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: ADAM9

Gene summary for ADAM9

Gene summary.

Gene information	Species	Human
	Gene symbol	ADAM9
	Gene ID	8754
	Gene name	ADAM metallopeptidase domain 9
	Gene Alias	CORD9
	Cytomap	8p11.22
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q13443

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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
8754	ADAM9	CA_HPV_2	Human	Cervix	CC	2.03e-03	2.30e-01	0.0391
8754	ADAM9	CCI_2	Human	Cervix	CC	2.23e-05	7.61e-01	0.5249
8754	ADAM9	CCI_3	Human	Cervix	CC	7.38e-03	5.06e-01	0.516
8754	ADAM9	Tumor	Human	Cervix	CC	3.07e-02	2.06e-01	0.1241
8754	ADAM9	sample3	Human	Cervix	CC	2.17e-10	3.19e-01	0.1387
8754	ADAM9	H2	Human	Cervix	HSIL_HPV	2.20e-03	1.97e-01	0.0632
8754	ADAM9	T3	Human	Cervix	CC	8.98e-07	3.24e-01	0.1389
8754	ADAM9	LZE4T	Human	Esophagus	ESCC	1.13e-12	5.06e-01	0.0811
8754	ADAM9	LZE7T	Human	Esophagus	ESCC	1.55e-04	-1.60e-02	0.0667
8754	ADAM9	LZE8T	Human	Esophagus	ESCC	4.43e-11	2.42e-01	0.067
8754	ADAM9	LZE20T	Human	Esophagus	ESCC	9.56e-19	1.14e+00	0.0662
8754	ADAM9	LZE22D1	Human	Esophagus	HGIN	1.83e-04	-4.57e-02	0.0595
8754	ADAM9	LZE22T	Human	Esophagus	ESCC	1.88e-02	7.52e-01	0.068
8754	ADAM9	LZE24T	Human	Esophagus	ESCC	8.35e-21	7.82e-01	0.0596
8754	ADAM9	LZE21T	Human	Esophagus	ESCC	6.59e-05	1.64e-01	0.0655
8754	ADAM9	P1T-E	Human	Esophagus	ESCC	4.14e-04	5.85e-01	0.0875
8754	ADAM9	P2T-E	Human	Esophagus	ESCC	6.66e-24	3.20e-01	0.1177
8754	ADAM9	P4T-E	Human	Esophagus	ESCC	2.16e-24	6.14e-01	0.1323
8754	ADAM9	P5T-E	Human	Esophagus	ESCC	2.63e-15	1.99e-01	0.1327
8754	ADAM9	P8T-E	Human	Esophagus	ESCC	1.17e-39	9.66e-01	0.0889

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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
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:004217610	Cervix	CC	regulation of protein catabolic process	104/2311	391/18723	9.39e-15	9.36e-12	104
GO:00315898	Cervix	CC	cell-substrate adhesion	96/2311	363/18723	1.48e-13	8.85e-11	96
GO:004586210	Cervix	CC	positive regulation of proteolysis	95/2311	372/18723	1.84e-12	6.86e-10	95
GO:009013210	Cervix	CC	epithelium migration	90/2311	360/18723	2.45e-11	6.11e-09	90
GO:00016679	Cervix	CC	ameboidal-type cell migration	110/2311	475/18723	2.66e-11	6.36e-09	110
GO:001063110	Cervix	CC	epithelial cell migration	89/2311	357/18723	3.72e-11	8.54e-09	89
GO:00085446	Cervix	CC	epidermis development	83/2311	324/18723	3.91e-11	8.54e-09	83
GO:009013010	Cervix	CC	tissue migration	90/2311	365/18723	5.42e-11	1.05e-08	90
GO:004573210	Cervix	CC	positive regulation of protein catabolic process	65/2311	231/18723	7.44e-11	1.39e-08	65
GO:00435884	Cervix	CC	skin development	71/2311	263/18723	8.04e-11	1.46e-08	71
GO:004578510	Cervix	CC	positive regulation of cell adhesion	101/2311	437/18723	1.96e-10	3.08e-08	101
GO:000697910	Cervix	CC	response to oxidative stress	102/2311	446/18723	2.99e-10	4.36e-08	102
GO:000989610	Cervix	CC	positive regulation of catabolic process	109/2311	492/18723	5.26e-10	6.99e-08	109
GO:001063210	Cervix	CC	regulation of epithelial cell migration	72/2311	292/18723	4.52e-09	4.43e-07	72
GO:003367410	Cervix	CC	positive regulation of kinase activity	101/2311	467/18723	8.66e-09	7.22e-07	101
GO:00071608	Cervix	CC	cell-matrix adhesion	60/2311	233/18723	1.58e-08	1.23e-06	60
GO:00302164	Cervix	CC	keratinocyte differentiation	42/2311	139/18723	1.74e-08	1.28e-06	42
GO:005122210	Cervix	CC	positive regulation of protein transport	72/2311	303/18723	2.36e-08	1.70e-06	72
GO:00099137	Cervix	CC	epidermal cell differentiation	53/2311	202/18723	5.48e-08	3.25e-06	53
GO:00458608	Cervix	CC	positive regulation of protein kinase activity	85/2311	386/18723	5.61e-08	3.29e-06	85

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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

ADAM9

SNV

Missense_Mutation

c.1158N>A

p.Ser386Arg

p.S386R

Q13443

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AR-A24Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ADAM9

SNV

Missense_Mutation

novel

c.1933N>C

p.Asp645His

p.D645H

Q13443

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-E2-A9RU-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

arimidex

ADAM9

SNV

Missense_Mutation

novel

c.1439N>T

p.Cys480Phe

p.C480F

Q13443

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-EW-A1PC-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

ADAM9

deletion

Frame_Shift_Del

novel

c.1942delN

p.Lys649SerfsTer43

p.K649Sfs*43

Q13443

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ADAM9

deletion

Frame_Shift_Del

novel

c.2429delC

p.Pro810LeufsTer26

p.P810Lfs*26

Q13443

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

ADAM9

SNV

Missense_Mutation

novel

c.1825N>C

p.Ser609Pro

p.S609P

Q13443

protein_coding

deleterious(0.01)

benign(0.405)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ADAM9

SNV

Missense_Mutation

c.2264N>T

p.Arg755Leu

p.R755L

Q13443

protein_coding

tolerated(0.15)

benign(0.018)

TCGA-EA-A1QS-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ADAM9

SNV

Missense_Mutation

c.1028C>T

p.Ser343Phe

p.S343F

Q13443

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-EX-A1H6-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ADAM9

SNV

Missense_Mutation

c.475N>C

p.Glu159Gln

p.E159Q

Q13443

protein_coding

tolerated(0.26)

possibly_damaging(0.629)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ADAM9

SNV

Missense_Mutation

c.605N>C

p.Arg202Pro

p.R202P

Q13443

protein_coding

deleterious(0)

probably_damaging(0.988)

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
8754	ADAM9	DRUGGABLE GENOME, PROTEASE, NEUTRAL ZINC METALLOPEPTIDASE, CELL SURFACE, ENZYME	inhibitor	178103981	ILOMASTAT

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