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: ATP2A3

Gene summary for ATP2A3

Gene summary.

Gene information	Species	Human
	Gene symbol	ATP2A3
	Gene ID	489
	Gene name	ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3
	Gene Alias	SERCA3
	Cytomap	17p13.2
	Gene Type	protein-coding
	GO ID	GO:0003008
	UniProtAcc	A8K9K1

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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
489	ATP2A3	HTA11_2487_2000001011	Human	Colorectum	SER	7.99e-07	5.96e-01	-0.1808
489	ATP2A3	HTA11_347_2000001011	Human	Colorectum	AD	6.21e-06	4.74e-01	-0.1954
489	ATP2A3	HTA11_411_2000001011	Human	Colorectum	SER	2.01e-04	1.15e+00	-0.2602
489	ATP2A3	HTA11_2112_2000001011	Human	Colorectum	SER	9.08e-08	1.32e+00	-0.2196
489	ATP2A3	HTA11_3361_2000001011	Human	Colorectum	AD	1.76e-02	3.69e-01	-0.1207
489	ATP2A3	HTA11_696_2000001011	Human	Colorectum	AD	6.70e-35	1.18e+00	-0.1464
489	ATP2A3	HTA11_866_2000001011	Human	Colorectum	AD	1.03e-14	5.88e-01	-0.1001
489	ATP2A3	HTA11_2992_2000001011	Human	Colorectum	SER	9.14e-04	7.79e-01	-0.1706
489	ATP2A3	HTA11_546_2000001011	Human	Colorectum	AD	1.68e-03	6.15e-01	-0.0842
489	ATP2A3	HTA11_99999970781_79442	Human	Colorectum	MSS	1.19e-03	-2.72e-01	0.294
489	ATP2A3	HTA11_99999971662_82457	Human	Colorectum	MSS	3.71e-08	-3.43e-01	0.3859
489	ATP2A3	HTA11_99999973899_84307	Human	Colorectum	MSS	3.06e-03	-3.58e-01	0.2585
489	ATP2A3	A015-C-203	Human	Colorectum	FAP	3.81e-11	4.16e-01	-0.1294
489	ATP2A3	A001-C-119	Human	Colorectum	FAP	1.23e-02	4.30e-01	-0.1557
489	ATP2A3	A002-C-205	Human	Colorectum	FAP	2.35e-04	-6.09e-02	-0.1236
489	ATP2A3	A015-C-005	Human	Colorectum	FAP	8.30e-06	5.65e-01	-0.0336
489	ATP2A3	A015-C-006	Human	Colorectum	FAP	1.74e-04	2.46e-01	-0.0994
489	ATP2A3	A002-C-114	Human	Colorectum	FAP	1.66e-07	3.64e-01	-0.1561
489	ATP2A3	A015-C-104	Human	Colorectum	FAP	4.07e-08	3.14e-01	-0.1899
489	ATP2A3	A002-C-016	Human	Colorectum	FAP	1.46e-02	6.83e-02	0.0521

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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

∗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:2000116111	Esophagus	ESCC	regulation of cysteine-type endopeptidase activity	158/8552	235/18723	1.67e-11	5.90e-10	158
GO:0043281111	Esophagus	ESCC	regulation of cysteine-type endopeptidase activity involved in apoptotic process	143/8552	209/18723	2.12e-11	7.31e-10	143
GO:004339320	Esophagus	ESCC	regulation of protein binding	135/8552	196/18723	3.69e-11	1.22e-09	135
GO:0010952111	Esophagus	ESCC	positive regulation of peptidase activity	133/8552	197/18723	4.31e-10	1.14e-08	133
GO:0052547111	Esophagus	ESCC	regulation of peptidase activity	275/8552	461/18723	7.54e-10	1.88e-08	275
GO:0051100111	Esophagus	ESCC	negative regulation of binding	109/8552	162/18723	2.10e-08	4.03e-07	109
GO:0052548111	Esophagus	ESCC	regulation of endopeptidase activity	253/8552	432/18723	3.68e-08	6.78e-07	253
GO:0070059111	Esophagus	ESCC	intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	50/8552	63/18723	4.37e-08	7.96e-07	50
GO:0010950111	Esophagus	ESCC	positive regulation of endopeptidase activity	116/8552	179/18723	1.77e-07	2.79e-06	116
GO:003209116	Esophagus	ESCC	negative regulation of protein binding	65/8552	94/18723	3.46e-06	3.82e-05	65
GO:0043280110	Esophagus	ESCC	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	84/8552	129/18723	6.38e-06	6.55e-05	84
GO:2001056110	Esophagus	ESCC	positive regulation of cysteine-type endopeptidase activity	94/8552	148/18723	8.87e-06	8.59e-05	94
GO:000691915	Esophagus	ESCC	activation of cysteine-type endopeptidase activity involved in apoptotic process	54/8552	78/18723	2.17e-05	1.87e-04	54

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05415	Colorectum	AD	Diabetic cardiomyopathy	114/2092	203/8465	3.65e-22	3.06e-20	1.95e-20	114
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
hsa054151	Colorectum	AD	Diabetic cardiomyopathy	114/2092	203/8465	3.65e-22	3.06e-20	1.95e-20	114
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
hsa054152	Colorectum	SER	Diabetic cardiomyopathy	103/1580	203/8465	1.45e-25	1.61e-23	1.17e-23	103
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
hsa050172	Colorectum	SER	Spinocerebellar ataxia	46/1580	143/8465	6.78e-05	7.51e-04	5.45e-04	46
hsa049192	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa042602	Colorectum	SER	Cardiac muscle contraction	31/1580	87/8465	1.30e-04	1.30e-03	9.47e-04	31

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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

ATP2A3

SNV

Missense_Mutation

rs61999330

c.2057G>A

p.Arg686His

p.R686H

Q93084

protein_coding

deleterious(0)

probably_damaging(0.944)

TCGA-A2-A3XV-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

ATP2A3

SNV

Missense_Mutation

c.2984N>C

p.Cys995Ser

p.C995S

Q93084

protein_coding

tolerated_low_confidence(0.52)

benign(0)

TCGA-B6-A0RS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATP2A3

SNV

Missense_Mutation

rs868053250

c.3104C>T

p.Ser1035Leu

p.S1035L

Q93084

protein_coding

deleterious_low_confidence(0.04)

benign(0)

TCGA-BH-A0DG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

ATP2A3

SNV

Missense_Mutation

c.2595N>G

p.Ile865Met

p.I865M

Q93084

protein_coding

tolerated(0.15)

benign(0.009)

TCGA-D8-A1JA-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

ATP2A3

insertion

Nonsense_Mutation

novel

c.2595_2596insTAAAACGTTGAGGCCTCAGAGGAATGAGCCCCTAAATGGTGGG

p.Asn866Ter

p.N866*

Q93084

protein_coding

TCGA-A2-A0CP-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ATP2A3

insertion

Frame_Shift_Ins

novel

c.2145_2146insCACACACTCAT

p.Ile716HisfsTer46

p.I716Hfs*46

Q93084

protein_coding

TCGA-BH-A0E7-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ATP2A3

insertion

Frame_Shift_Ins

novel

c.2144_2145insAGGATTTGTGCCGGCGTGTGACTGT

p.Ile716GlyfsTer31

p.I716Gfs*31

Q93084

protein_coding

TCGA-BH-A0E7-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ATP2A3

deletion

Frame_Shift_Del

novel

c.2409delN

p.Ala804ProfsTer41

p.A804Pfs*41

Q93084

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ATP2A3

deletion

Frame_Shift_Del

novel

c.2349delG

p.Glu785LysfsTer3

p.E785Kfs*3

Q93084

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

ATP2A3

SNV

Missense_Mutation

rs750110323

c.2980N>A

p.Ala994Thr

p.A994T

Q93084

protein_coding

tolerated_low_confidence(0.1)

benign(0.093)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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
489	ATP2A3	DRUGGABLE GENOME, TRANSPORTER, ENZYME		celecoxib	CELECOXIB	22336956

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