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: C3

Gene summary for C3

Gene summary.

Gene information	Species	Human
	Gene symbol	C3
	Gene ID	718
	Gene name	complement C3
	Gene Alias	AHUS5
	Cytomap	19p13.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	B4DR57

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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
718	C3	CA_HPV_1	Human	Cervix	CC	2.81e-16	-6.77e-01	0.0264
718	C3	CA_HPV_2	Human	Cervix	CC	5.69e-14	-6.93e-01	0.0391
718	C3	CA_HPV_3	Human	Cervix	CC	1.59e-11	-6.38e-01	0.0414
718	C3	HSIL_HPV_2	Human	Cervix	HSIL_HPV	1.15e-05	-3.77e-01	0.0208
718	C3	N_HPV_1	Human	Cervix	N_HPV	5.84e-08	-5.69e-01	0.0079
718	C3	N_HPV_2	Human	Cervix	N_HPV	7.40e-09	-5.13e-01	-0.0131
718	C3	CCI_1	Human	Cervix	CC	4.72e-05	-7.56e-01	0.528
718	C3	CCI_2	Human	Cervix	CC	2.04e-06	-7.76e-01	0.5249
718	C3	CCII_1	Human	Cervix	CC	1.08e-10	-7.53e-01	0.3249
718	C3	Tumor	Human	Cervix	CC	2.51e-17	-6.99e-01	0.1241
718	C3	sample1	Human	Cervix	CC	1.27e-03	-8.83e-02	0.0959
718	C3	sample3	Human	Cervix	CC	1.11e-15	-6.38e-01	0.1387
718	C3	L1	Human	Cervix	CC	5.63e-10	-7.17e-01	0.0802
718	C3	T1	Human	Cervix	CC	7.61e-07	3.87e-02	0.0918
718	C3	T3	Human	Cervix	CC	1.15e-14	-6.42e-01	0.1389
718	C3	AEH-subject1	Human	Endometrium	AEH	7.07e-65	1.25e+00	-0.3059
718	C3	AEH-subject2	Human	Endometrium	AEH	1.57e-48	1.18e+00	-0.2525
718	C3	AEH-subject3	Human	Endometrium	AEH	1.88e-35	8.97e-01	-0.2576
718	C3	AEH-subject4	Human	Endometrium	AEH	1.17e-22	7.89e-01	-0.2657
718	C3	EEC-subject2	Human	Endometrium	EEC	2.38e-40	1.01e+00	-0.2607

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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
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
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
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:00460349	Breast	Precancer	ATP metabolic process	82/1080	277/18723	1.94e-36	5.19e-33	82
GO:00971939	Breast	Precancer	intrinsic apoptotic signaling pathway	59/1080	288/18723	8.07e-18	3.60e-15	59
GO:20012339	Breast	Precancer	regulation of apoptotic signaling pathway	65/1080	356/18723	7.70e-17	3.17e-14	65
GO:20012429	Breast	Precancer	regulation of intrinsic apoptotic signaling pathway	41/1080	164/18723	6.48e-16	2.31e-13	41
GO:19026008	Breast	Precancer	proton transmembrane transport	39/1080	157/18723	4.18e-15	1.18e-12	39
GO:00069799	Breast	Precancer	response to oxidative stress	70/1080	446/18723	1.59e-14	4.26e-12	70
GO:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00159857	Breast	Precancer	energy coupled proton transport, down electrochemical gradient	16/1080	26/18723	4.15e-14	9.65e-12	16
GO:00159867	Breast	Precancer	ATP synthesis coupled proton transport	16/1080	26/18723	4.15e-14	9.65e-12	16
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:00083809	Breast	Precancer	RNA splicing	65/1080	434/18723	1.27e-12	2.53e-10	65
GO:00067547	Breast	Precancer	ATP biosynthetic process	21/1080	57/18723	2.31e-12	4.26e-10	21
GO:00434849	Breast	Precancer	regulation of RNA splicing	34/1080	148/18723	2.66e-12	4.75e-10	34
GO:20001169	Breast	Precancer	regulation of cysteine-type endopeptidase activity	43/1080	235/18723	1.30e-11	1.83e-09	43
GO:00068398	Breast	Precancer	mitochondrial transport	45/1080	254/18723	1.37e-11	1.88e-09	45
GO:00092067	Breast	Precancer	purine ribonucleoside triphosphate biosynthetic process	22/1080	68/18723	1.41e-11	1.88e-09	22
GO:00432819	Breast	Precancer	regulation of cysteine-type endopeptidase activity involved in apoptotic process	40/1080	209/18723	1.59e-11	2.07e-09	40
GO:00091457	Breast	Precancer	purine nucleoside triphosphate biosynthetic process	22/1080	69/18723	1.95e-11	2.43e-09	22
GO:00485459	Breast	Precancer	response to steroid hormone	53/1080	339/18723	3.07e-11	3.66e-09	53
GO:00092017	Breast	Precancer	ribonucleoside triphosphate biosynthetic process	22/1080	74/18723	9.18e-11	1.00e-08	22

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0517120	Cervix	CC	Coronavirus disease - COVID-19	111/1267	232/8465	1.82e-33	5.90e-31	3.49e-31	111
hsa0513120	Cervix	CC	Shigellosis	69/1267	247/8465	7.64e-08	1.03e-06	6.10e-07	69
hsa0414520	Cervix	CC	Phagosome	47/1267	152/8465	3.95e-07	4.26e-06	2.52e-06	47
hsa0513416	Cervix	CC	Legionellosis	20/1267	57/8465	1.29e-04	8.19e-04	4.85e-04	20
hsa05152	Cervix	CC	Tuberculosis	42/1267	180/8465	1.78e-03	7.21e-03	4.26e-03	42
hsa051337	Cervix	CC	Pertussis	21/1267	76/8465	3.08e-03	1.19e-02	7.03e-03	21
hsa05171110	Cervix	CC	Coronavirus disease - COVID-19	111/1267	232/8465	1.82e-33	5.90e-31	3.49e-31	111
hsa05131110	Cervix	CC	Shigellosis	69/1267	247/8465	7.64e-08	1.03e-06	6.10e-07	69
hsa04145110	Cervix	CC	Phagosome	47/1267	152/8465	3.95e-07	4.26e-06	2.52e-06	47
hsa0513417	Cervix	CC	Legionellosis	20/1267	57/8465	1.29e-04	8.19e-04	4.85e-04	20
hsa051521	Cervix	CC	Tuberculosis	42/1267	180/8465	1.78e-03	7.21e-03	4.26e-03	42
hsa0513312	Cervix	CC	Pertussis	21/1267	76/8465	3.08e-03	1.19e-02	7.03e-03	21
hsa0517125	Cervix	HSIL_HPV	Coronavirus disease - COVID-19	91/459	232/8465	2.14e-56	3.13e-54	2.53e-54	91
hsa051504	Cervix	HSIL_HPV	Staphylococcus aureus infection	21/459	96/8465	2.93e-08	1.43e-06	1.16e-06	21
hsa0414523	Cervix	HSIL_HPV	Phagosome	27/459	152/8465	3.58e-08	1.50e-06	1.21e-06	27
hsa0514022	Cervix	HSIL_HPV	Leishmaniasis	18/459	77/8465	9.82e-08	3.14e-06	2.54e-06	18
hsa0513423	Cervix	HSIL_HPV	Legionellosis	12/459	57/8465	4.24e-05	6.21e-04	5.02e-04	12
hsa05322	Cervix	HSIL_HPV	Systemic lupus erythematosus	19/459	137/8465	1.40e-04	1.74e-03	1.40e-03	19
hsa0513125	Cervix	HSIL_HPV	Shigellosis	27/459	247/8465	3.78e-04	3.49e-03	2.82e-03	27
hsa051522	Cervix	HSIL_HPV	Tuberculosis	19/459	180/8465	3.99e-03	2.39e-02	1.93e-02	19

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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
C3	C3AR1	C3_C3AR1	COMPLEMENT	Breast	DCIS
C3	ITGAM_ITGB2	C3_ITGAM_ITGB2	COMPLEMENT	Breast	DCIS
C3	ITGAX_ITGB2	C3_ITGAX_ITGB2	COMPLEMENT	Breast	DCIS
PTN	SDC3	PTN_SDC3	PTN	Breast	DCIS
ANGPTL4	SDC3	ANGPTL4_SDC3	ANGPTL	Breast	DCIS
C3	C3AR1	C3_C3AR1	COMPLEMENT	Breast	Healthy
C3	ITGAM_ITGB2	C3_ITGAM_ITGB2	COMPLEMENT	Breast	Healthy
C3	ITGAX_ITGB2	C3_ITGAX_ITGB2	COMPLEMENT	Breast	Healthy
ANGPTL4	SDC3	ANGPTL4_SDC3	ANGPTL	Breast	IDC
C3	C3AR1	C3_C3AR1	COMPLEMENT	Breast	IDC
C3	ITGAM_ITGB2	C3_ITGAM_ITGB2	COMPLEMENT	Breast	IDC
C3	ITGAX_ITGB2	C3_ITGAX_ITGB2	COMPLEMENT	Breast	IDC
DSG2	DSC3	DSG2_DSC3	DESMOSOME	Breast	IDC
C3	C3AR1	C3_C3AR1	COMPLEMENT	Cervix	ADJ
C3	ITGAM_ITGB2	C3_ITGAM_ITGB2	COMPLEMENT	Cervix	ADJ
C3	ITGAX_ITGB2	C3_ITGAX_ITGB2	COMPLEMENT	Cervix	ADJ
PTN	SDC3	PTN_SDC3	PTN	Cervix	CC
DSG2	DSC3	DSG2_DSC3	DESMOSOME	Cervix	CC
ANGPTL4	SDC3	ANGPTL4_SDC3	ANGPTL	Cervix	CC
C3	C3AR1	C3_C3AR1	COMPLEMENT	Cervix	CC

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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

SNV

Missense_Mutation

novel

c.2800N>C

p.Glu934Gln

p.E934Q

P01024

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-A2-A0CL-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

SNV

Missense_Mutation

c.1052C>T

p.Ser351Phe

p.S351F

P01024

protein_coding

deleterious(0)

probably_damaging(0.99)

TCGA-A2-A0SY-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

arimidex

SNV

Missense_Mutation

rs199911426

c.4594N>T

p.Arg1532Trp

p.R1532W

P01024

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

SNV

Missense_Mutation

c.4276N>A

p.Asp1426Asn

p.D1426N

P01024

protein_coding

deleterious(0.01)

probably_damaging(0.929)

TCGA-A8-A0A7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SNV

Missense_Mutation

c.3803N>G

p.Ser1268Cys

p.S1268C

P01024

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SNV

Missense_Mutation

c.1376N>T

p.Ser459Leu

p.S459L

P01024

protein_coding

tolerated(0.09)

possibly_damaging(0.599)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SNV

Missense_Mutation

novel

c.4408N>A

p.Glu1470Lys

p.E1470K

P01024

protein_coding

deleterious(0)

benign(0.188)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SNV

Missense_Mutation

novel

c.3118G>C

p.Glu1040Gln

p.E1040Q

P01024

protein_coding

tolerated(0.11)

benign(0.063)

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

SNV

Missense_Mutation

novel

c.2782N>G

p.Ser928Ala

p.S928A

P01024

protein_coding

tolerated(0.22)

benign(0.007)

TCGA-BH-A0DG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

SNV

Missense_Mutation

c.1452N>T

p.Glu484Asp

p.E484D

P01024

protein_coding

tolerated(0.52)

benign(0.003)

TCGA-D8-A1XG-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

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
718	C3	PROTEASE INHIBITOR, DRUGGABLE GENOME, CELL SURFACE		Imprime PGG immunotherapeutic
718	C3	PROTEASE INHIBITOR, DRUGGABLE GENOME, CELL SURFACE		POT-4		19025129
718	C3	PROTEASE INHIBITOR, DRUGGABLE GENOME, CELL SURFACE		COMPSTATIN	COMPSTATIN	25494040
718	C3	PROTEASE INHIBITOR, DRUGGABLE GENOME, CELL SURFACE		POT-4
718	C3	PROTEASE INHIBITOR, DRUGGABLE GENOME, CELL SURFACE		APL-2	PEGCETACOPLAN
718	C3	PROTEASE INHIBITOR, DRUGGABLE GENOME, CELL SURFACE		clozapine	CLOZAPINE	26503818

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