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: SLC9A1

Gene summary for SLC9A1

Gene summary.

Gene information	Species	Human
	Gene symbol	SLC9A1
	Gene ID	6548
	Gene name	solute carrier family 9 member A1
	Gene Alias	APNH
	Cytomap	1p36.11
	Gene Type	protein-coding
	GO ID	GO:0001508
	UniProtAcc	B2RAH2

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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
6548	SLC9A1	HTA11_2487_2000001011	Human	Colorectum	SER	7.88e-13	6.35e-01	-0.1808
6548	SLC9A1	HTA11_1938_2000001011	Human	Colorectum	AD	2.72e-07	3.64e-01	-0.0811
6548	SLC9A1	HTA11_347_2000001011	Human	Colorectum	AD	2.06e-18	6.47e-01	-0.1954
6548	SLC9A1	HTA11_411_2000001011	Human	Colorectum	SER	9.31e-03	8.29e-01	-0.2602
6548	SLC9A1	HTA11_2112_2000001011	Human	Colorectum	SER	1.23e-02	7.25e-01	-0.2196
6548	SLC9A1	HTA11_3361_2000001011	Human	Colorectum	AD	4.80e-06	5.56e-01	-0.1207
6548	SLC9A1	HTA11_83_2000001011	Human	Colorectum	SER	6.12e-05	5.17e-01	-0.1526
6548	SLC9A1	HTA11_696_2000001011	Human	Colorectum	AD	3.44e-14	7.66e-01	-0.1464
6548	SLC9A1	HTA11_866_2000001011	Human	Colorectum	AD	9.65e-03	2.88e-01	-0.1001
6548	SLC9A1	HTA11_1391_2000001011	Human	Colorectum	AD	7.84e-07	5.16e-01	-0.059
6548	SLC9A1	HTA11_5212_2000001011	Human	Colorectum	AD	1.93e-04	6.05e-01	-0.2061
6548	SLC9A1	A015-C-203	Human	Colorectum	FAP	4.96e-03	-1.14e-01	-0.1294
6548	SLC9A1	A002-C-205	Human	Colorectum	FAP	1.88e-03	-2.02e-01	-0.1236
6548	SLC9A1	A015-C-104	Human	Colorectum	FAP	4.47e-08	-2.17e-01	-0.1899
6548	SLC9A1	A001-C-014	Human	Colorectum	FAP	1.98e-02	-1.40e-01	0.0135
6548	SLC9A1	CRC-1-8810	Human	Colorectum	CRC	3.16e-03	-1.69e-01	0.6257
6548	SLC9A1	LZE7T	Human	Esophagus	ESCC	1.80e-03	1.43e-01	0.0667
6548	SLC9A1	LZE20T	Human	Esophagus	ESCC	2.44e-07	1.54e-01	0.0662
6548	SLC9A1	LZE24T	Human	Esophagus	ESCC	2.29e-10	2.39e-01	0.0596
6548	SLC9A1	P1T-E	Human	Esophagus	ESCC	2.69e-04	3.52e-01	0.0875

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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
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
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

∗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:00329705	Colorectum	CRC	regulation of actin filament-based process	89/2078	397/18723	5.25e-11	3.14e-08	89
GO:00071634	Colorectum	CRC	establishment or maintenance of cell polarity	57/2078	218/18723	3.96e-10	1.58e-07	57
GO:00108105	Colorectum	CRC	regulation of cell-substrate adhesion	57/2078	221/18723	6.94e-10	2.60e-07	57
GO:00020285	Colorectum	CRC	regulation of sodium ion transport	31/2078	90/18723	3.67e-09	9.56e-07	31
GO:00315894	Colorectum	CRC	cell-substrate adhesion	78/2078	363/18723	6.22e-09	1.49e-06	78
GO:00160494	Colorectum	CRC	cell growth	95/2078	482/18723	1.51e-08	2.75e-06	95
GO:19029035	Colorectum	CRC	regulation of supramolecular fiber organization	80/2078	383/18723	1.52e-08	2.75e-06	80
GO:00329565	Colorectum	CRC	regulation of actin cytoskeleton organization	76/2078	358/18723	1.68e-08	2.79e-06	76
GO:01100535	Colorectum	CRC	regulation of actin filament organization	63/2078	278/18723	2.21e-08	3.23e-06	63
GO:00343294	Colorectum	CRC	cell junction assembly	83/2078	420/18723	1.08e-07	1.29e-05	83
GO:19023055	Colorectum	CRC	regulation of sodium ion transmembrane transport	24/2078	68/18723	1.23e-07	1.45e-05	24
GO:00070444	Colorectum	CRC	cell-substrate junction assembly	29/2078	95/18723	2.34e-07	2.27e-05	29
GO:01501154	Colorectum	CRC	cell-substrate junction organization	30/2078	101/18723	2.85e-07	2.54e-05	30
GO:00019524	Colorectum	CRC	regulation of cell-matrix adhesion	35/2078	128/18723	2.86e-07	2.54e-05	35
GO:20006495	Colorectum	CRC	regulation of sodium ion transmembrane transporter activity	21/2078	58/18723	4.58e-07	3.39e-05	21
GO:00615724	Colorectum	CRC	actin filament bundle organization	40/2078	161/18723	6.72e-07	4.52e-05	40
GO:00510174	Colorectum	CRC	actin filament bundle assembly	39/2078	157/18723	9.26e-07	5.83e-05	39
GO:00310324	Colorectum	CRC	actomyosin structure organization	45/2078	196/18723	1.49e-06	8.14e-05	45
GO:00480414	Colorectum	CRC	focal adhesion assembly	26/2078	87/18723	1.52e-06	8.15e-05	26
GO:00107655	Colorectum	CRC	positive regulation of sodium ion transport	15/2078	35/18723	1.69e-06	8.71e-05	15

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa05205	Colorectum	AD	Proteoglycans in cancer	70/2092	205/8465	1.37e-03	8.46e-03	5.39e-03	70
hsa04810	Colorectum	AD	Regulation of actin cytoskeleton	75/2092	229/8465	3.36e-03	1.76e-02	1.12e-02	75
hsa04971	Colorectum	AD	Gastric acid secretion	29/2092	76/8465	6.25e-03	2.68e-02	1.71e-02	29
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
hsa049191	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa052051	Colorectum	AD	Proteoglycans in cancer	70/2092	205/8465	1.37e-03	8.46e-03	5.39e-03	70
hsa048101	Colorectum	AD	Regulation of actin cytoskeleton	75/2092	229/8465	3.36e-03	1.76e-02	1.12e-02	75
hsa049711	Colorectum	AD	Gastric acid secretion	29/2092	76/8465	6.25e-03	2.68e-02	1.71e-02	29
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
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
hsa049712	Colorectum	SER	Gastric acid secretion	27/1580	76/8465	3.65e-04	3.27e-03	2.38e-03	27
hsa052052	Colorectum	SER	Proteoglycans in cancer	58/1580	205/8465	4.37e-04	3.82e-03	2.77e-03	58
hsa048102	Colorectum	SER	Regulation of actin cytoskeleton	60/1580	229/8465	2.74e-03	2.02e-02	1.47e-02	60
hsa049722	Colorectum	SER	Pancreatic secretion	30/1580	102/8465	5.41e-03	3.28e-02	2.38e-02	30
hsa049193	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa042603	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

SLC9A1

SNV

Missense_Mutation

c.17N>A

p.Gly6Asp

p.G6D

P19634

protein_coding

deleterious_low_confidence(0)

possibly_damaging(0.672)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

SLC9A1

SNV

Missense_Mutation

novel

c.1710G>T

p.Glu570Asp

p.E570D

P19634

protein_coding

deleterious(0.02)

benign(0.119)

TCGA-C8-A1HK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC9A1

SNV

Missense_Mutation

c.2054N>A

p.Thr685Lys

p.T685K

P19634

protein_coding

deleterious(0.01)

benign(0.042)

TCGA-E2-A1IK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

SLC9A1

insertion

In_Frame_Ins

novel

c.984_985insTTTGGGAGG

p.Val328_Ile329insPheGlyArg

p.V328_I329insFGR

P19634

protein_coding

TCGA-AN-A0AL-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

SLC9A1

insertion

Frame_Shift_Ins

novel

c.983_984insGGCTCACGCCTGTAATCCCAGCA

p.Ile329AlafsTer37

p.I329Afs*37

P19634

protein_coding

TCGA-AN-A0AL-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

SLC9A1

deletion

Frame_Shift_Del

c.431delN

p.Gly144AlafsTer2

p.G144Afs*2

P19634

protein_coding

TCGA-BH-A0HA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC9A1

SNV

Missense_Mutation

novel

c.134C>T

p.Thr45Ile

p.T45I

P19634

protein_coding

deleterious_low_confidence(0.03)

benign(0)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SLC9A1

SNV

Missense_Mutation

rs556347900

c.2342N>T

p.Ala781Val

p.A781V

P19634

protein_coding

deleterious(0.03)

benign(0.03)

TCGA-BI-A0VS-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

SLC9A1

SNV

Missense_Mutation

novel

c.294N>A

p.His98Gln

p.H98Q

P19634

protein_coding

deleterious(0.01)

possibly_damaging(0.612)

TCGA-C5-A8YT-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SLC9A1

SNV

Missense_Mutation

c.487N>T

p.Leu163Phe

p.L163F

P19634

protein_coding

deleterious(0.03)

benign(0.12)

TCGA-EX-A69M-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
6548	SLC9A1	TRANSPORTER, DRUGGABLE GENOME, EXCHANGER, CELL SURFACE		CARIPORIDE	CARIPORIDE	17493937
6548	SLC9A1	TRANSPORTER, DRUGGABLE GENOME, EXCHANGER, CELL SURFACE		Zoniporide hydrochloride
6548	SLC9A1	TRANSPORTER, DRUGGABLE GENOME, EXCHANGER, CELL SURFACE		HOE-694	CHEMBL62231	17493937

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