Breast	ADJ
APP	CD74	APP_CD74	APP	Breast	DCIS
APP	CD74	APP_CD74	APP	Breast	Healthy
APP	CD74	APP_CD74	APP	Breast	IDC
APP	CD74	APP_CD74	APP	Breast	Precancer
APP	CD74	APP_CD74	APP	Cervix	ADJ
APP	CD74	APP_CD74	APP	Cervix	CC
APP	CD74	APP_CD74	APP	Cervix	Healthy
APP	CD74	APP_CD74	APP	Cervix	Precancer
APP	CD74	APP_CD74	APP	CRC	AD
APP	CD74	APP_CD74	APP	CRC	ADJ
APP	CD74	APP_CD74	APP	CRC	CRC
APP	CD74	APP_CD74	APP	CRC	FAP
APP	CD74	APP_CD74	APP	CRC	MSI-H
APP	CD74	APP_CD74	APP	CRC	MSS
APP	CD74	APP_CD74	APP	CRC	SER
APP	CD74	APP_CD74	APP	Endometrium	ADJ
APP	CD74	APP_CD74	APP	Endometrium	AEH
APP	CD74	APP_CD74	APP	Endometrium	EEC
APP	CD74	APP_CD74	APP	Endometrium	Healthy

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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

APP

SNV

Missense_Mutation

novel

c.1701G>C

p.Gln567His

p.Q567H

P05067

protein_coding

tolerated(0.1)

possibly_damaging(0.906)

TCGA-A2-A0CR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

APP

SNV

Missense_Mutation

rs201093867

c.710N>G

p.Val237Gly

p.V237G

P05067

protein_coding

tolerated(0.37)

benign(0.018)

TCGA-A2-A0T2-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

xeloda

APP

SNV

Missense_Mutation

c.533A>G

p.Lys178Arg

p.K178R

P05067

protein_coding

tolerated(1)

benign(0.007)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

APP

SNV

Missense_Mutation

c.853G>C

p.Glu285Gln

p.E285Q

P05067

protein_coding

tolerated(0.17)

benign(0.403)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

APP

SNV

Missense_Mutation

rs199549173

c.1406N>A

p.Arg469His

p.R469H

P05067

protein_coding

deleterious(0.01)

probably_damaging(0.999)

TCGA-AC-A6IW-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

APP

SNV

Missense_Mutation

rs760615902

c.1666N>A

p.Glu556Lys

p.E556K

P05067

protein_coding

deleterious(0.01)

benign(0.132)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

APP

SNV

Missense_Mutation

rs200521782

c.1690G>C

p.Glu564Gln

p.E564Q

P05067

protein_coding

deleterious(0.01)

possibly_damaging(0.757)

TCGA-AR-A251-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

APP

SNV

Missense_Mutation

rs201093867

c.710T>G

p.Val237Gly

p.V237G

P05067

protein_coding

tolerated(0.37)

benign(0.018)

TCGA-B6-A0I5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

APP

SNV

Missense_Mutation

c.124N>C

p.Asn42His

p.N42H

P05067

protein_coding

deleterious(0)

possibly_damaging(0.899)

TCGA-B6-A0RE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

APP

SNV

Missense_Mutation

rs201093867

c.710T>G

p.Val237Gly

p.V237G

P05067

protein_coding

tolerated(0.37)

benign(0.018)

TCGA-BH-A1F2-01

Breast

breast invasive carcinoma

Female

<65

III/IV

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
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		GENTIAN VIOLET	GENTIAN VIOLET
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		ALZ-801
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		Affitope AD-01		22506132
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		AAB-003/PF-05236812
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		CHEMBL2109300	GSK933776
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		MABT5102A	CRENEZUMAB
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		MER-5101
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		AAB-002
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		Gantenerumab	GANTENERUMAB
351	APP	DRUGGABLE GENOME, PROTEASE INHIBITOR, CELL SURFACE		Systebryl

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