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: TMEM176A

Gene summary for TMEM176A

Gene summary.

Gene information	Species	Human
	Gene symbol	TMEM176A
	Gene ID	55365
	Gene name	transmembrane protein 176A
	Gene Alias	GS188
	Cytomap	7q36.1
	Gene Type	protein-coding
	GO ID	GO:0002376
	UniProtAcc	A0A090N8H6

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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
55365	TMEM176A	CA_HPV_1	Human	Cervix	CC	6.14e-09	-4.13e-01	0.0264
55365	TMEM176A	CA_HPV_2	Human	Cervix	CC	3.94e-02	-3.24e-01	0.0391
55365	TMEM176A	CA_HPV_3	Human	Cervix	CC	9.83e-12	-4.74e-01	0.0414
55365	TMEM176A	CCI_1	Human	Cervix	CC	2.41e-07	-6.57e-01	0.528
55365	TMEM176A	CCI_2	Human	Cervix	CC	1.16e-06	-6.57e-01	0.5249
55365	TMEM176A	CCI_3	Human	Cervix	CC	4.27e-10	-6.57e-01	0.516
55365	TMEM176A	CCII_1	Human	Cervix	CC	2.62e-14	-6.57e-01	0.3249
55365	TMEM176A	Tumor	Human	Cervix	CC	6.97e-36	-6.57e-01	0.1241
55365	TMEM176A	sample1	Human	Cervix	CC	7.83e-12	-6.57e-01	0.0959
55365	TMEM176A	sample3	Human	Cervix	CC	5.21e-31	-6.54e-01	0.1387
55365	TMEM176A	H2	Human	Cervix	HSIL_HPV	1.68e-06	-3.99e-01	0.0632
55365	TMEM176A	L1	Human	Cervix	CC	1.61e-11	-6.26e-01	0.0802
55365	TMEM176A	T1	Human	Cervix	CC	1.89e-26	-6.57e-01	0.0918
55365	TMEM176A	T3	Human	Cervix	CC	1.21e-28	-6.55e-01	0.1389
55365	TMEM176A	HTA11_3410_2000001011	Human	Colorectum	AD	2.15e-39	7.44e-01	0.0155
55365	TMEM176A	HTA11_2487_2000001011	Human	Colorectum	SER	2.75e-31	8.68e-01	-0.1808
55365	TMEM176A	HTA11_2951_2000001011	Human	Colorectum	AD	5.13e-05	3.66e-01	0.0216
55365	TMEM176A	HTA11_1938_2000001011	Human	Colorectum	AD	8.56e-43	1.35e+00	-0.0811
55365	TMEM176A	HTA11_78_2000001011	Human	Colorectum	AD	1.15e-20	7.07e-01	-0.1088
55365	TMEM176A	HTA11_347_2000001011	Human	Colorectum	AD	3.08e-63	1.18e+00	-0.1954

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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
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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
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:00026837	Cervix	CC	negative regulation of immune system process	94/2311	434/18723	2.63e-08	1.87e-06	94
GO:190370610	Cervix	CC	regulation of hemopoiesis	80/2311	367/18723	2.14e-07	9.55e-06	80
GO:19021056	Cervix	CC	regulation of leukocyte differentiation	61/2311	279/18723	5.16e-06	1.29e-04	61
GO:19021064	Cervix	CC	negative regulation of leukocyte differentiation	29/2311	102/18723	1.02e-05	2.29e-04	29
GO:19037074	Cervix	CC	negative regulation of hemopoiesis	29/2311	106/18723	2.29e-05	4.01e-04	29
GO:19031314	Cervix	CC	mononuclear cell differentiation	76/2311	426/18723	5.66e-04	5.42e-03	76
GO:20011983	Cervix	CC	regulation of dendritic cell differentiation	6/2311	13/18723	2.78e-03	1.87e-02	6
GO:190370613	Cervix	HSIL_HPV	regulation of hemopoiesis	35/737	367/18723	1.35e-06	6.21e-05	35
GO:000268312	Cervix	HSIL_HPV	negative regulation of immune system process	39/737	434/18723	1.51e-06	6.60e-05	39
GO:190210512	Cervix	HSIL_HPV	regulation of leukocyte differentiation	28/737	279/18723	5.84e-06	2.13e-04	28
GO:190210612	Cervix	HSIL_HPV	negative regulation of leukocyte differentiation	11/737	102/18723	2.24e-03	2.26e-02	11
GO:190370712	Cervix	HSIL_HPV	negative regulation of hemopoiesis	11/737	106/18723	3.04e-03	2.80e-02	11
GO:190313112	Cervix	HSIL_HPV	mononuclear cell differentiation	29/737	426/18723	3.10e-03	2.84e-02	29
GO:1903706	Colorectum	AD	regulation of hemopoiesis	99/3918	367/18723	3.08e-03	2.28e-02	99
GO:19037061	Colorectum	MSS	regulation of hemopoiesis	89/3467	367/18723	3.39e-03	2.56e-02	89
GO:1903706110	Esophagus	ESCC	regulation of hemopoiesis	201/8552	367/18723	2.60e-04	1.58e-03	201
GO:000268316	Esophagus	ESCC	negative regulation of immune system process	231/8552	434/18723	8.48e-04	4.36e-03	231
GO:19031317	Esophagus	ESCC	mononuclear cell differentiation	226/8552	426/18723	1.20e-03	5.88e-03	226
GO:190210510	Esophagus	ESCC	regulation of leukocyte differentiation	152/8552	279/18723	1.82e-03	8.35e-03	152
GO:19037066	Stomach	GC	regulation of hemopoiesis	42/1159	367/18723	9.03e-05	1.87e-03	42

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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

TMEM176A

SNV

Missense_Mutation

c.201N>C

p.Leu67Phe

p.L67F

Q96HP8

protein_coding

tolerated(0.07)

benign(0.171)

TCGA-C5-A1BQ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

cisplatin

TMEM176A

SNV

Missense_Mutation

novel

c.155N>A

p.Arg52Gln

p.R52Q

Q96HP8

protein_coding

deleterious(0.04)

probably_damaging(0.995)

TCGA-ZJ-A8QO-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

TMEM176A

SNV

Missense_Mutation

c.674A>G

p.Asp225Gly

p.D225G

Q96HP8

protein_coding

deleterious(0.01)

benign(0.117)

TCGA-AA-3977-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

TMEM176A

SNV

Missense_Mutation

rs142016485

c.121C>T

p.Arg41Trp

p.R41W

Q96HP8

protein_coding

tolerated(0.05)

possibly_damaging(0.568)

TCGA-A5-A2K5-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

TMEM176A

SNV

Missense_Mutation

rs150662833

c.122N>A

p.Arg41Gln

p.R41Q

Q96HP8

protein_coding

tolerated(0.58)

benign(0.003)

TCGA-AP-A0LM-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

cisplatin

TMEM176A

SNV

Missense_Mutation

c.511N>A

p.Val171Ile

p.V171I

Q96HP8

protein_coding

tolerated(0.17)

benign(0.157)

TCGA-AP-A0LM-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

cisplatin

TMEM176A

SNV

Missense_Mutation

novel

c.419N>C

p.Phe140Ser

p.F140S

Q96HP8

protein_coding

deleterious(0)

possibly_damaging(0.729)

TCGA-B5-A3FA-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

TMEM176A

SNV

Missense_Mutation

c.487N>A

p.Ala163Thr

p.A163T

Q96HP8

protein_coding

tolerated(0.31)

benign(0.14)

TCGA-BG-A0M0-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

TMEM176A

SNV

Missense_Mutation

novel

c.100N>T

p.Leu34Phe

p.L34F

Q96HP8

protein_coding

deleterious(0.02)

possibly_damaging(0.656)

TCGA-BG-A221-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

TMEM176A

SNV

Missense_Mutation

rs144787897

c.422N>A

p.Arg141Gln

p.R141Q

Q96HP8

protein_coding

tolerated(0.66)

benign(0.001)

TCGA-BS-A0TC-01

Endometrium

uterine corpus endometrioid carcinoma

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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