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: KDM4C

Gene summary for KDM4C

Gene summary.

Gene information	Species	Human
	Gene symbol	KDM4C
	Gene ID	23081
	Gene name	lysine demethylase 4C
	Gene Alias	GASC1
	Cytomap	9p24.1
	Gene Type	protein-coding
	GO ID	GO:0006139
	UniProtAcc	Q9H3R0

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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
23081	KDM4C	CCI_1	Human	Cervix	CC	5.66e-08	7.48e-01	0.528
23081	KDM4C	CCI_2	Human	Cervix	CC	5.25e-17	1.31e+00	0.5249
23081	KDM4C	CCI_3	Human	Cervix	CC	3.24e-13	7.70e-01	0.516
23081	KDM4C	HTA11_3410_2000001011	Human	Colorectum	AD	1.89e-53	-1.14e+00	0.0155
23081	KDM4C	HTA11_2487_2000001011	Human	Colorectum	SER	1.84e-26	-9.74e-01	-0.1808
23081	KDM4C	HTA11_2951_2000001011	Human	Colorectum	AD	2.44e-09	-1.13e+00	0.0216
23081	KDM4C	HTA11_1938_2000001011	Human	Colorectum	AD	1.55e-19	-9.02e-01	-0.0811
23081	KDM4C	HTA11_78_2000001011	Human	Colorectum	AD	3.59e-16	-7.77e-01	-0.1088
23081	KDM4C	HTA11_347_2000001011	Human	Colorectum	AD	2.52e-17	-6.47e-01	-0.1954
23081	KDM4C	HTA11_411_2000001011	Human	Colorectum	SER	5.97e-03	-8.29e-01	-0.2602
23081	KDM4C	HTA11_2112_2000001011	Human	Colorectum	SER	4.79e-06	-9.56e-01	-0.2196
23081	KDM4C	HTA11_3361_2000001011	Human	Colorectum	AD	3.63e-27	-1.13e+00	-0.1207
23081	KDM4C	HTA11_83_2000001011	Human	Colorectum	SER	5.04e-21	-1.06e+00	-0.1526
23081	KDM4C	HTA11_696_2000001011	Human	Colorectum	AD	6.01e-60	-1.03e+00	-0.1464
23081	KDM4C	HTA11_866_2000001011	Human	Colorectum	AD	1.05e-51	-1.00e+00	-0.1001
23081	KDM4C	HTA11_1391_2000001011	Human	Colorectum	AD	5.48e-32	-9.82e-01	-0.059
23081	KDM4C	HTA11_2992_2000001011	Human	Colorectum	SER	4.67e-08	-9.45e-01	-0.1706
23081	KDM4C	HTA11_5212_2000001011	Human	Colorectum	AD	1.40e-10	-1.06e+00	-0.2061
23081	KDM4C	HTA11_5216_2000001011	Human	Colorectum	SER	9.57e-09	-1.07e+00	-0.1462
23081	KDM4C	HTA11_546_2000001011	Human	Colorectum	AD	2.67e-18	-1.03e+00	-0.0842

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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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ

∗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:00305189	Endometrium	AEH	intracellular steroid hormone receptor signaling pathway	27/2100	116/18723	1.65e-04	2.15e-03	27
GO:00434019	Endometrium	AEH	steroid hormone mediated signaling pathway	29/2100	136/18723	4.71e-04	4.91e-03	29
GO:00097558	Endometrium	AEH	hormone-mediated signaling pathway	37/2100	190/18723	5.64e-04	5.62e-03	37
GO:00305219	Endometrium	AEH	androgen receptor signaling pathway	12/2100	44/18723	2.62e-03	1.92e-02	12
GO:00063258	Endometrium	AEH	chromatin organization	64/2100	409/18723	3.69e-03	2.52e-02	64
GO:00331435	Endometrium	AEH	regulation of intracellular steroid hormone receptor signaling pathway	16/2100	74/18723	7.12e-03	4.09e-02	16
GO:003052215	Endometrium	EEC	intracellular receptor signaling pathway	65/2168	265/18723	2.52e-09	1.96e-07	65
GO:004854517	Endometrium	EEC	response to steroid hormone	77/2168	339/18723	3.80e-09	2.71e-07	77
GO:007138315	Endometrium	EEC	cellular response to steroid hormone stimulus	45/2168	204/18723	1.40e-05	2.79e-04	45
GO:003051814	Endometrium	EEC	intracellular steroid hormone receptor signaling pathway	28/2168	116/18723	1.11e-04	1.52e-03	28
GO:004340114	Endometrium	EEC	steroid hormone mediated signaling pathway	30/2168	136/18723	3.55e-04	3.90e-03	30
GO:000975513	Endometrium	EEC	hormone-mediated signaling pathway	38/2168	190/18723	5.18e-04	5.21e-03	38
GO:003052114	Endometrium	EEC	androgen receptor signaling pathway	13/2168	44/18723	1.05e-03	9.17e-03	13
GO:000632513	Endometrium	EEC	chromatin organization	65/2168	409/18723	4.98e-03	3.14e-02	65
GO:001657015	Esophagus	ESCC	histone modification	323/8552	463/18723	2.61e-26	7.88e-24	323
GO:0030522110	Esophagus	ESCC	intracellular receptor signaling pathway	170/8552	265/18723	8.58e-10	2.09e-08	170
GO:0048545111	Esophagus	ESCC	response to steroid hormone	204/8552	339/18723	4.47e-08	8.11e-07	204
GO:000632517	Esophagus	ESCC	chromatin organization	240/8552	409/18723	6.52e-08	1.14e-06	240
GO:0071383110	Esophagus	ESCC	cellular response to steroid hormone stimulus	127/8552	204/18723	1.26e-06	1.55e-05	127
GO:003051819	Esophagus	ESCC	intracellular steroid hormone receptor signaling pathway	76/8552	116/18723	1.25e-05	1.15e-04	76

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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

KDM4C

SNV

Missense_Mutation

rs780836880

c.362N>A

p.Arg121His

p.R121H

Q9H3R0

protein_coding

deleterious(0)

probably_damaging(0.985)

TCGA-A8-A07P-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

5-fluorouracil

KDM4C

SNV

Missense_Mutation

rs182255463

c.676N>G

p.Gln226Glu

p.Q226E

Q9H3R0

protein_coding

tolerated(0.24)

benign(0.24)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

KDM4C

SNV

Missense_Mutation

rs191848178

c.1888N>T

p.Ala630Ser

p.A630S

Q9H3R0

protein_coding

deleterious(0.01)

probably_damaging(0.957)

TCGA-BH-A0BG-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

KDM4C

SNV

Missense_Mutation

novel

c.1611N>A

p.Asn537Lys

p.N537K

Q9H3R0

protein_coding

tolerated(0.2)

benign(0.014)

TCGA-BH-A6R8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

KDM4C

SNV

Missense_Mutation

c.1439N>A

p.Ile480Lys

p.I480K

Q9H3R0

protein_coding

tolerated(0.95)

benign(0)

TCGA-D8-A1JK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

KDM4C

SNV

Missense_Mutation

c.145N>C

p.Val49Leu

p.V49L

Q9H3R0

protein_coding

deleterious(0)

benign(0.013)

TCGA-D8-A1X6-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

KDM4C

SNV

Missense_Mutation

rs373633491

c.1192N>A

p.Ala398Thr

p.A398T

Q9H3R0

protein_coding

tolerated(0.34)

benign(0.001)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

KDM4C

SNV

Missense_Mutation

c.1352C>T

p.Ser451Leu

p.S451L

Q9H3R0

protein_coding

tolerated(0.13)

benign(0.001)

TCGA-GM-A2D9-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

KDM4C

insertion

Frame_Shift_Ins

novel

c.1907_1908insCTGGTGCTCTGTAAGATTTTATAAAGTGCTGTTCTTGTGGAGT

p.Thr637TrpfsTer37

p.T637Wfs*37

Q9H3R0

protein_coding

TCGA-AN-A04C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

KDM4C

deletion

Frame_Shift_Del

c.2601delN

p.Asn869ThrfsTer2

p.N869Tfs*2

Q9H3R0

protein_coding

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

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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
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		PYROGALLOL RED	PYROGALLOL RED
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		Pyrido[1,2-a]indole-1.-carboxylic acid analog 2
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		Pyrido[1,2-a]indole-1.-carboxylic acid analog 4
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		PYRIDINE-2,4-DICARBOXYLIC ACID	CHEMBL316034
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		SKF-38393	SKF-38393
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		Pyrido[1,2-a]indole-1.-carboxylic acid analog 7
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		TYRPHOSTIN 23	TYRPHOSTIN 23
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		PMID25468267-Compound-46
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		N-METHOXYCARBONYLMETHYL-OXALAMIC ACID METHYL ESTER	CHEMBL92309	19359167
23081	KDM4C	CLINICALLY ACTIONABLE, ENZYME, DRUGGABLE GENOME		Pyrido[1,2-a]indole-1.-carboxylic acid analog 1

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