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: TRPM2

Gene summary for TRPM2

Gene summary.

Gene information	Species	Human
	Gene symbol	TRPM2
	Gene ID	7226
	Gene name	transient receptor potential cation channel subfamily M member 2
	Gene Alias	EREG1
	Cytomap	21q22.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	B4DVI8

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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
7226	TRPM2	P4T-E	Human	Esophagus	ESCC	4.90e-05	1.77e-01	0.1323
7226	TRPM2	P5T-E	Human	Esophagus	ESCC	1.47e-14	3.00e-01	0.1327
7226	TRPM2	P9T-E	Human	Esophagus	ESCC	1.11e-03	1.35e-01	0.1131
7226	TRPM2	P10T-E	Human	Esophagus	ESCC	8.56e-12	2.47e-01	0.116
7226	TRPM2	P11T-E	Human	Esophagus	ESCC	4.74e-03	1.78e-01	0.1426
7226	TRPM2	P16T-E	Human	Esophagus	ESCC	1.66e-02	9.76e-02	0.1153
7226	TRPM2	P17T-E	Human	Esophagus	ESCC	4.79e-04	1.90e-01	0.1278
7226	TRPM2	P21T-E	Human	Esophagus	ESCC	2.05e-07	1.76e-01	0.1617
7226	TRPM2	P24T-E	Human	Esophagus	ESCC	3.97e-04	1.33e-01	0.1287
7226	TRPM2	P26T-E	Human	Esophagus	ESCC	8.40e-04	1.19e-01	0.1276
7226	TRPM2	P27T-E	Human	Esophagus	ESCC	3.75e-03	8.70e-02	0.1055
7226	TRPM2	P28T-E	Human	Esophagus	ESCC	3.28e-14	2.64e-01	0.1149
7226	TRPM2	P31T-E	Human	Esophagus	ESCC	3.75e-03	9.73e-02	0.1251
7226	TRPM2	P32T-E	Human	Esophagus	ESCC	4.44e-08	1.73e-01	0.1666
7226	TRPM2	P37T-E	Human	Esophagus	ESCC	4.28e-02	9.24e-02	0.1371
7226	TRPM2	P39T-E	Human	Esophagus	ESCC	7.90e-03	1.09e-01	0.0894
7226	TRPM2	P49T-E	Human	Esophagus	ESCC	2.95e-08	5.18e-01	0.1768
7226	TRPM2	P62T-E	Human	Esophagus	ESCC	5.02e-08	1.95e-01	0.1302
7226	TRPM2	P74T-E	Human	Esophagus	ESCC	1.21e-21	5.70e-01	0.1479
7226	TRPM2	P76T-E	Human	Esophagus	ESCC	1.88e-04	1.10e-01	0.1207

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
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:0006979111	Esophagus	ESCC	response to oxidative stress	303/8552	446/18723	7.15e-22	1.30e-19	303
GO:0062197111	Esophagus	ESCC	cellular response to chemical stress	234/8552	337/18723	5.37e-19	5.97e-17	234
GO:1904951111	Esophagus	ESCC	positive regulation of establishment of protein localization	216/8552	319/18723	1.01e-15	6.86e-14	216
GO:0034599111	Esophagus	ESCC	cellular response to oxidative stress	197/8552	288/18723	3.76e-15	2.15e-13	197
GO:0051222111	Esophagus	ESCC	positive regulation of protein transport	204/8552	303/18723	1.56e-14	8.38e-13	204
GO:0000302111	Esophagus	ESCC	response to reactive oxygen species	150/8552	222/18723	3.06e-11	1.02e-09	150
GO:0042542111	Esophagus	ESCC	response to hydrogen peroxide	102/8552	146/18723	2.64e-09	5.81e-08	102
GO:0051235110	Esophagus	ESCC	maintenance of location	200/8552	327/18723	1.01e-08	2.02e-07	200
GO:0070997111	Esophagus	ESCC	neuron death	216/8552	361/18723	3.49e-08	6.45e-07	216
GO:003461420	Esophagus	ESCC	cellular response to reactive oxygen species	103/8552	155/18723	1.34e-07	2.17e-06	103
GO:0009408110	Esophagus	ESCC	response to heat	77/8552	110/18723	2.01e-07	3.11e-06	77
GO:0032970111	Esophagus	ESCC	regulation of actin filament-based process	231/8552	397/18723	2.91e-07	4.20e-06	231
GO:0032956111	Esophagus	ESCC	regulation of actin cytoskeleton organization	210/8552	358/18723	4.40e-07	6.00e-06	210
GO:00703018	Esophagus	ESCC	cellular response to hydrogen peroxide	68/8552	98/18723	1.70e-06	2.03e-05	68
GO:1901214111	Esophagus	ESCC	regulation of neuron death	186/8552	319/18723	3.35e-06	3.73e-05	186
GO:003153218	Esophagus	ESCC	actin cytoskeleton reorganization	72/8552	107/18723	5.03e-06	5.31e-05	72
GO:1901216111	Esophagus	ESCC	positive regulation of neuron death	65/8552	97/18723	1.76e-05	1.56e-04	65
GO:001003827	Esophagus	ESCC	response to metal ion	208/8552	373/18723	5.02e-05	3.90e-04	208
GO:0051651111	Esophagus	ESCC	maintenance of location in cell	126/8552	214/18723	6.57e-05	5.00e-04	126
GO:000926619	Esophagus	ESCC	response to temperature stimulus	106/8552	178/18723	1.30e-04	8.84e-04	106

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0462122	Esophagus	ESCC	NOD-like receptor signaling pathway	116/4205	186/8465	2.90e-04	1.03e-03	5.30e-04	116
hsa0462132	Esophagus	ESCC	NOD-like receptor signaling pathway	116/4205	186/8465	2.90e-04	1.03e-03	5.30e-04	116
hsa046218	Oral cavity	OSCC	NOD-like receptor signaling pathway	108/3704	186/8465	5.13e-05	2.07e-04	1.05e-04	108
hsa0462113	Oral cavity	OSCC	NOD-like receptor signaling pathway	108/3704	186/8465	5.13e-05	2.07e-04	1.05e-04	108
hsa0462121	Oral cavity	LP	NOD-like receptor signaling pathway	73/2418	186/8465	9.80e-04	4.53e-03	2.92e-03	73
hsa0462131	Oral cavity	LP	NOD-like receptor signaling pathway	73/2418	186/8465	9.80e-04	4.53e-03	2.92e-03	73
hsa046214	Oral cavity	EOLP	NOD-like receptor signaling pathway	48/1218	186/8465	2.51e-05	1.31e-04	7.70e-05	48
hsa049219	Oral cavity	EOLP	Oxytocin signaling pathway	36/1218	154/8465	1.79e-03	6.08e-03	3.58e-03	36
hsa046215	Oral cavity	EOLP	NOD-like receptor signaling pathway	48/1218	186/8465	2.51e-05	1.31e-04	7.70e-05	48
hsa0492112	Oral cavity	EOLP	Oxytocin signaling pathway	36/1218	154/8465	1.79e-03	6.08e-03	3.58e-03	36

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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

TRPM2

SNV

Missense_Mutation

novel

c.2871C>G

p.Ile957Met

p.I957M

protein_coding

deleterious(0)

probably_damaging(0.984)

TCGA-A7-A56D-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

TRPM2

SNV

Missense_Mutation

novel

c.2752N>G

p.Lys918Glu

p.K918E

protein_coding

deleterious(0.01)

possibly_damaging(0.446)

TCGA-A7-A6VY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

TRPM2

SNV

Missense_Mutation

c.3136G>A

p.Ala1046Thr

p.A1046T

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

TRPM2

SNV

Missense_Mutation

novel

c.1445N>T

p.Ser482Leu

p.S482L

protein_coding

deleterious(0.01)

possibly_damaging(0.548)

TCGA-BH-A2L8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

TRPM2

SNV

Missense_Mutation

rs375351173

c.1900N>T

p.Arg634Cys

p.R634C

protein_coding

deleterious(0)

possibly_damaging(0.847)

TCGA-C8-A12P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

TRPM2

SNV

Missense_Mutation

rs574190384

c.2122N>A

p.Val708Met

p.V708M

protein_coding

deleterious(0.04)

possibly_damaging(0.64)

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TRPM2

SNV

Missense_Mutation

novel

c.2899N>G

p.Phe967Val

p.F967V

protein_coding

tolerated(0.07)

benign(0.071)

TCGA-E2-A152-01

Breast

breast invasive carcinoma

Female

<65

I/II

Targeted Molecular therapy

trastuzumab

TRPM2

SNV

Missense_Mutation

c.3632N>G

p.Leu1211Arg

p.L1211R

protein_coding

tolerated(0.06)

benign(0.043)

TCGA-EW-A1PD-01

Breast

breast invasive carcinoma

Male

<65

I/II

Chemotherapy

docetaxel

TRPM2

SNV

Missense_Mutation

novel

c.434N>C

p.Val145Ala

p.V145A

protein_coding

deleterious(0)

benign(0.231)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TRPM2

SNV

Missense_Mutation

novel

c.789N>T

p.Glu263Asp

p.E263D

protein_coding

deleterious(0.04)

benign(0.031)

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
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	blocker	135650269
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	activator	135651442
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	activator	178102951
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	activator	53801022
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	blocker	135650220	ECONAZOLE
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	activator	135652736
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	blocker	135652738
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	activator	178101017
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	blocker	135650114	CLOTRIMAZOLE
7226	TRPM2	ION CHANNEL, DRUGGABLE GENOME	blocker	53801024	MICONAZOLE

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