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: ATP1A1

Gene summary for ATP1A1

Gene summary.

Gene information	Species	Human
	Gene symbol	ATP1A1
	Gene ID	476
	Gene name	ATPase Na+/K+ transporting subunit alpha 1
	Gene Alias	CMT2DD
	Cytomap	1p13.1
	Gene Type	protein-coding
	GO ID	GO:0001508
	UniProtAcc	P05023

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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
476	ATP1A1	GSM4909286	Human	Breast	IDC	8.34e-06	-2.37e-01	0.1081
476	ATP1A1	GSM4909287	Human	Breast	IDC	1.15e-03	-2.62e-01	0.2057
476	ATP1A1	GSM4909288	Human	Breast	IDC	1.33e-04	-5.21e-01	0.0988
476	ATP1A1	GSM4909290	Human	Breast	IDC	4.53e-03	-3.09e-01	0.2096
476	ATP1A1	GSM4909293	Human	Breast	IDC	3.85e-03	-2.85e-01	0.1581
476	ATP1A1	GSM4909294	Human	Breast	IDC	6.47e-18	-5.09e-01	0.2022
476	ATP1A1	GSM4909296	Human	Breast	IDC	1.04e-15	-3.22e-01	0.1524
476	ATP1A1	GSM4909297	Human	Breast	IDC	8.71e-23	-3.34e-01	0.1517
476	ATP1A1	GSM4909301	Human	Breast	IDC	7.29e-29	-6.00e-01	0.1577
476	ATP1A1	GSM4909302	Human	Breast	IDC	1.68e-11	-4.13e-01	0.1545
476	ATP1A1	GSM4909304	Human	Breast	IDC	2.61e-06	-3.05e-01	0.1636
476	ATP1A1	GSM4909306	Human	Breast	IDC	1.04e-07	-3.33e-01	0.1564
476	ATP1A1	GSM4909307	Human	Breast	IDC	4.60e-13	-4.55e-01	0.1569
476	ATP1A1	GSM4909308	Human	Breast	IDC	8.46e-17	-5.29e-01	0.158
476	ATP1A1	GSM4909309	Human	Breast	IDC	3.21e-04	-2.34e-01	0.0483
476	ATP1A1	GSM4909311	Human	Breast	IDC	2.32e-43	-3.85e-01	0.1534
476	ATP1A1	GSM4909312	Human	Breast	IDC	9.05e-18	-4.06e-01	0.1552
476	ATP1A1	GSM4909313	Human	Breast	IDC	1.11e-03	1.37e-01	0.0391
476	ATP1A1	GSM4909315	Human	Breast	IDC	3.55e-16	-4.89e-01	0.21
476	ATP1A1	GSM4909316	Human	Breast	IDC	1.36e-09	-6.30e-01	0.21

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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
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
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:007121415	Prostate	Tumor	cellular response to abiotic stimulus	92/3246	331/18723	1.25e-06	2.32e-05	92
GO:010400415	Prostate	Tumor	cellular response to environmental stimulus	92/3246	331/18723	1.25e-06	2.32e-05	92
GO:000961214	Prostate	Tumor	response to mechanical stimulus	60/3246	216/18723	8.45e-05	8.46e-04	60
GO:007126013	Prostate	Tumor	cellular response to mechanical stimulus	28/3246	81/18723	1.39e-04	1.27e-03	28
GO:000941017	Prostate	Tumor	response to xenobiotic stimulus	110/3246	462/18723	2.13e-04	1.84e-03	110
GO:009025713	Prostate	Tumor	regulation of muscle system process	66/3246	252/18723	2.54e-04	2.13e-03	66
GO:001631113	Prostate	Tumor	dephosphorylation	98/3246	417/18723	7.31e-04	5.08e-03	98
GO:000301214	Prostate	Tumor	muscle system process	105/3246	452/18723	7.44e-04	5.14e-03	105
GO:008600414	Prostate	Tumor	regulation of cardiac muscle cell contraction	14/3246	34/18723	9.26e-04	6.10e-03	14
GO:003004815	Prostate	Tumor	actin filament-based movement	36/3246	127/18723	1.38e-03	8.62e-03	36
GO:190311513	Prostate	Tumor	regulation of actin filament-based movement	15/3246	39/18723	1.42e-03	8.80e-03	15
GO:00323501	Prostate	Tumor	regulation of hormone metabolic process	13/3246	35/18723	4.14e-03	2.08e-02	13
GO:000202812	Prostate	Tumor	regulation of sodium ion transport	26/3246	90/18723	4.54e-03	2.24e-02	26
GO:00192166	Prostate	Tumor	regulation of lipid metabolic process	76/3246	331/18723	5.04e-03	2.45e-02	76
GO:0046885	Prostate	Tumor	regulation of hormone biosynthetic process	9/3246	21/18723	5.54e-03	2.61e-02	9
GO:008606413	Prostate	Tumor	cell communication by electrical coupling involved in cardiac conduction	10/3246	25/18723	6.30e-03	2.89e-02	10
GO:00468905	Prostate	Tumor	regulation of lipid biosynthetic process	42/3246	171/18723	1.02e-02	4.28e-02	42
GO:004854528	Skin	AK	response to steroid hormone	73/1910	339/18723	4.51e-10	5.24e-08	73
GO:007121420	Skin	AK	cellular response to abiotic stimulus	67/1910	331/18723	3.15e-08	1.71e-06	67
GO:010400420	Skin	AK	cellular response to environmental stimulus	67/1910	331/18723	3.15e-08	1.71e-06	67

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0426016	Breast	Precancer	Cardiac muscle contraction	22/684	87/8465	9.72e-07	1.62e-05	1.24e-05	22
hsa0496110	Breast	Precancer	Endocrine and other factor-regulated calcium reabsorption	11/684	53/8465	2.92e-03	1.81e-02	1.39e-02	11
hsa0497114	Breast	Precancer	Gastric acid secretion	13/684	76/8465	7.35e-03	4.07e-02	3.12e-02	13
hsa0426017	Breast	Precancer	Cardiac muscle contraction	22/684	87/8465	9.72e-07	1.62e-05	1.24e-05	22
hsa0496111	Breast	Precancer	Endocrine and other factor-regulated calcium reabsorption	11/684	53/8465	2.92e-03	1.81e-02	1.39e-02	11
hsa0497115	Breast	Precancer	Gastric acid secretion	13/684	76/8465	7.35e-03	4.07e-02	3.12e-02	13
hsa0426022	Breast	IDC	Cardiac muscle contraction	23/867	87/8465	1.39e-05	1.61e-04	1.21e-04	23
hsa0491916	Breast	IDC	Thyroid hormone signaling pathway	23/867	121/8465	2.45e-03	1.69e-02	1.27e-02	23
hsa0497122	Breast	IDC	Gastric acid secretion	16/867	76/8465	3.80e-03	2.33e-02	1.74e-02	16
hsa049704	Breast	IDC	Salivary secretion	18/867	93/8465	5.69e-03	3.13e-02	2.34e-02	18
hsa0496121	Breast	IDC	Endocrine and other factor-regulated calcium reabsorption	12/867	53/8465	6.29e-03	3.30e-02	2.47e-02	12
hsa0497812	Breast	IDC	Mineral absorption	13/867	60/8465	6.73e-03	3.42e-02	2.56e-02	13
hsa0426032	Breast	IDC	Cardiac muscle contraction	23/867	87/8465	1.39e-05	1.61e-04	1.21e-04	23
hsa0491917	Breast	IDC	Thyroid hormone signaling pathway	23/867	121/8465	2.45e-03	1.69e-02	1.27e-02	23
hsa0497132	Breast	IDC	Gastric acid secretion	16/867	76/8465	3.80e-03	2.33e-02	1.74e-02	16
hsa0497011	Breast	IDC	Salivary secretion	18/867	93/8465	5.69e-03	3.13e-02	2.34e-02	18
hsa0496131	Breast	IDC	Endocrine and other factor-regulated calcium reabsorption	12/867	53/8465	6.29e-03	3.30e-02	2.47e-02	12
hsa0497813	Breast	IDC	Mineral absorption	13/867	60/8465	6.73e-03	3.42e-02	2.56e-02	13
hsa0491918	Cervix	CC	Thyroid hormone signaling pathway	33/1267	121/8465	3.11e-04	1.65e-03	9.78e-04	33
hsa0497116	Cervix	CC	Gastric acid secretion	20/1267	76/8465	6.93e-03	2.27e-02	1.34e-02	20

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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

ATP1A1

SNV

Missense_Mutation

novel

c.784G>T

p.Gly262Trp

p.G262W

P05023

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A7-A0DB-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

ATP1A1

SNV

Missense_Mutation

c.208G>C

p.Glu70Gln

p.E70Q

P05023

protein_coding

tolerated(0.09)

benign(0.258)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATP1A1

SNV

Missense_Mutation

novel

c.1522A>C

p.Lys508Gln

p.K508Q

P05023

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATP1A1

SNV

Missense_Mutation

c.1553N>A

p.Cys518Tyr

p.C518Y

P05023

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-B6-A0IB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

ATP1A1

SNV

Missense_Mutation

novel

c.1534N>A

p.Glu512Lys

p.E512K

P05023

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATP1A1

SNV

Missense_Mutation

c.2450T>C

p.Val817Ala

p.V817A

P05023

protein_coding

tolerated(0.06)

possibly_damaging(0.466)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATP1A1

SNV

Missense_Mutation

c.2175G>T

p.Leu725Phe

p.L725F

P05023

protein_coding

deleterious(0.01)

possibly_damaging(0.747)

TCGA-C8-A1HM-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

ATP1A1

SNV

Missense_Mutation

c.1223G>A

p.Gly408Asp

p.G408D

P05023

protein_coding

tolerated(0.06)

benign(0.363)

TCGA-E2-A14Y-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

ATP1A1

insertion

In_Frame_Ins

novel

c.117_118insCTCACCCTTTGCCTGTCAGTTGTTCAGCGTGTAACAGTTCCCTGC

p.Val39_Ser40insLeuThrLeuCysLeuSerValValGlnArgValThrValProCys

p.V39_S40insLTLCLSVVQRVTVPC

P05023

protein_coding

TCGA-AN-A04A-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

ATP1A1

insertion

Frame_Shift_Ins

novel

c.2365_2366insTACCCCAGAAAAGGGAAAA

p.Pro789LeufsTer29

p.P789Lfs*29

P05023

protein_coding

TCGA-AO-A0JD-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

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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
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		ISTAROXIME	ISTAROXIME
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		Chloroprocaine	CHLOROPROCAINE
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		ACETYLDIGITOXIN	ACETYLDIGITOXIN
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		ALMITRINE	ALMITRINE
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		Deslanoside	DESLANOSIDE
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		DIGOXIN	DIGOXIN
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		DESLANOSIDE	DESLANOSIDE
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		DESLANOSIDE	DESLANOSIDE
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		BEPRIDIL	BEPRIDIL
476	ATP1A1	ION CHANNEL, DRUGGABLE GENOME, TRANSPORTER, ENZYME, CLINICALLY ACTIONABLE		DIGITOXIN	DIGITOXIN

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