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: NFAT5

Gene summary for NFAT5

Gene summary.

Gene information	Species	Human
	Gene symbol	NFAT5
	Gene ID	10725
	Gene name	nuclear factor of activated T cells 5
	Gene Alias	NF-AT5
	Cytomap	16q22.1
	Gene Type	protein-coding
	GO ID	GO:0001816
	UniProtAcc	O94916

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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
10725	NFAT5	CA_HPV_1	Human	Cervix	CC	5.90e-03	-5.80e-03	0.0264
10725	NFAT5	CCI_1	Human	Cervix	CC	3.15e-05	9.17e-01	0.528
10725	NFAT5	CCI_2	Human	Cervix	CC	1.05e-08	1.40e+00	0.5249
10725	NFAT5	CCI_3	Human	Cervix	CC	4.64e-14	1.47e+00	0.516
10725	NFAT5	L1	Human	Cervix	CC	5.82e-04	-3.11e-01	0.0802
10725	NFAT5	HTA11_1938_2000001011	Human	Colorectum	AD	7.33e-04	5.34e-01	-0.0811
10725	NFAT5	HTA11_347_2000001011	Human	Colorectum	AD	6.61e-14	6.73e-01	-0.1954
10725	NFAT5	HTA11_1391_2000001011	Human	Colorectum	AD	9.27e-05	7.34e-01	-0.059
10725	NFAT5	HTA11_99999965062_69753	Human	Colorectum	MSI-H	1.36e-17	1.27e+00	0.3487
10725	NFAT5	HTA11_99999965104_69814	Human	Colorectum	MSS	8.09e-19	1.18e+00	0.281
10725	NFAT5	HTA11_99999971662_82457	Human	Colorectum	MSS	3.71e-08	1.00e+00	0.3859
10725	NFAT5	HTA11_99999974143_84620	Human	Colorectum	MSS	4.67e-11	8.55e-01	0.3005
10725	NFAT5	F007	Human	Colorectum	FAP	4.66e-03	-2.79e-02	0.1176
10725	NFAT5	A002-C-010	Human	Colorectum	FAP	8.06e-03	-3.46e-02	0.242
10725	NFAT5	A001-C-207	Human	Colorectum	FAP	1.39e-04	-2.43e-01	0.1278
10725	NFAT5	A015-C-203	Human	Colorectum	FAP	3.07e-39	-4.42e-01	-0.1294
10725	NFAT5	A015-C-204	Human	Colorectum	FAP	6.85e-09	-3.43e-01	-0.0228
10725	NFAT5	A014-C-040	Human	Colorectum	FAP	6.92e-07	-3.71e-01	-0.1184
10725	NFAT5	A002-C-201	Human	Colorectum	FAP	2.62e-12	-2.70e-01	0.0324
10725	NFAT5	A002-C-203	Human	Colorectum	FAP	3.78e-03	-1.54e-01	0.2786

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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
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
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:002240710	Cervix	CC	regulation of cell-cell adhesion	103/2311	448/18723	1.78e-10	2.87e-08	103
GO:004578510	Cervix	CC	positive regulation of cell adhesion	101/2311	437/18723	1.96e-10	3.08e-08	101
GO:00071598	Cervix	CC	leukocyte cell-cell adhesion	85/2311	371/18723	8.27e-09	7.07e-07	85
GO:19030378	Cervix	CC	regulation of leukocyte cell-cell adhesion	77/2311	336/18723	4.08e-08	2.54e-06	77
GO:00224099	Cervix	CC	positive regulation of cell-cell adhesion	61/2311	284/18723	9.30e-06	2.11e-04	61
GO:19030397	Cervix	CC	positive regulation of leukocyte cell-cell adhesion	53/2311	239/18723	1.37e-05	2.74e-04	53
GO:0045785	Colorectum	AD	positive regulation of cell adhesion	122/3918	437/18723	2.65e-04	3.28e-03	122
GO:00457852	Colorectum	MSS	positive regulation of cell adhesion	110/3467	437/18723	2.94e-04	3.87e-03	110
GO:00457853	Colorectum	MSI-H	positive regulation of cell adhesion	48/1319	437/18723	1.47e-03	2.23e-02	48
GO:00457854	Colorectum	FAP	positive regulation of cell adhesion	92/2622	437/18723	3.09e-05	7.04e-04	92
GO:00069701	Colorectum	FAP	response to osmotic stress	25/2622	84/18723	1.43e-04	2.24e-03	25
GO:0048016	Colorectum	FAP	inositol phosphate-mediated signaling	16/2622	55/18723	2.78e-03	2.15e-02	16
GO:00457855	Colorectum	CRC	positive regulation of cell adhesion	81/2078	437/18723	2.28e-06	1.10e-04	81
GO:0097720	Colorectum	CRC	calcineurin-mediated signaling	13/2078	48/18723	1.72e-03	1.77e-02	13
GO:0033173	Colorectum	CRC	calcineurin-NFAT signaling cascade	12/2078	43/18723	1.93e-03	1.96e-02	12
GO:00480161	Colorectum	CRC	inositol phosphate-mediated signaling	14/2078	55/18723	2.21e-03	2.15e-02	14
GO:0070884	Colorectum	CRC	regulation of calcineurin-NFAT signaling cascade	10/2078	34/18723	2.96e-03	2.66e-02	10
GO:0106056	Colorectum	CRC	regulation of calcineurin-mediated signaling	10/2078	35/18723	3.74e-03	3.14e-02	10
GO:0022407	Colorectum	CRC	regulation of cell-cell adhesion	67/2078	448/18723	6.86e-03	4.81e-02	67
GO:004578516	Endometrium	AEH	positive regulation of cell adhesion	96/2100	437/18723	5.50e-11	7.18e-09	96

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
NFAT5	KER	Esophagus	HGIN	MALAT1,PARD6B,NEAT1, etc.	2.81e-01
NFAT5	INMON	Lung	AAH	SAMSN1,SRGN,JARID2, etc.	1.02e-01

∗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

NFAT5

SNV

Missense_Mutation

c.2602G>C

p.Glu868Gln

p.E868Q

O94916

protein_coding

deleterious_low_confidence(0)

benign(0.309)

TCGA-A2-A0YK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

NFAT5

SNV

Missense_Mutation

rs201563281

c.4295N>T

p.Ser1432Leu

p.S1432L

O94916

protein_coding

deleterious(0.01)

benign(0.028)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

NFAT5

SNV

Missense_Mutation

c.2134N>T

p.Ala712Ser

p.A712S

O94916

protein_coding

tolerated(0.62)

benign(0.012)

TCGA-BH-A1F6-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NFAT5

SNV

Missense_Mutation

novel

c.1514N>G

p.Ser505Cys

p.S505C

O94916

protein_coding

deleterious(0.04)

probably_damaging(0.993)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

NFAT5

SNV

Missense_Mutation

c.1693G>T

p.Ala565Ser

p.A565S

O94916

protein_coding

tolerated(0.69)

benign(0.01)

TCGA-E2-A10C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

NFAT5

SNV

Missense_Mutation

c.386N>T

p.Ala129Val

p.A129V

O94916

protein_coding

tolerated(0.08)

benign(0.069)

TCGA-E2-A1LH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

NFAT5

SNV

Missense_Mutation

novel

c.826C>G

p.Gln276Glu

p.Q276E

O94916

protein_coding

tolerated(0.51)

benign(0.034)

TCGA-E9-A3Q9-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

cyclophosphane

NFAT5

insertion

Frame_Shift_Ins

novel

c.2793dupA

p.Glu932ArgfsTer33

p.E932Rfs*33

O94916

protein_coding

TCGA-A8-A07B-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NFAT5

insertion

Frame_Shift_Ins

novel

c.3763_3764insCACAG

p.Ile1256GlnfsTer3

p.I1256Qfs*3

O94916

protein_coding

TCGA-A8-A09D-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

NFAT5

SNV

Missense_Mutation

novel

c.3418A>G

p.Thr1140Ala

p.T1140A

O94916

protein_coding

deleterious(0.03)

benign(0)

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

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