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: ATP2A2

Gene summary for ATP2A2

Gene summary.

Gene information	Species	Human
	Gene symbol	ATP2A2
	Gene ID	488
	Gene name	ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2
	Gene Alias	ATP2B
	Cytomap	12q24.11
	Gene Type	protein-coding
	GO ID	GO:0000045
	UniProtAcc	P16615

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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
488	ATP2A2	CA_HPV_1	Human	Cervix	CC	1.44e-05	-1.42e-01	0.0264
488	ATP2A2	CCI_1	Human	Cervix	CC	4.31e-09	9.21e-01	0.528
488	ATP2A2	CCI_2	Human	Cervix	CC	2.68e-04	7.88e-01	0.5249
488	ATP2A2	CCI_3	Human	Cervix	CC	5.91e-08	8.11e-01	0.516
488	ATP2A2	sample3	Human	Cervix	CC	4.31e-08	3.70e-01	0.1387
488	ATP2A2	T3	Human	Cervix	CC	1.47e-06	3.80e-01	0.1389
488	ATP2A2	HTA11_3410_2000001011	Human	Colorectum	AD	6.80e-05	-1.96e-01	0.0155
488	ATP2A2	HTA11_1938_2000001011	Human	Colorectum	AD	3.69e-02	4.25e-01	-0.0811
488	ATP2A2	HTA11_347_2000001011	Human	Colorectum	AD	5.24e-10	4.80e-01	-0.1954
488	ATP2A2	HTA11_411_2000001011	Human	Colorectum	SER	1.90e-05	9.73e-01	-0.2602
488	ATP2A2	HTA11_1391_2000001011	Human	Colorectum	AD	2.32e-04	5.54e-01	-0.059
488	ATP2A2	HTA11_99999965062_69753	Human	Colorectum	MSI-H	3.46e-05	1.01e+00	0.3487
488	ATP2A2	HTA11_99999965104_69814	Human	Colorectum	MSS	2.34e-02	4.14e-01	0.281
488	ATP2A2	F007	Human	Colorectum	FAP	1.29e-02	-3.16e-01	0.1176
488	ATP2A2	A002-C-010	Human	Colorectum	FAP	3.20e-04	-1.84e-01	0.242
488	ATP2A2	A001-C-207	Human	Colorectum	FAP	3.57e-02	-2.07e-01	0.1278
488	ATP2A2	A015-C-203	Human	Colorectum	FAP	1.08e-32	-4.34e-01	-0.1294
488	ATP2A2	A015-C-204	Human	Colorectum	FAP	1.93e-04	-3.29e-01	-0.0228
488	ATP2A2	A014-C-040	Human	Colorectum	FAP	1.22e-03	-3.57e-01	-0.1184
488	ATP2A2	A002-C-201	Human	Colorectum	FAP	4.98e-13	-3.76e-01	0.0324

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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
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:0061337	Colorectum	MSI-H	cardiac conduction	15/1319	98/18723	3.48e-03	4.18e-02	15
GO:00329704	Colorectum	FAP	regulation of actin filament-based process	105/2622	397/18723	3.15e-11	1.38e-08	105
GO:00300483	Colorectum	FAP	actin filament-based movement	44/2622	127/18723	3.48e-09	5.93e-07	44
GO:00621974	Colorectum	FAP	cellular response to chemical stress	83/2622	337/18723	1.15e-07	7.43e-06	83
GO:00069794	Colorectum	FAP	response to oxidative stress	102/2622	446/18723	2.29e-07	1.33e-05	102
GO:00162363	Colorectum	FAP	macroautophagy	70/2622	291/18723	2.73e-06	1.02e-04	70
GO:00224114	Colorectum	FAP	cellular component disassembly	97/2622	443/18723	3.44e-06	1.23e-04	97
GO:00989014	Colorectum	FAP	regulation of cardiac muscle cell action potential	14/2622	27/18723	3.58e-06	1.26e-04	14
GO:00345994	Colorectum	FAP	cellular response to oxidative stress	69/2622	288/18723	3.72e-06	1.29e-04	69
GO:00510984	Colorectum	FAP	regulation of binding	81/2622	363/18723	1.04e-05	2.97e-04	81
GO:00990032	Colorectum	FAP	vesicle-mediated transport in synapse	51/2622	200/18723	1.09e-05	3.08e-04	51
GO:00349764	Colorectum	FAP	response to endoplasmic reticulum stress	61/2622	256/18723	1.58e-05	4.10e-04	61
GO:00329844	Colorectum	FAP	protein-containing complex disassembly	54/2622	224/18723	3.37e-05	7.48e-04	54
GO:00995041	Colorectum	FAP	synaptic vesicle cycle	45/2622	181/18723	6.73e-05	1.28e-03	45
GO:00860012	Colorectum	FAP	cardiac muscle cell action potential	24/2622	76/18723	6.86e-05	1.29e-03	24
GO:00902574	Colorectum	FAP	regulation of muscle system process	58/2622	252/18723	7.22e-05	1.33e-03	58
GO:00069843	Colorectum	FAP	ER-nucleus signaling pathway	17/2622	46/18723	8.85e-05	1.57e-03	17
GO:00860044	Colorectum	FAP	regulation of cardiac muscle cell contraction	14/2622	34/18723	9.46e-05	1.61e-03	14
GO:0023061	Colorectum	FAP	signal release	94/2622	463/18723	1.06e-04	1.76e-03	94
GO:00702521	Colorectum	FAP	actin-mediated cell contraction	28/2622	97/18723	1.06e-04	1.76e-03	28

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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
hsa0491918	Cervix	CC	Thyroid hormone signaling pathway	33/1267	121/8465	3.11e-04	1.65e-03	9.78e-04	33
hsa0426018	Cervix	CC	Cardiac muscle contraction	23/1267	87/8465	3.71e-03	1.34e-02	7.91e-03	23
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
hsa0491919	Cervix	CC	Thyroid hormone signaling pathway	33/1267	121/8465	3.11e-04	1.65e-03	9.78e-04	33
hsa0426019	Cervix	CC	Cardiac muscle contraction	23/1267	87/8465	3.71e-03	1.34e-02	7.91e-03	23
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
hsa05017	Colorectum	AD	Spinocerebellar ataxia	60/2092	143/8465	3.78e-06	4.35e-05	2.78e-05	60
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa04260	Colorectum	AD	Cardiac muscle contraction	32/2092	87/8465	7.92e-03	3.13e-02	2.00e-02	32
hsa04972	Colorectum	AD	Pancreatic secretion	36/2092	102/8465	1.06e-02	3.98e-02	2.54e-02	36
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
hsa050171	Colorectum	AD	Spinocerebellar ataxia	60/2092	143/8465	3.78e-06	4.35e-05	2.78e-05	60
hsa049191	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa042601	Colorectum	AD	Cardiac muscle contraction	32/2092	87/8465	7.92e-03	3.13e-02	2.00e-02	32
hsa049721	Colorectum	AD	Pancreatic secretion	36/2092	102/8465	1.06e-02	3.98e-02	2.54e-02	36

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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

ATP2A2

SNV

Missense_Mutation

c.2234N>G

p.Ala745Gly

p.A745G

P16615

protein_coding

deleterious(0)

benign(0.305)

TCGA-A2-A0D0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ATP2A2

SNV

Missense_Mutation

c.2234N>G

p.Ala745Gly

p.A745G

P16615

protein_coding

deleterious(0)

benign(0.305)

TCGA-AN-A0AT-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATP2A2

SNV

Missense_Mutation

novel

c.1771A>G

p.Thr591Ala

p.T591A

P16615

protein_coding

deleterious(0)

probably_damaging(0.914)

TCGA-B6-A2IU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATP2A2

SNV

Missense_Mutation

c.2440N>A

p.Asp814Asn

p.D814N

P16615

protein_coding

tolerated(0.05)

benign(0.296)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ATP2A2

SNV

Missense_Mutation

c.2461N>T

p.Arg821Trp

p.R821W

P16615

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-E2-A14T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ATP2A2

SNV

Missense_Mutation

novel

c.3025N>A

p.Ala1009Thr

p.A1009T

P16615

protein_coding

tolerated_low_confidence(0.1)

probably_damaging(0.971)

TCGA-LL-A6FQ-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

ATP2A2

insertion

Frame_Shift_Ins

novel

c.244_245insGTCTGGAACTCTTGACCTC

p.Glu82GlyfsTer38

p.E82Gfs*38

P16615

protein_coding

TCGA-AQ-A04J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ATP2A2

insertion

Frame_Shift_Ins

novel

c.1849_1850insACTTGAGACAGCAGGAACCCATGTGTAGTTTAGAA

p.Gly617AspfsTer18

p.G617Dfs*18

P16615

protein_coding

TCGA-B6-A0IN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATP2A2

SNV

Missense_Mutation

c.1886N>A

p.Gly629Asp

p.G629D

P16615

protein_coding

tolerated(0.08)

benign(0.003)

TCGA-C5-A1BM-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

ATP2A2

SNV

Missense_Mutation

c.454N>C

p.Glu152Gln

p.E152Q

P16615

protein_coding

deleterious(0.01)

benign(0.183)

TCGA-EK-A2RJ-01

Cervix

cervical & endocervical cancer

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
488	ATP2A2	ENZYME, DRUGGABLE GENOME, TRANSPORTER		celecoxib	CELECOXIB	22336956
488	ATP2A2	ENZYME, DRUGGABLE GENOME, TRANSPORTER		ISTAROXIME	ISTAROXIME
488	ATP2A2	ENZYME, DRUGGABLE GENOME, TRANSPORTER		Gallopamil	GALLOPAMIL
488	ATP2A2	ENZYME, DRUGGABLE GENOME, TRANSPORTER		Mydicar

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