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: MTDH

Gene summary for MTDH

Gene summary.

Gene information	Species	Human
	Gene symbol	MTDH
	Gene ID	92140
	Gene name	metadherin
	Gene Alias	3D3
	Cytomap	8q22.1
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	A0A024R9D2

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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
92140	MTDH	GSM4909281	Human	Breast	IDC	3.42e-75	9.57e-01	0.21
92140	MTDH	GSM4909282	Human	Breast	IDC	3.14e-03	2.66e-01	-0.0288
92140	MTDH	GSM4909285	Human	Breast	IDC	1.15e-07	3.15e-01	0.21
92140	MTDH	GSM4909286	Human	Breast	IDC	9.45e-17	4.81e-01	0.1081
92140	MTDH	GSM4909287	Human	Breast	IDC	6.64e-30	6.13e-01	0.2057
92140	MTDH	GSM4909290	Human	Breast	IDC	1.88e-52	9.41e-01	0.2096
92140	MTDH	GSM4909291	Human	Breast	IDC	5.41e-49	9.19e-01	0.1753
92140	MTDH	GSM4909292	Human	Breast	IDC	2.35e-03	5.60e-01	0.1236
92140	MTDH	GSM4909293	Human	Breast	IDC	2.85e-17	4.62e-01	0.1581
92140	MTDH	GSM4909294	Human	Breast	IDC	4.83e-03	-1.75e-01	0.2022
92140	MTDH	GSM4909296	Human	Breast	IDC	6.94e-13	-1.22e-01	0.1524
92140	MTDH	GSM4909297	Human	Breast	IDC	1.56e-20	1.34e-01	0.1517
92140	MTDH	GSM4909298	Human	Breast	IDC	6.23e-20	4.98e-01	0.1551
92140	MTDH	GSM4909301	Human	Breast	IDC	6.46e-04	2.13e-01	0.1577
92140	MTDH	GSM4909302	Human	Breast	IDC	7.01e-03	2.60e-01	0.1545
92140	MTDH	GSM4909304	Human	Breast	IDC	2.34e-06	3.01e-01	0.1636
92140	MTDH	GSM4909305	Human	Breast	IDC	2.13e-09	4.75e-01	0.0436
92140	MTDH	GSM4909306	Human	Breast	IDC	3.18e-36	6.60e-01	0.1564
92140	MTDH	GSM4909307	Human	Breast	IDC	1.24e-27	5.86e-01	0.1569
92140	MTDH	GSM4909308	Human	Breast	IDC	5.80e-35	7.03e-01	0.158

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
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
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:00022378	Breast	Precancer	response to molecule of bacterial origin	43/1080	363/18723	6.05e-06	1.72e-04	43
GO:00324968	Breast	Precancer	response to lipopolysaccharide	41/1080	343/18723	7.94e-06	2.17e-04	41
GO:00098969	Breast	Precancer	positive regulation of catabolic process	48/1080	492/18723	2.62e-04	3.84e-03	48
GO:00313319	Breast	Precancer	positive regulation of cellular catabolic process	43/1080	427/18723	2.75e-04	4.00e-03	43
GO:0045766	Breast	Precancer	positive regulation of angiogenesis	23/1080	181/18723	3.09e-04	4.43e-03	23
GO:1904018	Breast	Precancer	positive regulation of vasculature development	23/1080	181/18723	3.09e-04	4.43e-03	23
GO:00712227	Breast	Precancer	cellular response to lipopolysaccharide	25/1080	209/18723	4.41e-04	5.85e-03	25
GO:00712167	Breast	Precancer	cellular response to biotic stimulus	28/1080	246/18723	4.67e-04	6.14e-03	28
GO:0045765	Breast	Precancer	regulation of angiogenesis	35/1080	342/18723	7.35e-04	8.80e-03	35
GO:1901342	Breast	Precancer	regulation of vasculature development	35/1080	348/18723	1.00e-03	1.12e-02	35
GO:00712197	Breast	Precancer	cellular response to molecule of bacterial origin	25/1080	221/18723	1.00e-03	1.12e-02	25
GO:00434912	Breast	Precancer	protein kinase B signaling	23/1080	211/18723	2.53e-03	2.30e-02	23
GO:00072496	Breast	Precancer	I-kappaB kinase/NF-kappaB signaling	27/1080	281/18723	6.58e-03	4.53e-02	27
GO:000989614	Breast	IDC	positive regulation of catabolic process	62/1434	492/18723	7.06e-05	1.42e-03	62
GO:003249612	Breast	IDC	response to lipopolysaccharide	47/1434	343/18723	7.13e-05	1.43e-03	47
GO:000223712	Breast	IDC	response to molecule of bacterial origin	49/1434	363/18723	7.40e-05	1.47e-03	49
GO:003133114	Breast	IDC	positive regulation of cellular catabolic process	54/1434	427/18723	1.85e-04	3.07e-03	54
GO:00457651	Breast	IDC	regulation of angiogenesis	45/1434	342/18723	2.57e-04	3.98e-03	45
GO:19013421	Breast	IDC	regulation of vasculature development	45/1434	348/18723	3.78e-04	5.38e-03	45
GO:00431227	Breast	IDC	regulation of I-kappaB kinase/NF-kappaB signaling	34/1434	249/18723	7.18e-04	8.77e-03	34

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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

MTDH

SNV

Missense_Mutation

novel

c.935N>T

p.Ala312Val

p.A312V

Q86UE4

protein_coding

tolerated(0.11)

benign(0.005)

TCGA-AR-A0TS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

MTDH

SNV

Missense_Mutation

novel

c.1741N>A

p.Glu581Lys

p.E581K

Q86UE4

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-BH-A2L8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

MTDH

SNV

Missense_Mutation

c.468C>A

p.Asp156Glu

p.D156E

Q86UE4

protein_coding

tolerated(0.83)

benign(0)

TCGA-E9-A22B-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

MTDH

deletion

Frame_Shift_Del

novel

c.1476delC

p.Ile493Ter

p.I493*

Q86UE4

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

MTDH

SNV

Missense_Mutation

novel

c.712N>A

p.Ala238Thr

p.A238T

Q86UE4

protein_coding

tolerated(0.08)

benign(0.003)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

MTDH

SNV

Missense_Mutation

c.1060G>A

p.Glu354Lys

p.E354K

Q86UE4

protein_coding

deleterious(0.01)

possibly_damaging(0.754)

TCGA-C5-A1MH-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

cisplatin

MTDH

SNV

Missense_Mutation

c.1060N>A

p.Glu354Lys

p.E354K

Q86UE4

protein_coding

deleterious(0.01)

possibly_damaging(0.754)

TCGA-EK-A3GK-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MTDH

SNV

Missense_Mutation

c.641N>G

p.Ser214Cys

p.S214C

Q86UE4

protein_coding

tolerated(0.12)

possibly_damaging(0.855)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

MTDH

SNV

Missense_Mutation

c.1677G>C

p.Gln559His

p.Q559H

Q86UE4

protein_coding

tolerated(0.08)

probably_damaging(0.997)

TCGA-JX-A3Q0-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

MTDH

SNV

Missense_Mutation

novel

c.130N>T

p.Pro44Ser

p.P44S

Q86UE4

protein_coding

deleterious(0.01)

probably_damaging(0.964)

TCGA-VS-A9UJ-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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