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: SLC12A2

Gene summary for SLC12A2

Gene summary.

Gene information	Species	Human
	Gene symbol	SLC12A2
	Gene ID	6558
	Gene name	solute carrier family 12 member 2
	Gene Alias	BSC
	Cytomap	5q23.3
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	P55011

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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
6558	SLC12A2	GSM4909281	Human	Breast	IDC	2.83e-04	-3.39e-01	0.21
6558	SLC12A2	GSM4909285	Human	Breast	IDC	1.84e-16	-4.63e-01	0.21
6558	SLC12A2	GSM4909287	Human	Breast	IDC	8.91e-08	-3.09e-01	0.2057
6558	SLC12A2	GSM4909289	Human	Breast	IDC	1.56e-02	4.04e-01	0.1064
6558	SLC12A2	GSM4909292	Human	Breast	IDC	1.22e-02	-4.98e-01	0.1236
6558	SLC12A2	GSM4909293	Human	Breast	IDC	4.69e-05	2.78e-01	0.1581
6558	SLC12A2	GSM4909294	Human	Breast	IDC	3.08e-06	4.00e-02	0.2022
6558	SLC12A2	GSM4909296	Human	Breast	IDC	9.64e-14	-4.23e-01	0.1524
6558	SLC12A2	GSM4909297	Human	Breast	IDC	7.68e-46	8.80e-01	0.1517
6558	SLC12A2	GSM4909299	Human	Breast	IDC	2.36e-29	7.28e-01	0.035
6558	SLC12A2	GSM4909301	Human	Breast	IDC	5.37e-09	-3.95e-01	0.1577
6558	SLC12A2	GSM4909302	Human	Breast	IDC	4.53e-06	-2.76e-01	0.1545
6558	SLC12A2	GSM4909309	Human	Breast	IDC	1.62e-02	2.35e-01	0.0483
6558	SLC12A2	GSM4909311	Human	Breast	IDC	1.82e-22	-4.31e-01	0.1534
6558	SLC12A2	GSM4909312	Human	Breast	IDC	5.04e-16	-4.01e-01	0.1552
6558	SLC12A2	GSM4909313	Human	Breast	IDC	3.20e-09	4.34e-01	0.0391
6558	SLC12A2	GSM4909315	Human	Breast	IDC	7.86e-16	-4.63e-01	0.21
6558	SLC12A2	GSM4909316	Human	Breast	IDC	1.11e-08	-4.98e-01	0.21
6558	SLC12A2	GSM4909319	Human	Breast	IDC	3.54e-24	-4.91e-01	0.1563
6558	SLC12A2	GSM4909320	Human	Breast	IDC	1.12e-07	-4.68e-01	0.1575

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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
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
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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:00509006	Breast	Precancer	leukocyte migration	47/1080	369/18723	2.82e-07	1.39e-05	47
GO:00100389	Breast	Precancer	response to metal ion	47/1080	373/18723	3.88e-07	1.79e-05	47
GO:00305956	Breast	Precancer	leukocyte chemotaxis	34/1080	230/18723	4.16e-07	1.89e-05	34
GO:00603266	Breast	Precancer	cell chemotaxis	41/1080	310/18723	5.99e-07	2.55e-05	41
GO:00420609	Breast	Precancer	wound healing	48/1080	422/18723	5.48e-06	1.63e-04	48
GO:00075688	Breast	Precancer	aging	41/1080	339/18723	5.95e-06	1.71e-04	41
GO:00716744	Breast	Precancer	mononuclear cell migration	24/1080	196/18723	4.03e-04	5.44e-03	24
GO:00712488	Breast	Precancer	cellular response to metal ion	24/1080	197/18723	4.35e-04	5.79e-03	24
GO:00712418	Breast	Precancer	cellular response to inorganic substance	26/1080	226/18723	6.23e-04	7.78e-03	26
GO:00356335	Breast	Precancer	maintenance of blood-brain barrier	8/1080	35/18723	6.95e-04	8.43e-03	8
GO:0045765	Breast	Precancer	regulation of angiogenesis	35/1080	342/18723	7.35e-04	8.80e-03	35
GO:0030007	Breast	Precancer	cellular potassium ion homeostasis	5/1080	14/18723	8.17e-04	9.55e-03	5
GO:1901342	Breast	Precancer	regulation of vasculature development	35/1080	348/18723	1.00e-03	1.12e-02	35
GO:00507086	Breast	Precancer	regulation of protein secretion	28/1080	268/18723	1.76e-03	1.74e-02	28
GO:00018948	Breast	Precancer	tissue homeostasis	27/1080	268/18723	3.49e-03	2.90e-02	27
GO:19030348	Breast	Precancer	regulation of response to wounding	19/1080	167/18723	3.60e-03	2.98e-02	19
GO:00716926	Breast	Precancer	protein localization to extracellular region	34/1080	368/18723	4.65e-03	3.58e-02	34
GO:00093067	Breast	Precancer	protein secretion	33/1080	359/18723	5.65e-03	4.08e-02	33
GO:00355927	Breast	Precancer	establishment of protein localization to extracellular region	33/1080	360/18723	5.89e-03	4.21e-02	33
GO:00300046	Breast	Precancer	cellular monovalent inorganic cation homeostasis	13/1080	103/18723	6.26e-03	4.40e-02	13

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0511014	Breast	Precancer	Vibrio cholerae infection	14/684	50/8465	2.67e-05	2.64e-04	2.02e-04	14
hsa0511015	Breast	Precancer	Vibrio cholerae infection	14/684	50/8465	2.67e-05	2.64e-04	2.02e-04	14
hsa0511022	Breast	IDC	Vibrio cholerae infection	17/867	50/8465	4.82e-06	6.82e-05	5.10e-05	17
hsa049704	Breast	IDC	Salivary secretion	18/867	93/8465	5.69e-03	3.13e-02	2.34e-02	18
hsa0511032	Breast	IDC	Vibrio cholerae infection	17/867	50/8465	4.82e-06	6.82e-05	5.10e-05	17
hsa0497011	Breast	IDC	Salivary secretion	18/867	93/8465	5.69e-03	3.13e-02	2.34e-02	18
hsa0511041	Breast	DCIS	Vibrio cholerae infection	17/846	50/8465	3.45e-06	4.45e-05	3.28e-05	17
hsa0511051	Breast	DCIS	Vibrio cholerae infection	17/846	50/8465	3.45e-06	4.45e-05	3.28e-05	17
hsa05110	Colorectum	AD	Vibrio cholerae infection	29/2092	50/8465	5.10e-07	7.12e-06	4.54e-06	29
hsa04972	Colorectum	AD	Pancreatic secretion	36/2092	102/8465	1.06e-02	3.98e-02	2.54e-02	36
hsa051101	Colorectum	AD	Vibrio cholerae infection	29/2092	50/8465	5.10e-07	7.12e-06	4.54e-06	29
hsa049721	Colorectum	AD	Pancreatic secretion	36/2092	102/8465	1.06e-02	3.98e-02	2.54e-02	36
hsa051102	Colorectum	SER	Vibrio cholerae infection	24/1580	50/8465	2.17e-06	3.13e-05	2.28e-05	24
hsa049722	Colorectum	SER	Pancreatic secretion	30/1580	102/8465	5.41e-03	3.28e-02	2.38e-02	30
hsa051103	Colorectum	SER	Vibrio cholerae infection	24/1580	50/8465	2.17e-06	3.13e-05	2.28e-05	24
hsa049723	Colorectum	SER	Pancreatic secretion	30/1580	102/8465	5.41e-03	3.28e-02	2.38e-02	30
hsa051104	Colorectum	MSS	Vibrio cholerae infection	27/1875	50/8465	8.58e-07	1.20e-05	7.34e-06	27
hsa049724	Colorectum	MSS	Pancreatic secretion	33/1875	102/8465	1.09e-02	3.75e-02	2.30e-02	33
hsa051105	Colorectum	MSS	Vibrio cholerae infection	27/1875	50/8465	8.58e-07	1.20e-05	7.34e-06	27
hsa049725	Colorectum	MSS	Pancreatic secretion	33/1875	102/8465	1.09e-02	3.75e-02	2.30e-02	33

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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

SLC12A2

SNV

Missense_Mutation

c.2921N>T

p.Thr974Ile

p.T974I

P55011

protein_coding

tolerated(0.35)

benign(0)

TCGA-A8-A08S-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

SLC12A2

SNV

Missense_Mutation

c.2813T>C

p.Leu938Ser

p.L938S

P55011

protein_coding

tolerated(0.28)

benign(0.115)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SLC12A2

SNV

Missense_Mutation

rs772305204

c.1461N>G

p.Phe487Leu

p.F487L

P55011

protein_coding

deleterious(0.01)

probably_damaging(0.998)

TCGA-BH-A0B5-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

SLC12A2

SNV

Missense_Mutation

c.985N>A

p.Val329Ile

p.V329I

P55011

protein_coding

tolerated(0.06)

probably_damaging(0.99)

TCGA-BH-A0HL-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

SLC12A2

SNV

Missense_Mutation

rs111986207

c.2739A>G

p.Ile913Met

p.I913M

P55011

protein_coding

tolerated(0.27)

benign(0.097)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SLC12A2

SNV

Missense_Mutation

c.1593N>T

p.Leu531Phe

p.L531F

P55011

protein_coding

tolerated(0.06)

benign(0.401)

TCGA-E9-A1RH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

SLC12A2

SNV

Missense_Mutation

c.1594N>A

p.Val532Ile

p.V532I

P55011

protein_coding

tolerated(0.24)

possibly_damaging(0.728)

TCGA-E9-A1RH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

SLC12A2

SNV

Missense_Mutation

novel

c.1070C>T

p.Ser357Phe

p.S357F

P55011

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-XX-A89A-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SLC12A2

insertion

In_Frame_Ins

novel

c.1124_1125insAGATTTTATTTACTCTTTTTCCAGTTT

p.Ala375_Asn376insAspPheIleTyrSerPheSerSerPhe

p.A375_N376insDFIYSFSSF

P55011

protein_coding

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

SLC12A2

SNV

Missense_Mutation

c.1129G>A

p.Ala377Thr

p.A377T

P55011

protein_coding

deleterious(0.04)

probably_damaging(0.996)

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
6558	SLC12A2	DRUGGABLE GENOME, TRANSPORTER, EXTERNAL SIDE OF PLASMA MEMBRANE		BUMETANIDE	BUMETANIDE
6558	SLC12A2	DRUGGABLE GENOME, TRANSPORTER, EXTERNAL SIDE OF PLASMA MEMBRANE		BUMETANIDE	BUMETANIDE
6558	SLC12A2	DRUGGABLE GENOME, TRANSPORTER, EXTERNAL SIDE OF PLASMA MEMBRANE	inhibitor	178101453	PIRETANIDE
6558	SLC12A2	DRUGGABLE GENOME, TRANSPORTER, EXTERNAL SIDE OF PLASMA MEMBRANE	inhibitor	178101539	BUMETANIDE
6558	SLC12A2	DRUGGABLE GENOME, TRANSPORTER, EXTERNAL SIDE OF PLASMA MEMBRANE	inhibitor	178101541	FUROSEMIDE

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