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:003432931	Lung	MIAC	cell junction assembly	48/967	420/18723	2.13e-07	4.11e-05	48
GO:003133132	Lung	MIAC	positive regulation of cellular catabolic process	46/967	427/18723	2.00e-06	2.44e-04	46
GO:004521623	Lung	MIAC	cell-cell junction organization	26/967	200/18723	1.38e-05	9.86e-04	26
GO:00518972	Lung	MIAC	positive regulation of protein kinase B signaling	16/967	120/18723	4.51e-04	1.25e-02	16
GO:000704322	Lung	MIAC	cell-cell junction assembly	18/967	146/18723	5.38e-04	1.39e-02	18
GO:00518963	Lung	MIAC	regulation of protein kinase B signaling	21/967	185/18723	5.95e-04	1.49e-02	21
GO:00434911	Lung	MIAC	protein kinase B signaling	22/967	211/18723	1.39e-03	2.51e-02	22
GO:012019322	Lung	MIAC	tight junction organization	11/967	80/18723	2.63e-03	3.71e-02	11
GO:000989620	Oral cavity	OSCC	positive regulation of catabolic process	307/7305	492/18723	2.29e-26	7.64e-24	307
GO:003133120	Oral cavity	OSCC	positive regulation of cellular catabolic process	273/7305	427/18723	6.39e-26	2.02e-23	273
GO:001050610	Oral cavity	OSCC	regulation of autophagy	198/7305	317/18723	1.63e-17	1.51e-15	198
GO:004312218	Oral cavity	OSCC	regulation of I-kappaB kinase/NF-kappaB signaling	155/7305	249/18723	7.79e-14	4.14e-12	155
GO:004312310	Oral cavity	OSCC	positive regulation of I-kappaB kinase/NF-kappaB signaling	122/7305	186/18723	1.68e-13	8.52e-12	122
GO:000724910	Oral cavity	OSCC	I-kappaB kinase/NF-kappaB signaling	169/7305	281/18723	4.69e-13	2.25e-11	169
GO:00105087	Oral cavity	OSCC	positive regulation of autophagy	77/7305	124/18723	1.59e-07	2.61e-06	77
GO:003249617	Oral cavity	OSCC	response to lipopolysaccharide	178/7305	343/18723	7.27e-07	1.03e-05	178
GO:00510907	Oral cavity	OSCC	regulation of DNA-binding transcription factor activity	221/7305	440/18723	9.06e-07	1.23e-05	221
GO:007121615	Oral cavity	OSCC	cellular response to biotic stimulus	129/7305	246/18723	1.20e-05	1.23e-04	129
GO:000223717	Oral cavity	OSCC	response to molecule of bacterial origin	181/7305	363/18723	1.48e-05	1.49e-04	181
GO:00510917	Oral cavity	OSCC	positive regulation of DNA-binding transcription factor activity	134/7305	260/18723	2.52e-05	2.35e-04	134

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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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