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: TMEM2

Gene summary for TMEM2

Gene summary.

Gene information	Species	Human
	Gene symbol	TMEM2
	Gene ID	23670
	Gene name	cell migration inducing hyaluronidase 2
	Gene Alias	TMEM2
	Cytomap	9q21.13
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	Q9UHN6

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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
23670	TMEM2	HTA11_99999970781_79442	Human	Colorectum	MSS	1.43e-109	1.73e+00	0.294
23670	TMEM2	HTA11_99999965062_69753	Human	Colorectum	MSI-H	8.49e-22	2.28e+00	0.3487
23670	TMEM2	HTA11_99999965104_69814	Human	Colorectum	MSS	6.31e-46	1.34e+00	0.281
23670	TMEM2	HTA11_99999971662_82457	Human	Colorectum	MSS	1.36e-60	1.41e+00	0.3859
23670	TMEM2	HTA11_99999973899_84307	Human	Colorectum	MSS	1.05e-12	4.83e-01	0.2585
23670	TMEM2	HTA11_99999974143_84620	Human	Colorectum	MSS	6.03e-38	6.47e-01	0.3005
23670	TMEM2	LZE24T	Human	Esophagus	ESCC	4.31e-02	-2.27e-01	0.0596
23670	TMEM2	P2T-E	Human	Esophagus	ESCC	5.65e-14	2.10e-01	0.1177
23670	TMEM2	P4T-E	Human	Esophagus	ESCC	9.36e-05	1.99e-01	0.1323
23670	TMEM2	P8T-E	Human	Esophagus	ESCC	1.14e-10	1.86e-01	0.0889
23670	TMEM2	P9T-E	Human	Esophagus	ESCC	9.44e-09	3.50e-01	0.1131
23670	TMEM2	P10T-E	Human	Esophagus	ESCC	2.19e-16	1.88e-01	0.116
23670	TMEM2	P11T-E	Human	Esophagus	ESCC	7.26e-13	1.02e+00	0.1426
23670	TMEM2	P12T-E	Human	Esophagus	ESCC	2.48e-15	5.31e-01	0.1122
23670	TMEM2	P15T-E	Human	Esophagus	ESCC	2.92e-28	7.56e-01	0.1149
23670	TMEM2	P16T-E	Human	Esophagus	ESCC	9.05e-12	3.04e-01	0.1153
23670	TMEM2	P20T-E	Human	Esophagus	ESCC	9.08e-04	-1.91e-02	0.1124
23670	TMEM2	P21T-E	Human	Esophagus	ESCC	1.24e-10	1.05e-01	0.1617
23670	TMEM2	P22T-E	Human	Esophagus	ESCC	1.20e-08	7.13e-02	0.1236
23670	TMEM2	P23T-E	Human	Esophagus	ESCC	3.37e-07	3.44e-01	0.108

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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
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

∗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:00164852	Colorectum	MSS	protein processing	57/3467	225/18723	6.60e-03	4.38e-02	57
GO:00516568	Endometrium	AEH	establishment of organelle localization	77/2100	390/18723	4.89e-07	1.94e-05	77
GO:00516507	Endometrium	AEH	establishment of vesicle localization	32/2100	161/18723	8.99e-04	8.24e-03	32
GO:00516487	Endometrium	AEH	vesicle localization	32/2100	177/18723	4.33e-03	2.86e-02	32
GO:00484891	Endometrium	AEH	synaptic vesicle transport	11/2100	42/18723	5.45e-03	3.37e-02	11
GO:005165613	Endometrium	EEC	establishment of organelle localization	75/2168	390/18723	6.23e-06	1.49e-04	75
GO:005165013	Endometrium	EEC	establishment of vesicle localization	31/2168	161/18723	2.99e-03	2.10e-02	31
GO:004217627	Esophagus	HGIN	regulation of protein catabolic process	119/2587	391/18723	8.09e-18	2.43e-15	119
GO:001049826	Esophagus	HGIN	proteasomal protein catabolic process	139/2587	490/18723	1.20e-17	3.41e-15	139
GO:004586227	Esophagus	HGIN	positive regulation of proteolysis	107/2587	372/18723	2.61e-14	4.60e-12	107
GO:190336227	Esophagus	HGIN	regulation of cellular protein catabolic process	81/2587	255/18723	1.16e-13	1.93e-11	81
GO:003497625	Esophagus	HGIN	response to endoplasmic reticulum stress	81/2587	256/18723	1.47e-13	2.32e-11	81
GO:000989626	Esophagus	HGIN	positive regulation of catabolic process	126/2587	492/18723	1.46e-12	2.09e-10	126
GO:003133126	Esophagus	HGIN	positive regulation of cellular catabolic process	112/2587	427/18723	5.15e-12	6.72e-10	112
GO:190305027	Esophagus	HGIN	regulation of proteolysis involved in cellular protein catabolic process	70/2587	221/18723	6.21e-12	7.76e-10	70
GO:006113627	Esophagus	HGIN	regulation of proteasomal protein catabolic process	60/2587	187/18723	1.10e-10	1.12e-08	60
GO:004573227	Esophagus	HGIN	positive regulation of protein catabolic process	69/2587	231/18723	1.66e-10	1.64e-08	69
GO:190336427	Esophagus	HGIN	positive regulation of cellular protein catabolic process	51/2587	155/18723	1.01e-09	8.15e-08	51
GO:190180020	Esophagus	HGIN	positive regulation of proteasomal protein catabolic process	41/2587	114/18723	2.25e-09	1.67e-07	41
GO:190305219	Esophagus	HGIN	positive regulation of proteolysis involved in cellular protein catabolic process	45/2587	133/18723	3.55e-09	2.53e-07	45

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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

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

TMEM2

SNV

Missense_Mutation

novel

c.3527G>A

p.Arg1176Lys

p.R1176K

Q9UHN6

protein_coding

tolerated(0.66)

benign(0)

TCGA-A8-A06Q-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

TMEM2

SNV

Missense_Mutation

novel

c.3357N>A

p.Phe1119Leu

p.F1119L

Q9UHN6

protein_coding

deleterious(0.03)

possibly_damaging(0.49)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TMEM2

SNV

Missense_Mutation

c.1139N>G

p.Gln380Arg

p.Q380R

Q9UHN6

protein_coding

tolerated(0.68)

benign(0.001)

TCGA-AR-A0TX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

TMEM2

insertion

Nonsense_Mutation

novel

c.922_923insCTGAATCTGTGGGATCTACTAAAGTTTA

p.Arg308ProfsTer10

p.R308Pfs*10

Q9UHN6

protein_coding

TCGA-AO-A0JF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

TMEM2

SNV

Missense_Mutation

novel

c.3854N>T

p.Ser1285Phe

p.S1285F

Q9UHN6

protein_coding

deleterious(0.01)

probably_damaging(0.996)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TMEM2

SNV

Missense_Mutation

rs772803934

c.1469N>A

p.Arg490Gln

p.R490Q

Q9UHN6

protein_coding

deleterious(0.03)

benign(0.264)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TMEM2

SNV

Missense_Mutation

c.415N>T

p.Asp139Tyr

p.D139Y

Q9UHN6

protein_coding

tolerated(0.07)

possibly_damaging(0.87)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TMEM2

SNV

Missense_Mutation

novel

c.1885N>G

p.Thr629Ala

p.T629A

Q9UHN6

protein_coding

deleterious(0.05)

benign(0.083)

TCGA-EA-A410-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

TMEM2

SNV

Missense_Mutation

rs776808520

c.314C>T

p.Ser105Leu

p.S105L

Q9UHN6

protein_coding

deleterious(0)

benign(0.03)

TCGA-FU-A3HY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TMEM2

SNV

Missense_Mutation

c.2635C>T

p.His879Tyr

p.H879Y

Q9UHN6

protein_coding

tolerated(1)

benign(0.171)

TCGA-JW-A5VL-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

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