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: CS

Gene summary for CS

Gene summary.

Gene information	Species	Human
	Gene symbol	CS
	Gene ID	1431
	Gene name	citrate synthase
	Gene Alias	CS
	Cytomap	12q13.3
	Gene Type	protein-coding
	GO ID	GO:0005975
	UniProtAcc	A0A024RB75

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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
1431	CS	HTA11_2487_2000001011	Human	Colorectum	SER	2.84e-05	3.73e-01	-0.1808
1431	CS	HTA11_1938_2000001011	Human	Colorectum	AD	2.11e-06	4.73e-01	-0.0811
1431	CS	HTA11_78_2000001011	Human	Colorectum	AD	1.04e-13	6.24e-01	-0.1088
1431	CS	HTA11_347_2000001011	Human	Colorectum	AD	2.50e-28	8.78e-01	-0.1954
1431	CS	HTA11_83_2000001011	Human	Colorectum	SER	1.52e-13	7.87e-01	-0.1526
1431	CS	HTA11_1391_2000001011	Human	Colorectum	AD	7.79e-08	4.96e-01	-0.059
1431	CS	HTA11_2992_2000001011	Human	Colorectum	SER	1.92e-07	9.02e-01	-0.1706
1431	CS	HTA11_5212_2000001011	Human	Colorectum	AD	2.63e-09	7.38e-01	-0.2061
1431	CS	HTA11_5216_2000001011	Human	Colorectum	SER	6.87e-03	5.81e-01	-0.1462
1431	CS	HTA11_546_2000001011	Human	Colorectum	AD	6.82e-04	5.04e-01	-0.0842
1431	CS	HTA11_7862_2000001011	Human	Colorectum	AD	3.03e-03	2.82e-01	-0.0179
1431	CS	HTA11_866_3004761011	Human	Colorectum	AD	4.55e-05	3.86e-01	0.096
1431	CS	HTA11_4255_2000001011	Human	Colorectum	SER	1.84e-03	5.03e-01	0.0446
1431	CS	HTA11_10623_2000001011	Human	Colorectum	AD	7.49e-06	5.48e-01	-0.0177
1431	CS	HTA11_6801_2000001011	Human	Colorectum	SER	1.53e-09	9.32e-01	0.0171
1431	CS	HTA11_7696_3000711011	Human	Colorectum	AD	4.70e-08	5.56e-01	0.0674
1431	CS	HTA11_7469_2000001011	Human	Colorectum	AD	1.09e-04	7.52e-01	-0.0124
1431	CS	HTA11_99999970781_79442	Human	Colorectum	MSS	1.81e-07	6.35e-01	0.294
1431	CS	HTA11_99999965062_69753	Human	Colorectum	MSI-H	1.77e-05	1.08e+00	0.3487
1431	CS	HTA11_99999965104_69814	Human	Colorectum	MSS	2.19e-21	7.57e-01	0.281

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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
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:00061199	Breast	Precancer	oxidative phosphorylation	53/1080	141/18723	1.15e-29	2.04e-26	53
GO:00090608	Breast	Precancer	aerobic respiration	58/1080	189/18723	5.69e-27	7.62e-24	58
GO:00060918	Breast	Precancer	generation of precursor metabolites and energy	94/1080	490/18723	1.54e-25	1.64e-22	94
GO:00453338	Breast	Precancer	cellular respiration	59/1080	230/18723	5.97e-23	5.32e-20	59
GO:00159808	Breast	Precancer	energy derivation by oxidation of organic compounds	70/1080	318/18723	8.33e-23	6.37e-20	70
GO:00196468	Breast	Precancer	aerobic electron transport chain	34/1080	87/18723	3.95e-20	2.64e-17	34
GO:00427738	Breast	Precancer	ATP synthesis coupled electron transport	35/1080	95/18723	1.08e-19	5.76e-17	35
GO:00427758	Breast	Precancer	mitochondrial ATP synthesis coupled electron transport	35/1080	95/18723	1.08e-19	5.76e-17	35
GO:20012339	Breast	Precancer	regulation of apoptotic signaling pathway	65/1080	356/18723	7.70e-17	3.17e-14	65
GO:00229048	Breast	Precancer	respiratory electron transport chain	35/1080	114/18723	8.51e-17	3.26e-14	35
GO:00229008	Breast	Precancer	electron transport chain	42/1080	175/18723	1.37e-15	4.59e-13	42
GO:00525479	Breast	Precancer	regulation of peptidase activity	71/1080	461/18723	2.72e-14	6.94e-12	71
GO:00525489	Breast	Precancer	regulation of endopeptidase activity	67/1080	432/18723	1.06e-13	2.36e-11	67
GO:00064578	Breast	Precancer	protein folding	43/1080	212/18723	3.48e-13	7.45e-11	43
GO:00064138	Breast	Precancer	translational initiation	30/1080	118/18723	3.23e-12	5.58e-10	30
GO:00064179	Breast	Precancer	regulation of translation	67/1080	468/18723	4.71e-12	7.64e-10	67
GO:20001169	Breast	Precancer	regulation of cysteine-type endopeptidase activity	43/1080	235/18723	1.30e-11	1.83e-09	43
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:00160329	Breast	Precancer	viral process	58/1080	415/18723	3.42e-10	3.16e-08	58

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa01200	Colorectum	AD	Carbon metabolism	55/2092	115/8465	5.53e-08	8.42e-07	5.37e-07	55
hsa00020	Colorectum	AD	Citrate cycle (TCA cycle)	20/2092	30/8465	1.43e-06	1.77e-05	1.13e-05	20
hsa00630	Colorectum	AD	Glyoxylate and dicarboxylate metabolism	14/2092	30/8465	7.25e-03	2.97e-02	1.89e-02	14
hsa01230	Colorectum	AD	Biosynthesis of amino acids	28/2092	75/8465	9.99e-03	3.89e-02	2.48e-02	28
hsa012001	Colorectum	AD	Carbon metabolism	55/2092	115/8465	5.53e-08	8.42e-07	5.37e-07	55
hsa000201	Colorectum	AD	Citrate cycle (TCA cycle)	20/2092	30/8465	1.43e-06	1.77e-05	1.13e-05	20
hsa006301	Colorectum	AD	Glyoxylate and dicarboxylate metabolism	14/2092	30/8465	7.25e-03	2.97e-02	1.89e-02	14
hsa012301	Colorectum	AD	Biosynthesis of amino acids	28/2092	75/8465	9.99e-03	3.89e-02	2.48e-02	28
hsa012002	Colorectum	SER	Carbon metabolism	40/1580	115/8465	2.77e-05	3.41e-04	2.47e-04	40
hsa012302	Colorectum	SER	Biosynthesis of amino acids	23/1580	75/8465	8.11e-03	4.14e-02	3.01e-02	23
hsa012003	Colorectum	SER	Carbon metabolism	40/1580	115/8465	2.77e-05	3.41e-04	2.47e-04	40
hsa012303	Colorectum	SER	Biosynthesis of amino acids	23/1580	75/8465	8.11e-03	4.14e-02	3.01e-02	23
hsa012004	Colorectum	MSS	Carbon metabolism	43/1875	115/8465	1.37e-04	1.17e-03	7.19e-04	43
hsa012005	Colorectum	MSS	Carbon metabolism	43/1875	115/8465	1.37e-04	1.17e-03	7.19e-04	43
hsa006302	Colorectum	MSI-H	Glyoxylate and dicarboxylate metabolism	8/797	30/8465	5.34e-03	4.94e-02	4.14e-02	8
hsa006303	Colorectum	MSI-H	Glyoxylate and dicarboxylate metabolism	8/797	30/8465	5.34e-03	4.94e-02	4.14e-02	8
hsa012006	Colorectum	FAP	Carbon metabolism	38/1404	115/8465	1.04e-05	1.44e-04	8.76e-05	38
hsa000206	Colorectum	FAP	Citrate cycle (TCA cycle)	14/1404	30/8465	1.16e-04	1.02e-03	6.21e-04	14
hsa012007	Colorectum	FAP	Carbon metabolism	38/1404	115/8465	1.04e-05	1.44e-04	8.76e-05	38
hsa000207	Colorectum	FAP	Citrate cycle (TCA cycle)	14/1404	30/8465	1.16e-04	1.02e-03	6.21e-04	14

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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
CSF1	CSF1R	CSF1_CSF1R	CSF	Breast	DCIS
CSF3	CSF3R	CSF3_CSF3R	CSF3	Breast	Healthy
CSF3	CSF3R	CSF3_CSF3R	CSF3	Cervix	ADJ
ULBP1	KLRK1_HCST	ULBP1_KLRK1_HCST	NKG2D	Cervix	ADJ
CSF1	CSF1R	CSF1_CSF1R	CSF	Cervix	ADJ
CSF3	CSF3R	CSF3_CSF3R	CSF3	Cervix	CC
IL34	CSF1R	IL34_CSF1R	CSF	Cervix	CC
CSF1	CSF1R	CSF1_CSF1R	CSF	Cervix	CC
CSF3	CSF3R	CSF3_CSF3R	CSF3	Cervix	Healthy
CSF1	CSF1R	CSF1_CSF1R	CSF	Cervix	Precancer
IL34	CSF1R	IL34_CSF1R	CSF	CRC	AD
CSF1	CSF1R	CSF1_CSF1R	CSF	CRC	AD
CSF1	CSF1R	CSF1_CSF1R	CSF	CRC	ADJ
CSF1	CSF1R	CSF1_CSF1R	CSF	CRC	MSI-H
CSF1	CSF1R	CSF1_CSF1R	CSF	CRC	SER
CSF1	CSF1R	CSF1_CSF1R	CSF	Endometrium	ADJ
CSF1	CSF1R	CSF1_CSF1R	CSF	Endometrium	AEH
CSF3	CSF3R	CSF3_CSF3R	CSF3	Endometrium	EEC
CSF1	CSF1R	CSF1_CSF1R	CSF	Endometrium	EEC
CSF1	CSF1R	CSF1_CSF1R	CSF	Endometrium	Healthy

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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

c.964N>C

p.Asp322His

p.D322H

O75390

protein_coding

tolerated(0.05)

benign(0.021)

TCGA-A2-A0CX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

SNV

Missense_Mutation

novel

c.1363N>C

p.Glu455Gln

p.E455Q

O75390

protein_coding

tolerated(0.18)

benign(0.04)

TCGA-AC-A5XS-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

femara

SNV

Missense_Mutation

novel

c.820N>C

p.Thr274Pro

p.T274P

O75390

protein_coding

deleterious(0.03)

probably_damaging(0.976)

TCGA-D8-A1JM-01

Breast

breast invasive carcinoma

Female

<65

I/II

ChemotherapyHormone Therapy

doxorubicine

insertion

Frame_Shift_Ins

novel

c.323_324insCAGTCAGTCAT

p.Lys109SerfsTer20

p.K109Sfs*20

O75390

protein_coding

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

insertion

In_Frame_Ins

novel

c.321_322insTCTAGGAGGACTAAT

p.Lys107_Ala108insSerArgArgThrAsn

p.K107_A108insSRRTN

O75390

protein_coding

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

SNV

Missense_Mutation

novel

c.1374G>T

p.Met458Ile

p.M458I

O75390

protein_coding

tolerated(0.31)

benign(0)

TCGA-VS-A9UP-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SNV

Missense_Mutation

c.91N>G

p.Thr31Ala

p.T31A

O75390

protein_coding

tolerated(0.54)

benign(0)

TCGA-A6-2686-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

SNV

Missense_Mutation

c.1327N>T

p.Gly443Cys

p.G443C

O75390

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AD-5900-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

SNV

Missense_Mutation

rs779289848

c.274N>T

p.Arg92Cys

p.R92C

O75390

protein_coding

deleterious(0.03)

benign(0.154)

TCGA-AZ-4615-01

Colorectum

colon adenocarcinoma

Male

>=65

III/IV

Chemotherapy

xeloda

SNV

Missense_Mutation

rs140943640

c.370G>A

p.Val124Ile

p.V124I

O75390

protein_coding

tolerated(0.08)

benign(0.011)

TCGA-CK-4951-01

Colorectum

colon adenocarcinoma

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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