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: GAREM1

Gene summary for GAREM1

Gene summary.

Gene information	Species	Human
	Gene symbol	GAREM1
	Gene ID	64762
	Gene name	GRB2 associated regulator of MAPK1 subtype 1
	Gene Alias	C18orf11
	Cytomap	18q12.1
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	Q9H706

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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
64762	GAREM1	CCI_1	Human	Cervix	CC	3.26e-12	7.79e-01	0.528
64762	GAREM1	CCI_2	Human	Cervix	CC	4.57e-09	8.14e-01	0.5249
64762	GAREM1	CCI_3	Human	Cervix	CC	7.84e-10	5.34e-01	0.516
64762	GAREM1	HTA11_1938_2000001011	Human	Colorectum	AD	3.06e-03	6.11e-01	-0.0811
64762	GAREM1	HTA11_78_2000001011	Human	Colorectum	AD	1.51e-07	7.61e-01	-0.1088
64762	GAREM1	HTA11_347_2000001011	Human	Colorectum	AD	2.19e-18	8.36e-01	-0.1954
64762	GAREM1	HTA11_1391_2000001011	Human	Colorectum	AD	3.70e-06	6.03e-01	-0.059
64762	GAREM1	HTA11_7862_2000001011	Human	Colorectum	AD	5.71e-03	5.94e-01	-0.0179
64762	GAREM1	HTA11_866_3004761011	Human	Colorectum	AD	7.22e-13	7.87e-01	0.096
64762	GAREM1	HTA11_4255_2000001011	Human	Colorectum	SER	7.56e-03	7.45e-01	0.0446
64762	GAREM1	HTA11_7663_2000001011	Human	Colorectum	SER	5.29e-05	8.38e-01	0.0131
64762	GAREM1	HTA11_10623_2000001011	Human	Colorectum	AD	1.21e-08	9.05e-01	-0.0177
64762	GAREM1	HTA11_6801_2000001011	Human	Colorectum	SER	1.78e-12	1.60e+00	0.0171
64762	GAREM1	HTA11_7469_2000001011	Human	Colorectum	AD	1.70e-02	8.31e-01	-0.0124
64762	GAREM1	HTA11_99999970781_79442	Human	Colorectum	MSS	6.73e-19	1.16e+00	0.294
64762	GAREM1	HTA11_99999965062_69753	Human	Colorectum	MSI-H	3.66e-16	2.22e+00	0.3487
64762	GAREM1	HTA11_99999971662_82457	Human	Colorectum	MSS	7.25e-08	8.45e-01	0.3859
64762	GAREM1	A015-C-203	Human	Colorectum	FAP	1.23e-27	-4.03e-01	-0.1294
64762	GAREM1	A015-C-204	Human	Colorectum	FAP	5.28e-05	-3.09e-01	-0.0228
64762	GAREM1	A002-C-201	Human	Colorectum	FAP	2.09e-08	-3.00e-01	0.0324

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
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
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:00071738	Cervix	CC	epidermal growth factor receptor signaling pathway	36/2311	108/18723	1.04e-08	8.44e-07	36
GO:00381278	Cervix	CC	ERBB signaling pathway	37/2311	121/18723	8.57e-08	4.88e-06	37
GO:00434104	Cervix	CC	positive regulation of MAPK cascade	90/2311	480/18723	2.92e-05	4.83e-04	90
GO:00713648	Cervix	CC	cellular response to epidermal growth factor stimulus	16/2311	45/18723	5.24e-05	7.83e-04	16
GO:00708498	Cervix	CC	response to epidermal growth factor	16/2311	49/18723	1.67e-04	1.99e-03	16
GO:00513021	Cervix	CC	regulation of cell division	39/2311	177/18723	2.05e-04	2.33e-03	39
GO:00703714	Cervix	CC	ERK1 and ERK2 cascade	60/2311	330/18723	1.28e-03	1.02e-02	60
GO:00703723	Cervix	CC	regulation of ERK1 and ERK2 cascade	54/2311	309/18723	5.11e-03	3.02e-02	54
GO:0038127	Colorectum	AD	ERBB signaling pathway	55/3918	121/18723	1.19e-09	8.85e-08	55
GO:0007173	Colorectum	AD	epidermal growth factor receptor signaling pathway	50/3918	108/18723	3.08e-09	2.07e-07	50
GO:0070849	Colorectum	AD	response to epidermal growth factor	23/3918	49/18723	4.18e-05	7.37e-04	23
GO:0071364	Colorectum	AD	cellular response to epidermal growth factor stimulus	21/3918	45/18723	9.94e-05	1.50e-03	21
GO:00708491	Colorectum	SER	response to epidermal growth factor	20/2897	49/18723	1.72e-05	5.15e-04	20
GO:00713641	Colorectum	SER	cellular response to epidermal growth factor stimulus	18/2897	45/18723	6.20e-05	1.44e-03	18
GO:00381271	Colorectum	SER	ERBB signaling pathway	35/2897	121/18723	1.21e-04	2.49e-03	35
GO:00071731	Colorectum	SER	epidermal growth factor receptor signaling pathway	32/2897	108/18723	1.42e-04	2.82e-03	32
GO:00071732	Colorectum	MSS	epidermal growth factor receptor signaling pathway	43/3467	108/18723	1.92e-07	8.31e-06	43
GO:00381272	Colorectum	MSS	ERBB signaling pathway	46/3467	121/18723	3.63e-07	1.45e-05	46
GO:00708492	Colorectum	MSS	response to epidermal growth factor	20/3467	49/18723	2.36e-04	3.24e-03	20
GO:00713642	Colorectum	MSS	cellular response to epidermal growth factor stimulus	18/3467	45/18723	6.38e-04	6.99e-03	18

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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

GAREM1

SNV

Missense_Mutation

novel

c.561N>G

p.Ile187Met

p.I187M

Q9H706

protein_coding

deleterious(0.04)

possibly_damaging(0.824)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

GAREM1

SNV

Missense_Mutation

c.1124N>T

p.Ala375Val

p.A375V

Q9H706

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-A2-A0ET-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

GAREM1

SNV

Missense_Mutation

c.2254N>A

p.Glu752Lys

p.E752K

Q9H706

protein_coding

tolerated(0.08)

possibly_damaging(0.551)

TCGA-AN-A0FY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

GAREM1

insertion

Nonsense_Mutation

novel

c.941_942insTTTAGGAATTAGAGTTTTACTCTATGTCTGATGAGAACCTC

p.Lys314AsnfsTer11

p.K314Nfs*11

Q9H706

protein_coding

TCGA-A2-A0EX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

GAREM1

insertion

Nonsense_Mutation

novel

c.398_399insATTTGTATGAATCACCGGACCAACGAAAGCATTAGCCT

p.Ser134PhefsTer3

p.S134Ffs*3

Q9H706

protein_coding

TCGA-A7-A0CJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

GAREM1

insertion

Nonsense_Mutation

novel

c.2221_2222insTTGCAGGTGAAGAAGATAATGCAATTCATTAATGGCTGGAGG

p.Thr741delinsIleAlaGlyGluGluAspAsnAlaIleHisTerTrpLeuGluAla

p.T741delinsIAGEEDNAIH*WLEA

Q9H706

protein_coding

TCGA-A7-A0D9-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

GAREM1

insertion

Nonsense_Mutation

novel

c.1395_1396insACAACAAATTAGCTGGGCGTGGTGGCGGGCGCCTCTAGTCCCAAG

p.His465_Gln466insThrThrAsnTerLeuGlyValValAlaGlyAlaSerSerProLys

p.H465_Q466insTTN*LGVVAGASSPK

Q9H706

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

GAREM1

insertion

Frame_Shift_Ins

novel

c.2104_2105insGGAGGCC

p.Ser702TrpfsTer50

p.S702Wfs*50

Q9H706

protein_coding

TCGA-BH-A0BM-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

GAREM1

insertion

Nonsense_Mutation

novel

c.2102_2103insTAATGCAATTCATTAATGG

p.Ser702AsnfsTer5

p.S702Nfs*5

Q9H706

protein_coding

TCGA-BH-A0BM-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

GAREM1

SNV

Missense_Mutation

c.2506N>A

p.Glu836Lys

p.E836K

Q9H706

protein_coding

deleterious(0)

probably_damaging(0.985)

TCGA-EK-A3GK-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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