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: ATP2C1

Gene summary for ATP2C1

Gene summary.

Gene information	Species	Human
	Gene symbol	ATP2C1
	Gene ID	27032
	Gene name	ATPase secretory pathway Ca2+ transporting 1
	Gene Alias	ATP2C1A
	Cytomap	3q22.1
	Gene Type	protein-coding
	GO ID	GO:0000041
	UniProtAcc	P98194

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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
27032	ATP2C1	CA_HPV_2	Human	Cervix	CC	4.48e-02	2.63e-01	0.0391
27032	ATP2C1	CCI_1	Human	Cervix	CC	9.64e-04	7.07e-01	0.528
27032	ATP2C1	CCI_2	Human	Cervix	CC	6.77e-10	1.12e+00	0.5249
27032	ATP2C1	CCI_3	Human	Cervix	CC	1.13e-15	1.17e+00	0.516
27032	ATP2C1	Tumor	Human	Cervix	CC	6.97e-09	4.55e-01	0.1241
27032	ATP2C1	sample3	Human	Cervix	CC	7.38e-16	4.77e-01	0.1387
27032	ATP2C1	T3	Human	Cervix	CC	4.87e-12	4.55e-01	0.1389
27032	ATP2C1	HTA11_3410_2000001011	Human	Colorectum	AD	1.78e-06	-4.23e-01	0.0155
27032	ATP2C1	HTA11_3361_2000001011	Human	Colorectum	AD	6.82e-03	-4.50e-01	-0.1207
27032	ATP2C1	HTA11_696_2000001011	Human	Colorectum	AD	1.30e-02	-3.87e-01	-0.1464
27032	ATP2C1	HTA11_866_2000001011	Human	Colorectum	AD	2.42e-02	-3.33e-01	-0.1001
27032	ATP2C1	HTA11_866_3004761011	Human	Colorectum	AD	4.02e-04	-3.91e-01	0.096
27032	ATP2C1	HTA11_10711_2000001011	Human	Colorectum	AD	4.33e-03	-3.74e-01	0.0338
27032	ATP2C1	HTA11_7696_3000711011	Human	Colorectum	AD	8.09e-03	-3.22e-01	0.0674
27032	ATP2C1	HTA11_99999974143_84620	Human	Colorectum	MSS	1.12e-12	-5.16e-01	0.3005
27032	ATP2C1	A015-C-203	Human	Colorectum	FAP	2.36e-17	-3.35e-01	-0.1294
27032	ATP2C1	A015-C-204	Human	Colorectum	FAP	3.63e-04	-2.99e-01	-0.0228
27032	ATP2C1	A014-C-040	Human	Colorectum	FAP	4.08e-02	-3.64e-01	-0.1184
27032	ATP2C1	A002-C-201	Human	Colorectum	FAP	3.31e-08	-2.85e-01	0.0324
27032	ATP2C1	A001-C-119	Human	Colorectum	FAP	5.92e-06	-3.72e-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
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:004819321	Liver	HCC	Golgi vesicle transport	217/7958	296/18723	2.58e-27	1.02e-24	217
GO:190382922	Liver	HCC	positive regulation of cellular protein localization	199/7958	276/18723	1.15e-23	2.62e-21	199
GO:190495122	Liver	HCC	positive regulation of establishment of protein localization	207/7958	319/18723	3.95e-16	3.29e-14	207
GO:005122222	Liver	HCC	positive regulation of protein transport	194/7958	303/18723	2.41e-14	1.56e-12	194
GO:009015012	Liver	HCC	establishment of protein localization to membrane	168/7958	260/18723	4.07e-13	2.13e-11	168
GO:007265921	Liver	HCC	protein localization to plasma membrane	177/7958	284/18723	1.02e-11	4.18e-10	177
GO:199077821	Liver	HCC	protein localization to cell periphery	200/7958	333/18723	6.07e-11	2.23e-09	200
GO:000689221	Liver	HCC	post-Golgi vesicle-mediated transport	77/7958	104/18723	6.14e-11	2.24e-09	77
GO:009887621	Liver	HCC	vesicle-mediated transport to the plasma membrane	92/7958	136/18723	2.57e-09	7.07e-08	92
GO:190547511	Liver	HCC	regulation of protein localization to membrane	113/7958	175/18723	2.90e-09	7.78e-08	113
GO:190437521	Liver	HCC	regulation of protein localization to cell periphery	83/7958	125/18723	5.60e-08	1.19e-06	83
GO:190307621	Liver	HCC	regulation of protein localization to plasma membrane	69/7958	104/18723	7.58e-07	1.17e-05	69
GO:000689321	Liver	HCC	Golgi to plasma membrane transport	44/7958	60/18723	1.24e-06	1.81e-05	44
GO:004300121	Liver	HCC	Golgi to plasma membrane protein transport	32/7958	40/18723	1.40e-06	2.01e-05	32
GO:190547711	Liver	HCC	positive regulation of protein localization to membrane	68/7958	106/18723	5.50e-06	6.82e-05	68
GO:000724912	Liver	HCC	I-kappaB kinase/NF-kappaB signaling	156/7958	281/18723	6.66e-06	8.00e-05	156
GO:004312312	Liver	HCC	positive regulation of I-kappaB kinase/NF-kappaB signaling	108/7958	186/18723	1.28e-05	1.43e-04	108
GO:004312212	Liver	HCC	regulation of I-kappaB kinase/NF-kappaB signaling	138/7958	249/18723	2.47e-05	2.58e-04	138
GO:006195111	Liver	HCC	establishment of protein localization to plasma membrane	41/7958	60/18723	4.65e-05	4.49e-04	41
GO:190437712	Liver	HCC	positive regulation of protein localization to cell periphery	45/7958	69/18723	1.16e-04	9.80e-04	45

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

ATP2C1

SNV

Missense_Mutation

c.514N>C

p.Glu172Gln

p.E172Q

P98194

protein_coding

tolerated(0.17)

benign(0.037)

TCGA-A1-A0SI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATP2C1

SNV

Missense_Mutation

c.2170N>A

p.Glu724Lys

p.E724K

P98194

protein_coding

deleterious(0.02)

probably_damaging(0.995)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATP2C1

SNV

Missense_Mutation

c.359N>C

p.Leu120Pro

p.L120P

P98194

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ATP2C1

SNV

Missense_Mutation

c.1271G>C

p.Gly424Ala

p.G424A

P98194

protein_coding

tolerated(0.3)

benign(0.406)

TCGA-AR-A24Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ATP2C1

SNV

Missense_Mutation

c.1339N>C

p.Asp447His

p.D447H

P98194

protein_coding

deleterious(0.01)

possibly_damaging(0.81)

TCGA-D8-A1JA-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

ATP2C1

SNV

Missense_Mutation

rs145949576

c.1994C>T

p.Ser665Leu

p.S665L

P98194

protein_coding

deleterious(0)

possibly_damaging(0.611)

TCGA-EW-A6SA-01

Breast

breast invasive carcinoma

Male

<65

I/II

Unknown

ATP2C1

insertion

Nonsense_Mutation

novel

c.195_196insTAGAATAAT

p.Val65_Ser66insTer

p.V65_S66ins*

P98194

protein_coding

TCGA-A7-A26I-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

ATP2C1

deletion

Frame_Shift_Del

c.685delT

p.Cys229ValfsTer4

p.C229Vfs*4

P98194

protein_coding

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATP2C1

deletion

Frame_Shift_Del

c.340delN

p.Asn115IlefsTer16

p.N115Ifs*16

P98194

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ATP2C1

SNV

Missense_Mutation

novel

c.2336C>T

p.Pro779Leu

p.P779L

P98194

protein_coding

deleterious(0)

probably_damaging(1)

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
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		ENFLURANE	ENFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		ISOFLURANE	ISOFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		SEVOFLURANE	SEVOFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		ISOFLURANE	ISOFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		ENFLURANE	ENFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		SEVOFLURANE	SEVOFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		DESFLURANE	DESFLURANE
27032	ATP2C1	ENZYME, TRANSPORTER, DRUGGABLE GENOME		DESFLURANE	DESFLURANE

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