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: TRPM4

Gene summary for TRPM4

Gene summary.

Gene information	Species	Human
	Gene symbol	TRPM4
	Gene ID	54795
	Gene name	transient receptor potential cation channel subfamily M member 4
	Gene Alias	EKVP6
	Cytomap	19q13.33
	Gene Type	protein-coding
	GO ID	GO:0001503
	UniProtAcc	Q8TD43

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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
54795	TRPM4	HTA11_3410_2000001011	Human	Colorectum	AD	9.37e-11	-5.13e-01	0.0155
54795	TRPM4	HTA11_347_2000001011	Human	Colorectum	AD	1.19e-03	2.86e-01	-0.1954
54795	TRPM4	HTA11_99999970781_79442	Human	Colorectum	MSS	6.21e-14	-4.98e-01	0.294
54795	TRPM4	HTA11_99999971662_82457	Human	Colorectum	MSS	3.81e-07	-3.90e-01	0.3859
54795	TRPM4	HTA11_99999974143_84620	Human	Colorectum	MSS	4.82e-27	-6.58e-01	0.3005
54795	TRPM4	A002-C-010	Human	Colorectum	FAP	2.44e-04	-3.01e-01	0.242
54795	TRPM4	A015-C-203	Human	Colorectum	FAP	1.43e-30	-2.30e-01	-0.1294
54795	TRPM4	A015-C-204	Human	Colorectum	FAP	3.55e-04	-1.30e-01	-0.0228
54795	TRPM4	A014-C-040	Human	Colorectum	FAP	4.32e-04	-4.69e-01	-0.1184
54795	TRPM4	A002-C-201	Human	Colorectum	FAP	3.16e-10	-2.38e-01	0.0324
54795	TRPM4	A002-C-203	Human	Colorectum	FAP	1.81e-03	-7.57e-02	0.2786
54795	TRPM4	A001-C-119	Human	Colorectum	FAP	4.17e-10	-5.45e-01	-0.1557
54795	TRPM4	A001-C-108	Human	Colorectum	FAP	7.16e-24	-2.82e-01	-0.0272
54795	TRPM4	A002-C-205	Human	Colorectum	FAP	4.79e-20	-3.44e-01	-0.1236
54795	TRPM4	A001-C-104	Human	Colorectum	FAP	6.31e-07	-2.20e-01	0.0184
54795	TRPM4	A015-C-006	Human	Colorectum	FAP	3.23e-12	-4.26e-01	-0.0994
54795	TRPM4	A015-C-106	Human	Colorectum	FAP	1.80e-14	-2.36e-01	-0.0511
54795	TRPM4	A002-C-114	Human	Colorectum	FAP	1.10e-16	-2.39e-01	-0.1561
54795	TRPM4	A015-C-104	Human	Colorectum	FAP	1.10e-31	-1.73e-01	-0.1899
54795	TRPM4	A001-C-014	Human	Colorectum	FAP	4.76e-16	-3.41e-01	0.0135

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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
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
Prostate		BPH: Benign Prostatic Hyperplasia

∗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:0032970	Colorectum	AD	regulation of actin filament-based process	142/3918	397/18723	4.05e-12	5.90e-10	142
GO:1904951	Colorectum	AD	positive regulation of establishment of protein localization	112/3918	319/18723	2.55e-09	1.80e-07	112
GO:0051222	Colorectum	AD	positive regulation of protein transport	106/3918	303/18723	8.45e-09	5.08e-07	106
GO:0009743	Colorectum	AD	response to carbohydrate	86/3918	253/18723	8.43e-07	2.90e-05	86
GO:0034284	Colorectum	AD	response to monosaccharide	76/3918	225/18723	4.64e-06	1.23e-04	76
GO:0030111	Colorectum	AD	regulation of Wnt signaling pathway	102/3918	328/18723	8.51e-06	2.03e-04	102
GO:0033500	Colorectum	AD	carbohydrate homeostasis	84/3918	259/18723	9.10e-06	2.15e-04	84
GO:0009746	Colorectum	AD	response to hexose	73/3918	219/18723	1.20e-05	2.65e-04	73
GO:0009749	Colorectum	AD	response to glucose	71/3918	212/18723	1.31e-05	2.85e-04	71
GO:0042593	Colorectum	AD	glucose homeostasis	83/3918	258/18723	1.44e-05	3.11e-04	83
GO:0001678	Colorectum	AD	cellular glucose homeostasis	60/3918	172/18723	1.49e-05	3.18e-04	60
GO:0016055	Colorectum	AD	Wnt signaling pathway	130/3918	444/18723	1.60e-05	3.37e-04	130
GO:0198738	Colorectum	AD	cell-cell signaling by wnt	130/3918	446/18723	2.02e-05	4.10e-04	130
GO:0071322	Colorectum	AD	cellular response to carbohydrate stimulus	56/3918	163/18723	4.61e-05	7.97e-04	56
GO:0050708	Colorectum	AD	regulation of protein secretion	83/3918	268/18723	6.59e-05	1.07e-03	83
GO:0071333	Colorectum	AD	cellular response to glucose stimulus	52/3918	151/18723	7.88e-05	1.25e-03	52
GO:0098901	Colorectum	AD	regulation of cardiac muscle cell action potential	15/3918	27/18723	8.20e-05	1.29e-03	15
GO:0098911	Colorectum	AD	regulation of ventricular cardiac muscle cell action potential	9/3918	12/18723	9.01e-05	1.38e-03	9
GO:0009306	Colorectum	AD	protein secretion	105/3918	359/18723	1.05e-04	1.57e-03	105
GO:0071331	Colorectum	AD	cellular response to hexose stimulus	52/3918	153/18723	1.16e-04	1.71e-03	52

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04911	Colorectum	FAP	Insulin secretion	23/1404	86/8465	1.12e-02	3.92e-02	2.38e-02	23
hsa049111	Colorectum	FAP	Insulin secretion	23/1404	86/8465	1.12e-02	3.92e-02	2.38e-02	23
hsa049112	Colorectum	CRC	Insulin secretion	20/1091	86/8465	5.61e-03	2.88e-02	1.95e-02	20
hsa049113	Colorectum	CRC	Insulin secretion	20/1091	86/8465	5.61e-03	2.88e-02	1.95e-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

TRPM4

SNV

Missense_Mutation

novel

c.949G>A

p.Asp317Asn

p.D317N

Q8TD43

protein_coding

tolerated(0.49)

benign(0.011)

TCGA-A8-A092-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

TRPM4

SNV

Missense_Mutation

c.2866N>A

p.Asp956Asn

p.D956N

Q8TD43

protein_coding

deleterious(0.02)

probably_damaging(0.998)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TRPM4

SNV

Missense_Mutation

c.929N>A

p.Cys310Tyr

p.C310Y

Q8TD43

protein_coding

deleterious(0.02)

benign(0.243)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

TRPM4

SNV

Missense_Mutation

novel

c.3370N>G

p.Trp1124Gly

p.W1124G

Q8TD43

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-LL-A73Z-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

TRPM4

SNV

Missense_Mutation

novel

c.3568N>A

p.Ala1190Thr

p.A1190T

Q8TD43

protein_coding

tolerated(0.09)

benign(0.027)

TCGA-PL-A8LV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

TRPM4

insertion

Nonsense_Mutation

novel

c.2960_2961insTTGAAGAGGAACCTGTACTTTACTTTTTA

p.Met988Ter

p.M988*

Q8TD43

protein_coding

TCGA-BH-A0DZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

docetaxel

TRPM4

insertion

Nonsense_Mutation

novel

c.2060_2061insGGTTAAAATGTCACAGTACCCTCTTACTGAAATTTAGTGGTCTCT

p.Thr687_Thr688insValLysMetSerGlnTyrProLeuThrGluIleTerTrpSerLeu

p.T687_T688insVKMSQYPLTEI*WSL

Q8TD43

protein_coding

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

TRPM4

deletion

Frame_Shift_Del

novel

c.1331delN

p.Leu444ProfsTer12

p.L444Pfs*12

Q8TD43

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

TRPM4

SNV

Missense_Mutation

rs886054577

c.721N>A

p.Gly241Ser

p.G241S

Q8TD43

protein_coding

deleterious(0.01)

possibly_damaging(0.881)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TRPM4

SNV

Missense_Mutation

novel

c.871N>A

p.Ala291Thr

p.A291T

Q8TD43

protein_coding

deleterious(0)

possibly_damaging(0.45)

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
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	inhibitor	135651427	ADENOSINE DIPHOSPHATE
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	blocker	135651426	ADENOSINE
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	activator	135651544
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	blocker	135651562	SPERMINE
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	inhibitor	375973226
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	inhibitor	53801012
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	activator	135650028
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	inhibitor	135651437
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	blocker	178100936
54795	TRPM4	ION CHANNEL, TRANSPORTER, DRUGGABLE GENOME	activator	135652731

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