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: SEMA3C

Gene summary for SEMA3C

Gene summary.

Gene information	Species	Human
	Gene symbol	SEMA3C
	Gene ID	10512
	Gene name	semaphorin 3C
	Gene Alias	SEMAE
	Cytomap	7q21.11
	Gene Type	protein-coding
	GO ID	GO:0000902
	UniProtAcc	Q99985

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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
10512	SEMA3C	CCI_1	Human	Cervix	CC	1.26e-04	1.29e+00	0.528
10512	SEMA3C	CCI_3	Human	Cervix	CC	1.73e-23	1.17e+00	0.516
10512	SEMA3C	HTA11_3410_2000001011	Human	Colorectum	AD	2.08e-10	-4.35e-01	0.0155
10512	SEMA3C	HTA11_2487_2000001011	Human	Colorectum	SER	2.70e-05	-4.77e-01	-0.1808
10512	SEMA3C	HTA11_2951_2000001011	Human	Colorectum	AD	6.06e-03	-6.39e-01	0.0216
10512	SEMA3C	HTA11_3361_2000001011	Human	Colorectum	AD	3.93e-07	-6.25e-01	-0.1207
10512	SEMA3C	HTA11_83_2000001011	Human	Colorectum	SER	7.50e-04	-5.56e-01	-0.1526
10512	SEMA3C	HTA11_5212_2000001011	Human	Colorectum	AD	2.33e-02	-5.92e-01	-0.2061
10512	SEMA3C	HTA11_8622_2000001021	Human	Colorectum	SER	2.06e-06	-7.70e-01	0.0528
10512	SEMA3C	HTA11_10711_2000001011	Human	Colorectum	AD	7.74e-06	-4.91e-01	0.0338
10512	SEMA3C	HTA11_7696_3000711011	Human	Colorectum	AD	2.13e-02	-3.60e-01	0.0674
10512	SEMA3C	HTA11_99999965104_69814	Human	Colorectum	MSS	8.89e-04	6.44e-01	0.281
10512	SEMA3C	HTA11_99999974143_84620	Human	Colorectum	MSS	8.97e-19	-6.71e-01	0.3005
10512	SEMA3C	A002-C-010	Human	Colorectum	FAP	5.15e-05	2.32e-01	0.242
10512	SEMA3C	A015-C-203	Human	Colorectum	FAP	1.35e-27	-4.18e-01	-0.1294
10512	SEMA3C	A015-C-204	Human	Colorectum	FAP	6.00e-08	-4.01e-01	-0.0228
10512	SEMA3C	A014-C-040	Human	Colorectum	FAP	1.45e-02	-2.75e-01	-0.1184
10512	SEMA3C	A002-C-201	Human	Colorectum	FAP	1.30e-11	-2.60e-01	0.0324
10512	SEMA3C	A002-C-203	Human	Colorectum	FAP	4.93e-02	2.19e-01	0.2786
10512	SEMA3C	A001-C-119	Human	Colorectum	FAP	8.34e-08	-3.31e-01	-0.1557

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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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
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:00016679	Cervix	CC	ameboidal-type cell migration	110/2311	475/18723	2.66e-11	6.36e-09	110
GO:00109757	Cervix	CC	regulation of neuron projection development	88/2311	445/18723	4.26e-06	1.09e-04	88
GO:00509203	Cervix	CC	regulation of chemotaxis	51/2311	223/18723	8.03e-06	1.86e-04	51
GO:00160498	Cervix	CC	cell growth	92/2311	482/18723	1.16e-05	2.49e-04	92
GO:00325359	Cervix	CC	regulation of cellular component size	76/2311	383/18723	1.66e-05	3.21e-04	76
GO:00615647	Cervix	CC	axon development	89/2311	467/18723	1.71e-05	3.27e-04	89
GO:004873210	Cervix	CC	gland development	84/2311	436/18723	1.93e-05	3.54e-04	84
GO:00400133	Cervix	CC	negative regulation of locomotion	76/2311	391/18723	3.47e-05	5.60e-04	76
GO:00488634	Cervix	CC	stem cell differentiation	46/2311	206/18723	4.11e-05	6.36e-04	46
GO:00605375	Cervix	CC	muscle tissue development	76/2311	403/18723	9.76e-05	1.27e-03	76
GO:00074097	Cervix	CC	axonogenesis	78/2311	418/18723	1.14e-04	1.43e-03	78
GO:00015588	Cervix	CC	regulation of cell growth	77/2311	414/18723	1.40e-04	1.70e-03	77
GO:00147064	Cervix	CC	striated muscle tissue development	72/2311	384/18723	1.76e-04	2.07e-03	72
GO:00507705	Cervix	CC	regulation of axonogenesis	34/2311	154/18723	4.87e-04	4.76e-03	34
GO:00313456	Cervix	CC	negative regulation of cell projection organization	39/2311	186/18723	5.86e-04	5.57e-03	39
GO:00321022	Cervix	CC	negative regulation of response to external stimulus	75/2311	420/18723	5.96e-04	5.61e-03	75
GO:00486386	Cervix	CC	regulation of developmental growth	61/2311	330/18723	7.69e-04	6.85e-03	61
GO:00605606	Cervix	CC	developmental growth involved in morphogenesis	46/2311	234/18723	8.82e-04	7.63e-03	46
GO:00519603	Cervix	CC	regulation of nervous system development	77/2311	443/18723	1.13e-03	9.30e-03	77
GO:00507676	Cervix	CC	regulation of neurogenesis	65/2311	364/18723	1.33e-03	1.05e-02	65

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa043609	Cervix	CC	Axon guidance	47/1267	182/8465	8.13e-05	5.38e-04	3.18e-04	47
hsa0436012	Cervix	CC	Axon guidance	47/1267	182/8465	8.13e-05	5.38e-04	3.18e-04	47
hsa04360	Colorectum	AD	Axon guidance	61/2092	182/8465	4.36e-03	2.17e-02	1.38e-02	61
hsa043601	Colorectum	AD	Axon guidance	61/2092	182/8465	4.36e-03	2.17e-02	1.38e-02	61
hsa043602	Colorectum	MSS	Axon guidance	54/1875	182/8465	1.03e-02	3.69e-02	2.26e-02	54
hsa043603	Colorectum	MSS	Axon guidance	54/1875	182/8465	1.03e-02	3.69e-02	2.26e-02	54
hsa043604	Colorectum	FAP	Axon guidance	47/1404	182/8465	9.09e-04	5.20e-03	3.16e-03	47
hsa043605	Colorectum	FAP	Axon guidance	47/1404	182/8465	9.09e-04	5.20e-03	3.16e-03	47
hsa0436010	Endometrium	AEH	Axon guidance	39/1197	182/8465	4.47e-03	2.46e-02	1.80e-02	39
hsa0436013	Endometrium	AEH	Axon guidance	39/1197	182/8465	4.47e-03	2.46e-02	1.80e-02	39
hsa0436022	Endometrium	EEC	Axon guidance	39/1237	182/8465	7.78e-03	3.66e-02	2.73e-02	39
hsa0436032	Endometrium	EEC	Axon guidance	39/1237	182/8465	7.78e-03	3.66e-02	2.73e-02	39
hsa0436016	Esophagus	ESCC	Axon guidance	108/4205	182/8465	5.13e-03	1.30e-02	6.67e-03	108
hsa0436017	Esophagus	ESCC	Axon guidance	108/4205	182/8465	5.13e-03	1.30e-02	6.67e-03	108
hsa0436014	Oral cavity	OSCC	Axon guidance	97/3704	182/8465	5.59e-03	1.33e-02	6.76e-03	97
hsa0436015	Oral cavity	OSCC	Axon guidance	97/3704	182/8465	5.59e-03	1.33e-02	6.76e-03	97

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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
SEMA3C	NRP1_PLXNA4	SEMA3C_NRP1_PLXNA4	SEMA3	Breast	DCIS
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Breast	DCIS
SEMA3C	PLXND1	SEMA3C_PLXND1	SEMA3	Breast	DCIS
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	Breast	Healthy
SEMA3C	NRP2_PLXNA2	SEMA3C_NRP2_PLXNA2	SEMA3	Breast	Healthy
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Breast	Healthy
SEMA3C	PLXND1	SEMA3C_PLXND1	SEMA3	Breast	Healthy
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Cervix	ADJ
SEMA3C	PLXND1	SEMA3C_PLXND1	SEMA3	Cervix	ADJ
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	Cervix	CC
SEMA3C	NRP2_PLXNA2	SEMA3C_NRP2_PLXNA2	SEMA3	Cervix	CC
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Cervix	CC
SEMA3C	PLXND1	SEMA3C_PLXND1	SEMA3	Cervix	CC
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	Cervix	Precancer
SEMA3C	PLXND1	SEMA3C_PLXND1	SEMA3	Cervix	Precancer
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	CRC	AD
SEMA3C	NRP2_PLXNA2	SEMA3C_NRP2_PLXNA2	SEMA3	CRC	AD
SEMA3C	NRP1_NRP2	SEMA3C_NRP1_NRP2	SEMA3	CRC	AD
SEMA3C	PLXND1	SEMA3C_PLXND1	SEMA3	CRC	AD
SEMA3C	NRP1_PLXNA2	SEMA3C_NRP1_PLXNA2	SEMA3	CRC	ADJ

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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

SEMA3C

SNV

Missense_Mutation

novel

c.2225N>A

p.Arg742Lys

p.R742K

Q99985

protein_coding

deleterious(0.02)

possibly_damaging(0.9)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

SEMA3C

SNV

Missense_Mutation

c.534N>A

p.Met178Ile

p.M178I

Q99985

protein_coding

deleterious(0.01)

benign(0.215)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SEMA3C

SNV

Missense_Mutation

novel

c.280N>A

p.Ser94Thr

p.S94T

Q99985

protein_coding

tolerated(0.58)

benign(0.1)

TCGA-AC-A8OP-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SEMA3C

SNV

Missense_Mutation

c.401N>T

p.Ala134Val

p.A134V

Q99985

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-AO-A124-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

SEMA3C

SNV

Missense_Mutation

c.400N>A

p.Ala134Thr

p.A134T

Q99985

protein_coding

deleterious(0.01)

probably_damaging(0.998)

TCGA-AO-A124-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

SEMA3C

SNV

Missense_Mutation

rs769829474

c.620C>T

p.Ala207Val

p.A207V

Q99985

protein_coding

tolerated(0.22)

benign(0.292)

TCGA-BH-A0EE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

SEMA3C

SNV

Missense_Mutation

c.2156G>A

p.Gly719Glu

p.G719E

Q99985

protein_coding

tolerated(1)

benign(0.001)

TCGA-D8-A1J8-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

nolvadex

SEMA3C

SNV

Missense_Mutation

novel

c.314N>C

p.Gly105Ala

p.G105A

Q99985

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-GI-A2C8-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

Adriamycin

SEMA3C

SNV

Missense_Mutation

novel

c.251A>C

p.Gln84Pro

p.Q84P

Q99985

protein_coding

deleterious(0)

possibly_damaging(0.646)

TCGA-C5-A7X8-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SEMA3C

SNV

Missense_Mutation

novel

c.181N>A

p.Glu61Lys

p.E61K

Q99985

protein_coding

deleterious(0)

probably_damaging(0.976)

TCGA-EX-A1H6-01

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
10512	SEMA3C	CLINICALLY ACTIONABLE, DRUGGABLE GENOME		irinotecan	IRINOTECAN	22664479

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