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: C4orf3

Gene summary for C4ORF3

Gene summary.

Gene information	Species	Human
	Gene symbol	C4orf3
	Gene ID	401152
	Gene name	chromosome 4 open reading frame 3
	Gene Alias	ALN
	Cytomap	4q26
	Gene Type	protein-coding
	GO ID	GO:0006810
	UniProtAcc	Q8WVX3

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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
401152	C4orf3	GSM4909281	Human	Breast	IDC	5.14e-07	4.04e-01	0.21
401152	C4orf3	GSM4909286	Human	Breast	IDC	6.66e-06	1.18e-01	0.1081
401152	C4orf3	GSM4909288	Human	Breast	IDC	2.61e-02	2.47e-01	0.0988
401152	C4orf3	GSM4909293	Human	Breast	IDC	9.45e-04	-1.36e-01	0.1581
401152	C4orf3	GSM4909294	Human	Breast	IDC	2.39e-04	2.24e-01	0.2022
401152	C4orf3	GSM4909296	Human	Breast	IDC	1.55e-02	7.94e-03	0.1524
401152	C4orf3	GSM4909297	Human	Breast	IDC	7.81e-10	-1.98e-01	0.1517
401152	C4orf3	GSM4909298	Human	Breast	IDC	1.41e-02	1.91e-01	0.1551
401152	C4orf3	GSM4909311	Human	Breast	IDC	4.52e-30	-4.01e-01	0.1534
401152	C4orf3	GSM4909312	Human	Breast	IDC	3.76e-06	-2.13e-01	0.1552
401152	C4orf3	GSM4909315	Human	Breast	IDC	1.62e-35	7.06e-01	0.21
401152	C4orf3	GSM4909316	Human	Breast	IDC	9.26e-10	4.33e-01	0.21
401152	C4orf3	GSM4909319	Human	Breast	IDC	8.96e-38	-3.52e-01	0.1563
401152	C4orf3	GSM4909320	Human	Breast	IDC	3.93e-06	-2.84e-01	0.1575
401152	C4orf3	GSM4909321	Human	Breast	IDC	4.35e-13	-3.78e-01	0.1559
401152	C4orf3	ctrl6	Human	Breast	Precancer	1.36e-28	8.54e-01	-0.0061
401152	C4orf3	brca1	Human	Breast	Precancer	1.36e-02	-2.91e-01	-0.0338
401152	C4orf3	brca2	Human	Breast	Precancer	3.12e-06	2.18e-02	-0.024
401152	C4orf3	brca3	Human	Breast	Precancer	2.10e-08	4.39e-01	-0.0263
401152	C4orf3	brca7	Human	Breast	Precancer	1.41e-09	8.33e-01	-0.009

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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
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:1904063	Endometrium	AEH	negative regulation of cation transmembrane transport	20/2100	102/18723	8.88e-03	4.82e-02	20
GO:19040623	Endometrium	AEH	regulation of cation transmembrane transport	55/2100	357/18723	9.18e-03	4.96e-02	55
GO:005109817	Endometrium	EEC	regulation of binding	83/2168	363/18723	6.72e-10	6.61e-08	83
GO:005110016	Endometrium	EEC	negative regulation of binding	35/2168	162/18723	1.85e-04	2.26e-03	35
GO:005105111	Endometrium	EEC	negative regulation of transport	80/2168	470/18723	2.53e-04	2.93e-03	80
GO:001095914	Endometrium	EEC	regulation of metal ion transport	70/2168	406/18723	4.12e-04	4.35e-03	70
GO:00347661	Endometrium	EEC	negative regulation of ion transmembrane transport	22/2168	109/18723	6.39e-03	3.76e-02	22
GO:005109825	Esophagus	HGIN	regulation of binding	78/2587	363/18723	3.73e-05	9.30e-04	78
GO:005110020	Esophagus	HGIN	negative regulation of binding	35/2587	162/18723	4.32e-03	3.84e-02	35
GO:0051098111	Esophagus	ESCC	regulation of binding	251/8552	363/18723	6.73e-20	8.46e-18	251
GO:0051100111	Esophagus	ESCC	negative regulation of binding	109/8552	162/18723	2.10e-08	4.03e-07	109
GO:005109812	Liver	Cirrhotic	regulation of binding	148/4634	363/18723	9.14e-12	5.97e-10	148
GO:00511006	Liver	Cirrhotic	negative regulation of binding	63/4634	162/18723	4.54e-05	5.31e-04	63
GO:00510514	Liver	Cirrhotic	negative regulation of transport	141/4634	470/18723	5.06e-03	2.62e-02	141
GO:005109822	Liver	HCC	regulation of binding	225/7958	363/18723	3.78e-14	2.37e-12	225
GO:005110012	Liver	HCC	negative regulation of binding	94/7958	162/18723	4.69e-05	4.50e-04	94
GO:005109832	Liver	Cyst	regulation of binding	21/496	363/18723	7.29e-04	1.98e-02	21
GO:00228983	Liver	Cyst	regulation of transmembrane transporter activity	17/496	278/18723	1.26e-03	3.10e-02	17
GO:00324094	Liver	Cyst	regulation of transporter activity	18/496	310/18723	1.64e-03	3.78e-02	18
GO:00324123	Liver	Cyst	regulation of ion transmembrane transporter activity	16/496	267/18723	2.12e-03	4.38e-02	16

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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

C4orf3

SNV

Missense_Mutation

novel

c.397G>A

p.Glu133Lys

p.E133K

Q8WVX3

protein_coding

tolerated_low_confidence(0.06)

possibly_damaging(0.497)

TCGA-A7-A6VY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

C4orf3

SNV

Missense_Mutation

c.452N>C

p.Arg151Pro

p.R151P

Q8WVX3

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.935)

TCGA-AN-A0XW-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

C4orf3

SNV

Missense_Mutation

c.353T>G

p.Leu118Arg

p.L118R

Q8WVX3

protein_coding

deleterious_low_confidence(0)

benign(0.003)

TCGA-AR-A2LE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

C4orf3

SNV

Missense_Mutation

c.383N>A

p.Arg128Gln

p.R128Q

Q8WVX3

protein_coding

tolerated_low_confidence(0.05)

benign(0)

TCGA-EK-A3GK-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

C4orf3

SNV

Missense_Mutation

c.591T>G

p.Phe197Leu

p.F197L

Q8WVX3

protein_coding

tolerated_low_confidence(0.27)

benign(0)

TCGA-AA-3510-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

C4orf3

SNV

Missense_Mutation

novel

c.349N>A

p.Glu117Lys

p.E117K

Q8WVX3

protein_coding

tolerated_low_confidence(0.12)

possibly_damaging(0.497)

TCGA-AZ-4315-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

C4orf3

insertion

Frame_Shift_Ins

rs760121305

c.593_594insT

p.Leu198PhefsTer20

p.L198Ffs*20

Q8WVX3

protein_coding

TCGA-A6-5661-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

C4orf3

SNV

Missense_Mutation

rs767655670

c.560T>C

p.Phe187Ser

p.F187S

Q8WVX3

protein_coding

deleterious_low_confidence(0)

possibly_damaging(0.466)

TCGA-A5-A0GP-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

C4orf3

SNV

Missense_Mutation

novel

c.473G>T

p.Arg158Met

p.R158M

Q8WVX3

protein_coding

deleterious_low_confidence(0)

benign(0.391)

TCGA-AP-A05O-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Chemotherapy

carboplatin

C4orf3

SNV

Missense_Mutation

rs772979807

c.88N>C

p.Tyr30His

p.Y30H

Q8WVX3

protein_coding

possibly_damaging(0.617)

TCGA-AX-A0J0-01

Endometrium

uterine corpus endometrioid carcinoma

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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