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: ARHGAP35

Gene summary for ARHGAP35

Gene summary.

Gene information	Species	Human
	Gene symbol	ARHGAP35
	Gene ID	2909
	Gene name	Rho GTPase activating protein 35
	Gene Alias	GRF-1
	Cytomap	19q13.32
	Gene Type	protein-coding
	GO ID	GO:0000902
	UniProtAcc	Q9NRY4

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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
2909	ARHGAP35	CA_HPV_2	Human	Cervix	CC	6.92e-03	2.37e-01	0.0391
2909	ARHGAP35	CCI_2	Human	Cervix	CC	1.53e-03	5.15e-01	0.5249
2909	ARHGAP35	CCI_3	Human	Cervix	CC	2.99e-09	7.42e-01	0.516
2909	ARHGAP35	LZE2T	Human	Esophagus	ESCC	7.30e-03	5.68e-01	0.082
2909	ARHGAP35	LZE4T	Human	Esophagus	ESCC	1.68e-04	2.24e-01	0.0811
2909	ARHGAP35	LZE7T	Human	Esophagus	ESCC	9.73e-04	2.16e-01	0.0667
2909	ARHGAP35	LZE20T	Human	Esophagus	ESCC	3.89e-04	1.02e-01	0.0662
2909	ARHGAP35	LZE24T	Human	Esophagus	ESCC	1.37e-12	2.26e-01	0.0596
2909	ARHGAP35	LZE21T	Human	Esophagus	ESCC	3.21e-03	2.81e-01	0.0655
2909	ARHGAP35	P1T-E	Human	Esophagus	ESCC	7.87e-06	3.14e-01	0.0875
2909	ARHGAP35	P2T-E	Human	Esophagus	ESCC	1.33e-08	1.17e-01	0.1177
2909	ARHGAP35	P4T-E	Human	Esophagus	ESCC	7.36e-09	1.63e-01	0.1323
2909	ARHGAP35	P5T-E	Human	Esophagus	ESCC	3.95e-02	-1.07e-03	0.1327
2909	ARHGAP35	P8T-E	Human	Esophagus	ESCC	1.22e-25	6.39e-01	0.0889
2909	ARHGAP35	P9T-E	Human	Esophagus	ESCC	3.34e-11	1.43e-01	0.1131
2909	ARHGAP35	P10T-E	Human	Esophagus	ESCC	2.20e-24	4.35e-01	0.116
2909	ARHGAP35	P12T-E	Human	Esophagus	ESCC	8.36e-17	2.68e-01	0.1122
2909	ARHGAP35	P15T-E	Human	Esophagus	ESCC	5.88e-25	5.03e-01	0.1149
2909	ARHGAP35	P16T-E	Human	Esophagus	ESCC	9.98e-04	6.79e-02	0.1153
2909	ARHGAP35	P17T-E	Human	Esophagus	ESCC	5.48e-03	1.54e-01	0.1278

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
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:00074095	Liver	NAFLD	axonogenesis	58/1882	418/18723	7.16e-03	4.96e-02	58
GO:000701512	Liver	Cirrhotic	actin filament organization	171/4634	442/18723	3.93e-11	2.30e-09	171
GO:002260412	Liver	Cirrhotic	regulation of cell morphogenesis	127/4634	309/18723	1.45e-10	7.44e-09	127
GO:190290312	Liver	Cirrhotic	regulation of supramolecular fiber organization	148/4634	383/18723	8.85e-10	4.08e-08	148
GO:003297012	Liver	Cirrhotic	regulation of actin filament-based process	152/4634	397/18723	1.12e-09	5.00e-08	152
GO:003295612	Liver	Cirrhotic	regulation of actin cytoskeleton organization	136/4634	358/18723	1.47e-08	5.49e-07	136
GO:004206012	Liver	Cirrhotic	wound healing	155/4634	422/18723	2.12e-08	7.56e-07	155
GO:007149612	Liver	Cirrhotic	cellular response to external stimulus	123/4634	320/18723	3.27e-08	1.10e-06	123
GO:000836012	Liver	Cirrhotic	regulation of cell shape	69/4634	154/18723	4.21e-08	1.36e-06	69
GO:011005312	Liver	Cirrhotic	regulation of actin filament organization	108/4634	278/18723	1.17e-07	3.32e-06	108
GO:004873212	Liver	Cirrhotic	gland development	154/4634	436/18723	4.03e-07	9.42e-06	154
GO:00316686	Liver	Cirrhotic	cellular response to extracellular stimulus	96/4634	246/18723	4.55e-07	1.05e-05	96
GO:000815412	Liver	Cirrhotic	actin polymerization or depolymerization	86/4634	218/18723	1.04e-06	2.13e-05	86
GO:003253512	Liver	Cirrhotic	regulation of cellular component size	135/4634	383/18723	2.32e-06	4.26e-05	135
GO:00080647	Liver	Cirrhotic	regulation of actin polymerization or depolymerization	74/4634	188/18723	6.26e-06	9.92e-05	74
GO:00308327	Liver	Cirrhotic	regulation of actin filament length	74/4634	189/18723	7.83e-06	1.18e-04	74
GO:000726511	Liver	Cirrhotic	Ras protein signal transduction	119/4634	337/18723	8.16e-06	1.22e-04	119
GO:000716312	Liver	Cirrhotic	establishment or maintenance of cell polarity	82/4634	218/18723	1.55e-05	2.11e-04	82
GO:000726611	Liver	Cirrhotic	Rho protein signal transduction	53/4634	137/18723	2.05e-04	1.89e-03	53
GO:1902115	Liver	Cirrhotic	regulation of organelle assembly	66/4634	186/18723	6.66e-04	5.04e-03	66

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0451010	Cervix	CC	Focal adhesion	59/1267	203/8465	1.53e-07	1.84e-06	1.09e-06	59
hsa0481016	Cervix	CC	Regulation of actin cytoskeleton	64/1267	229/8465	2.24e-07	2.59e-06	1.53e-06	64
hsa0467020	Cervix	CC	Leukocyte transendothelial migration	36/1267	114/8465	5.22e-06	4.83e-05	2.86e-05	36
hsa046115	Cervix	CC	Platelet activation	28/1267	124/8465	1.50e-02	4.45e-02	2.63e-02	28
hsa0451014	Cervix	CC	Focal adhesion	59/1267	203/8465	1.53e-07	1.84e-06	1.09e-06	59
hsa0481017	Cervix	CC	Regulation of actin cytoskeleton	64/1267	229/8465	2.24e-07	2.59e-06	1.53e-06	64
hsa04670110	Cervix	CC	Leukocyte transendothelial migration	36/1267	114/8465	5.22e-06	4.83e-05	2.86e-05	36
hsa0461113	Cervix	CC	Platelet activation	28/1267	124/8465	1.50e-02	4.45e-02	2.63e-02	28
hsa0451020	Esophagus	ESCC	Focal adhesion	127/4205	203/8465	1.25e-04	4.99e-04	2.56e-04	127
hsa0481028	Esophagus	ESCC	Regulation of actin cytoskeleton	133/4205	229/8465	5.94e-03	1.48e-02	7.56e-03	133
hsa04510111	Esophagus	ESCC	Focal adhesion	127/4205	203/8465	1.25e-04	4.99e-04	2.56e-04	127
hsa04810112	Esophagus	ESCC	Regulation of actin cytoskeleton	133/4205	229/8465	5.94e-03	1.48e-02	7.56e-03	133
hsa0481010	Liver	NAFLD	Regulation of actin cytoskeleton	50/1043	229/8465	3.01e-05	7.59e-04	6.11e-04	50
hsa0467014	Liver	NAFLD	Leukocyte transendothelial migration	25/1043	114/8465	2.65e-03	2.71e-02	2.19e-02	25
hsa045106	Liver	NAFLD	Focal adhesion	38/1043	203/8465	5.13e-03	4.43e-02	3.57e-02	38
hsa0481011	Liver	NAFLD	Regulation of actin cytoskeleton	50/1043	229/8465	3.01e-05	7.59e-04	6.11e-04	50
hsa0467015	Liver	NAFLD	Leukocyte transendothelial migration	25/1043	114/8465	2.65e-03	2.71e-02	2.19e-02	25
hsa0451011	Liver	NAFLD	Focal adhesion	38/1043	203/8465	5.13e-03	4.43e-02	3.57e-02	38
hsa0451021	Liver	Cirrhotic	Focal adhesion	93/2530	203/8465	9.27e-07	1.10e-05	6.80e-06	93
hsa0481021	Liver	Cirrhotic	Regulation of actin cytoskeleton	100/2530	229/8465	5.28e-06	5.50e-05	3.39e-05	100

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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

ARHGAP35

SNV

Missense_Mutation

novel

c.3966N>C

p.Lys1322Asn

p.K1322N

Q9NRY4

protein_coding

deleterious(0)

probably_damaging(0.989)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

ARHGAP35

SNV

Missense_Mutation

novel

c.2231G>T

p.Arg744Leu

p.R744L

Q9NRY4

protein_coding

deleterious(0.01)

possibly_damaging(0.82)

TCGA-A2-A0D1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

taxotere

ARHGAP35

SNV

Missense_Mutation

novel

c.1097N>G

p.Ala366Gly

p.A366G

Q9NRY4

protein_coding

tolerated(0.08)

possibly_damaging(0.583)

TCGA-A2-A0D2-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

ARHGAP35

SNV

Missense_Mutation

rs778118639

c.1301N>A

p.Arg434Lys

p.R434K

Q9NRY4

protein_coding

tolerated(1)

benign(0.017)

TCGA-A2-A0D4-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

ARHGAP35

SNV

Missense_Mutation

rs376792949

c.2495N>A

p.Arg832Gln

p.R832Q

Q9NRY4

protein_coding

deleterious(0.03)

possibly_damaging(0.856)

TCGA-A2-A0EV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ARHGAP35

SNV

Missense_Mutation

rs751013716

c.844A>G

p.Ser282Gly

p.S282G

Q9NRY4

protein_coding

tolerated(0.39)

benign(0.138)

TCGA-AQ-A04H-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxotere

ARHGAP35

SNV

Missense_Mutation

c.4001N>T

p.Pro1334Leu

p.P1334L

Q9NRY4

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-B6-A0IC-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ARHGAP35

SNV

Missense_Mutation

c.2456N>G

p.Ser819Cys

p.S819C

Q9NRY4

protein_coding

tolerated(0.06)

possibly_damaging(0.614)

TCGA-BH-A0AY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

ARHGAP35

SNV

Missense_Mutation

c.4204N>A

p.Pro1402Thr

p.P1402T

Q9NRY4

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0C0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

ARHGAP35

SNV

Missense_Mutation

c.3090N>C

p.Glu1030Asp

p.E1030D

Q9NRY4

protein_coding

tolerated(0.29)

benign(0.283)

TCGA-D8-A1JN-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozolum

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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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