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: HMGCS2

Gene summary for HMGCS2

Gene summary.

Gene information	Species	Human
	Gene symbol	HMGCS2
	Gene ID	3158
	Gene name	3-hydroxy-3-methylglutaryl-CoA synthase 2
	Gene Alias	HMGCS2
	Cytomap	1p12
	Gene Type	protein-coding
	GO ID	GO:0006066
	UniProtAcc	P54868

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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
3158	HMGCS2	HTA11_3410_2000001011	Human	Colorectum	AD	5.01e-32	1.30e+00	0.0155
3158	HMGCS2	HTA11_2487_2000001011	Human	Colorectum	SER	2.69e-22	1.50e+00	-0.1808
3158	HMGCS2	HTA11_1938_2000001011	Human	Colorectum	AD	4.41e-40	2.56e+00	-0.0811
3158	HMGCS2	HTA11_78_2000001011	Human	Colorectum	AD	4.59e-23	1.91e+00	-0.1088
3158	HMGCS2	HTA11_347_2000001011	Human	Colorectum	AD	3.29e-83	3.02e+00	-0.1954
3158	HMGCS2	HTA11_411_2000001011	Human	Colorectum	SER	1.03e-03	6.38e-01	-0.2602
3158	HMGCS2	HTA11_2112_2000001011	Human	Colorectum	SER	2.93e-02	9.95e-01	-0.2196
3158	HMGCS2	HTA11_3361_2000001011	Human	Colorectum	AD	7.06e-22	1.71e+00	-0.1207
3158	HMGCS2	HTA11_83_2000001011	Human	Colorectum	SER	7.00e-41	2.73e+00	-0.1526
3158	HMGCS2	HTA11_696_2000001011	Human	Colorectum	AD	9.32e-21	1.08e+00	-0.1464
3158	HMGCS2	HTA11_866_2000001011	Human	Colorectum	AD	9.65e-47	1.85e+00	-0.1001
3158	HMGCS2	HTA11_1391_2000001011	Human	Colorectum	AD	2.26e-38	2.43e+00	-0.059
3158	HMGCS2	HTA11_2992_2000001011	Human	Colorectum	SER	4.76e-17	1.61e+00	-0.1706
3158	HMGCS2	HTA11_5212_2000001011	Human	Colorectum	AD	2.69e-20	1.69e+00	-0.2061
3158	HMGCS2	HTA11_5216_2000001011	Human	Colorectum	SER	9.40e-20	2.21e+00	-0.1462
3158	HMGCS2	HTA11_546_2000001011	Human	Colorectum	AD	7.81e-25	1.88e+00	-0.0842
3158	HMGCS2	HTA11_9341_2000001011	Human	Colorectum	SER	6.24e-18	1.58e+00	-0.00410000000000005
3158	HMGCS2	HTA11_7862_2000001011	Human	Colorectum	AD	4.06e-27	1.83e+00	-0.0179
3158	HMGCS2	HTA11_4255_2000001011	Human	Colorectum	SER	1.14e-25	1.85e+00	0.0446
3158	HMGCS2	HTA11_9408_2000001011	Human	Colorectum	AD	4.73e-08	1.02e+00	0.0451

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease

∗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:00196931	Colorectum	SER	ribose phosphate metabolic process	105/2897	396/18723	8.15e-09	7.14e-07	105
GO:00091171	Colorectum	SER	nucleotide metabolic process	122/2897	489/18723	2.50e-08	1.76e-06	122
GO:00067531	Colorectum	SER	nucleoside phosphate metabolic process	122/2897	497/18723	6.64e-08	4.33e-06	122
GO:00060661	Colorectum	SER	alcohol metabolic process	79/2897	353/18723	3.50e-04	5.50e-03	79
GO:00067901	Colorectum	SER	sulfur compound metabolic process	73/2897	339/18723	1.75e-03	1.81e-02	73
GO:00066441	Colorectum	SER	phospholipid metabolic process	79/2897	383/18723	3.94e-03	3.24e-02	79
GO:00060912	Colorectum	MSS	generation of precursor metabolites and energy	186/3467	490/18723	1.14e-24	2.15e-21	186
GO:00061632	Colorectum	MSS	purine nucleotide metabolic process	128/3467	396/18723	2.04e-11	3.02e-09	128
GO:00091502	Colorectum	MSS	purine ribonucleotide metabolic process	121/3467	368/18723	2.08e-11	3.02e-09	121
GO:00725212	Colorectum	MSS	purine-containing compound metabolic process	132/3467	416/18723	4.13e-11	4.86e-09	132
GO:00092592	Colorectum	MSS	ribonucleotide metabolic process	123/3467	385/18723	1.17e-10	1.20e-08	123
GO:00196932	Colorectum	MSS	ribose phosphate metabolic process	124/3467	396/18723	4.11e-10	3.49e-08	124
GO:00091172	Colorectum	MSS	nucleotide metabolic process	144/3467	489/18723	1.87e-09	1.35e-07	144
GO:00067532	Colorectum	MSS	nucleoside phosphate metabolic process	145/3467	497/18723	3.25e-09	2.23e-07	145
GO:00060662	Colorectum	MSS	alcohol metabolic process	92/3467	353/18723	2.57e-04	3.46e-03	92
GO:00067902	Colorectum	MSS	sulfur compound metabolic process	85/3467	339/18723	1.52e-03	1.39e-02	85
GO:00060914	Colorectum	FAP	generation of precursor metabolites and energy	128/2622	490/18723	5.58e-13	4.28e-10	128
GO:00091504	Colorectum	FAP	purine ribonucleotide metabolic process	96/2622	368/18723	4.91e-10	1.20e-07	96
GO:00061634	Colorectum	FAP	purine nucleotide metabolic process	100/2622	396/18723	1.45e-09	2.77e-07	100
GO:00092593	Colorectum	FAP	ribonucleotide metabolic process	97/2622	385/18723	2.90e-09	5.07e-07	97

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa00280	Colorectum	AD	Valine, leucine and isoleucine degradation	25/2092	48/8465	3.97e-05	3.41e-04	2.18e-04	25
hsa002801	Colorectum	AD	Valine, leucine and isoleucine degradation	25/2092	48/8465	3.97e-05	3.41e-04	2.18e-04	25
hsa002802	Colorectum	MSS	Valine, leucine and isoleucine degradation	21/1875	48/8465	6.73e-04	4.51e-03	2.76e-03	21
hsa002803	Colorectum	MSS	Valine, leucine and isoleucine degradation	21/1875	48/8465	6.73e-04	4.51e-03	2.76e-03	21
hsa002804	Colorectum	FAP	Valine, leucine and isoleucine degradation	18/1404	48/8465	3.94e-04	3.06e-03	1.86e-03	18
hsa002805	Colorectum	FAP	Valine, leucine and isoleucine degradation	18/1404	48/8465	3.94e-04	3.06e-03	1.86e-03	18
hsa002806	Liver	NAFLD	Valine, leucine and isoleucine degradation	20/1043	48/8465	3.03e-07	1.65e-05	1.33e-05	20
hsa033206	Liver	NAFLD	PPAR signaling pathway	25/1043	75/8465	1.61e-06	6.62e-05	5.33e-05	25
hsa0028011	Liver	NAFLD	Valine, leucine and isoleucine degradation	20/1043	48/8465	3.03e-07	1.65e-05	1.33e-05	20
hsa0332011	Liver	NAFLD	PPAR signaling pathway	25/1043	75/8465	1.61e-06	6.62e-05	5.33e-05	25
hsa0028021	Liver	Cirrhotic	Valine, leucine and isoleucine degradation	32/2530	48/8465	1.45e-07	2.02e-06	1.24e-06	32
hsa006502	Liver	Cirrhotic	Butanoate metabolism	15/2530	27/8465	4.71e-03	1.74e-02	1.07e-02	15
hsa0332021	Liver	Cirrhotic	PPAR signaling pathway	32/2530	75/8465	1.24e-02	3.92e-02	2.42e-02	32
hsa0028031	Liver	Cirrhotic	Valine, leucine and isoleucine degradation	32/2530	48/8465	1.45e-07	2.02e-06	1.24e-06	32
hsa006503	Liver	Cirrhotic	Butanoate metabolism	15/2530	27/8465	4.71e-03	1.74e-02	1.07e-02	15
hsa0332031	Liver	Cirrhotic	PPAR signaling pathway	32/2530	75/8465	1.24e-02	3.92e-02	2.42e-02	32
hsa0028041	Liver	HCC	Valine, leucine and isoleucine degradation	41/4020	48/8465	4.84e-08	7.05e-07	3.92e-07	41
hsa033204	Liver	HCC	PPAR signaling pathway	48/4020	75/8465	2.83e-03	9.37e-03	5.21e-03	48
hsa00900	Liver	HCC	Terpenoid backbone biosynthesis	17/4020	23/8465	9.26e-03	2.46e-02	1.37e-02	17
hsa006504	Liver	HCC	Butanoate metabolism	19/4020	27/8465	1.37e-02	3.33e-02	1.85e-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

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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

HMGCS2

SNV

Missense_Mutation

c.1144N>C

p.Tyr382His

p.Y382H

P54868

protein_coding

deleterious(0)

probably_damaging(0.987)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

rs770800317

c.1355G>A

p.Arg452Gln

p.R452Q

P54868

protein_coding

deleterious(0)

probably_damaging(0.997)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

c.1058N>T

p.Asp353Val

p.D353V

P54868

protein_coding

deleterious(0)

benign(0.204)

TCGA-AN-A0XU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

c.35T>C

p.Leu12Pro

p.L12P

P54868

protein_coding

deleterious_low_confidence(0)

possibly_damaging(0.65)

TCGA-B6-A0I6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

rs775277893

c.1015G>A

p.Gly339Arg

p.G339R

P54868

protein_coding

tolerated(1)

benign(0.001)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HMGCS2

SNV

Missense_Mutation

novel

c.1392N>A

p.Met464Ile

p.M464I

P54868

protein_coding

tolerated(0.25)

possibly_damaging(0.514)

TCGA-JW-A5VJ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

c.74N>A

p.Pro25His

p.P25H

P54868

protein_coding

deleterious_low_confidence(0.02)

benign(0.436)

TCGA-VS-A9UJ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

rs61729865

c.1342N>T

p.Arg448Cys

p.R448C

P54868

protein_coding

deleterious(0.04)

probably_damaging(0.988)

TCGA-AA-3713-01

Colorectum

colon adenocarcinoma

Male

>=65

III/IV

Chemotherapy

5-fluorouracil

HMGCS2

SNV

Missense_Mutation

c.617N>A

p.Arg206His

p.R206H

P54868

protein_coding

deleterious(0.03)

probably_damaging(0.986)

TCGA-AU-6004-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HMGCS2

SNV

Missense_Mutation

novel

c.1366N>C

p.Ser456Pro

p.S456P

P54868

protein_coding

tolerated(0.27)

benign(0.005)

TCGA-AZ-6598-01

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
3158	HMGCS2	DRUGGABLE GENOME, ENZYME		hydrochlorothiazide	HYDROCHLOROTHIAZIDE	29523524
3158	HMGCS2	DRUGGABLE GENOME, ENZYME		chlorothiazide	CHLOROTHIAZIDE	29523524

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