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: NDUFS2

Gene summary for NDUFS2

Gene summary.

Gene information	Species	Human
	Gene symbol	NDUFS2
	Gene ID	4720
	Gene name	NADH:ubiquinone oxidoreductase core subunit S2
	Gene Alias	CI-49
	Cytomap	1q23.3
	Gene Type	protein-coding
	GO ID	GO:0006091
	UniProtAcc	B7Z792

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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
4720	NDUFS2	HTA11_3410_2000001011	Human	Colorectum	AD	6.46e-27	6.50e-01	0.0155
4720	NDUFS2	HTA11_2487_2000001011	Human	Colorectum	SER	5.60e-36	9.96e-01	-0.1808
4720	NDUFS2	HTA11_2951_2000001011	Human	Colorectum	AD	3.51e-07	7.78e-01	0.0216
4720	NDUFS2	HTA11_1938_2000001011	Human	Colorectum	AD	1.77e-35	1.25e+00	-0.0811
4720	NDUFS2	HTA11_78_2000001011	Human	Colorectum	AD	1.14e-20	8.05e-01	-0.1088
4720	NDUFS2	HTA11_347_2000001011	Human	Colorectum	AD	7.36e-57	1.39e+00	-0.1954
4720	NDUFS2	HTA11_411_2000001011	Human	Colorectum	SER	4.40e-20	1.78e+00	-0.2602
4720	NDUFS2	HTA11_2112_2000001011	Human	Colorectum	SER	4.79e-14	1.38e+00	-0.2196
4720	NDUFS2	HTA11_3361_2000001011	Human	Colorectum	AD	1.80e-20	8.67e-01	-0.1207
4720	NDUFS2	HTA11_83_2000001011	Human	Colorectum	SER	1.94e-37	1.45e+00	-0.1526
4720	NDUFS2	HTA11_696_2000001011	Human	Colorectum	AD	4.01e-64	1.35e+00	-0.1464
4720	NDUFS2	HTA11_866_2000001011	Human	Colorectum	AD	8.92e-24	7.09e-01	-0.1001
4720	NDUFS2	HTA11_1391_2000001011	Human	Colorectum	AD	2.46e-45	1.47e+00	-0.059
4720	NDUFS2	HTA11_2992_2000001011	Human	Colorectum	SER	2.40e-23	1.62e+00	-0.1706
4720	NDUFS2	HTA11_5212_2000001011	Human	Colorectum	AD	3.13e-17	1.10e+00	-0.2061
4720	NDUFS2	HTA11_5216_2000001011	Human	Colorectum	SER	2.83e-17	1.26e+00	-0.1462
4720	NDUFS2	HTA11_546_2000001011	Human	Colorectum	AD	5.36e-18	9.59e-01	-0.0842
4720	NDUFS2	HTA11_9341_2000001011	Human	Colorectum	SER	6.33e-07	9.38e-01	-0.00410000000000005
4720	NDUFS2	HTA11_7862_2000001011	Human	Colorectum	AD	5.60e-29	1.14e+00	-0.0179
4720	NDUFS2	HTA11_866_3004761011	Human	Colorectum	AD	2.84e-33	9.39e-01	0.096

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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
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:0046034	Colorectum	AD	ATP metabolic process	142/3918	277/18723	2.64e-29	8.26e-26	142
GO:0006091	Colorectum	AD	generation of precursor metabolites and energy	209/3918	490/18723	3.17e-28	6.61e-25	209
GO:0009060	Colorectum	AD	aerobic respiration	108/3918	189/18723	9.14e-28	1.43e-24	108
GO:0045333	Colorectum	AD	cellular respiration	119/3918	230/18723	3.21e-25	4.02e-22	119
GO:0006119	Colorectum	AD	oxidative phosphorylation	83/3918	141/18723	7.95e-23	8.30e-20	83
GO:0015980	Colorectum	AD	energy derivation by oxidation of organic compounds	143/3918	318/18723	2.78e-22	2.49e-19	143
GO:0022900	Colorectum	AD	electron transport chain	89/3918	175/18723	1.42e-18	8.91e-16	89
GO:0019646	Colorectum	AD	aerobic electron transport chain	53/3918	87/18723	5.58e-16	2.16e-13	53
GO:0042773	Colorectum	AD	ATP synthesis coupled electron transport	56/3918	95/18723	6.76e-16	2.22e-13	56
GO:0042775	Colorectum	AD	mitochondrial ATP synthesis coupled electron transport	56/3918	95/18723	6.76e-16	2.22e-13	56
GO:0022904	Colorectum	AD	respiratory electron transport chain	63/3918	114/18723	8.23e-16	2.45e-13	63
GO:0006120	Colorectum	AD	mitochondrial electron transport, NADH to ubiquinone	32/3918	51/18723	1.12e-10	1.11e-08	32
GO:0010257	Colorectum	AD	NADH dehydrogenase complex assembly	34/3918	57/18723	2.15e-10	1.89e-08	34
GO:0032981	Colorectum	AD	mitochondrial respiratory chain complex I assembly	34/3918	57/18723	2.15e-10	1.89e-08	34
GO:0033108	Colorectum	AD	mitochondrial respiratory chain complex assembly	46/3918	93/18723	8.95e-10	6.91e-08	46
GO:0006979	Colorectum	AD	response to oxidative stress	145/3918	446/18723	5.16e-09	3.23e-07	145
GO:0070482	Colorectum	AD	response to oxygen levels	99/3918	347/18723	4.29e-04	4.82e-03	99
GO:0071453	Colorectum	AD	cellular response to oxygen levels	55/3918	177/18723	9.48e-04	8.96e-03	55
GO:00090601	Colorectum	SER	aerobic respiration	96/2897	189/18723	5.53e-30	1.70e-26	96
GO:00460341	Colorectum	SER	ATP metabolic process	117/2897	277/18723	5.54e-27	1.13e-23	117

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05012	Colorectum	AD	Parkinson disease	147/2092	266/8465	2.53e-27	8.48e-25	5.41e-25	147
hsa05208	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa00190	Colorectum	AD	Oxidative phosphorylation	86/2092	134/8465	2.47e-22	2.76e-20	1.76e-20	86
hsa05415	Colorectum	AD	Diabetic cardiomyopathy	114/2092	203/8465	3.65e-22	3.06e-20	1.95e-20	114
hsa05010	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa05016	Colorectum	AD	Huntington disease	147/2092	306/8465	1.93e-19	9.26e-18	5.91e-18	147
hsa04714	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa04932	Colorectum	AD	Non-alcoholic fatty liver disease	90/2092	155/8465	4.83e-19	1.80e-17	1.15e-17	90
hsa05020	Colorectum	AD	Prion disease	133/2092	273/8465	2.47e-18	8.29e-17	5.29e-17	133
hsa05014	Colorectum	AD	Amyotrophic lateral sclerosis	164/2092	364/8465	4.28e-18	1.27e-16	8.09e-17	164
hsa05022	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa04723	Colorectum	AD	Retrograde endocannabinoid signaling	59/2092	148/8465	2.94e-05	2.73e-04	1.74e-04	59
hsa050121	Colorectum	AD	Parkinson disease	147/2092	266/8465	2.53e-27	8.48e-25	5.41e-25	147
hsa052081	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa001901	Colorectum	AD	Oxidative phosphorylation	86/2092	134/8465	2.47e-22	2.76e-20	1.76e-20	86
hsa054151	Colorectum	AD	Diabetic cardiomyopathy	114/2092	203/8465	3.65e-22	3.06e-20	1.95e-20	114
hsa050101	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa050161	Colorectum	AD	Huntington disease	147/2092	306/8465	1.93e-19	9.26e-18	5.91e-18	147
hsa047141	Colorectum	AD	Thermogenesis	120/2092	232/8465	2.76e-19	1.16e-17	7.37e-18	120
hsa049321	Colorectum	AD	Non-alcoholic fatty liver disease	90/2092	155/8465	4.83e-19	1.80e-17	1.15e-17	90

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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

NDUFS2

SNV

Missense_Mutation

c.1363N>A

p.Asp455Asn

p.D455N

O75306

protein_coding

deleterious(0)

probably_damaging(0.987)

TCGA-A2-A0YJ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

NDUFS2

SNV

Missense_Mutation

c.898N>C

p.Trp300Arg

p.W300R

O75306

protein_coding

deleterious(0)

possibly_damaging(0.464)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NDUFS2

SNV

Missense_Mutation

novel

c.103C>T

p.Arg35Trp

p.R35W

O75306

protein_coding

deleterious_low_confidence(0.01)

possibly_damaging(0.757)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NDUFS2

SNV

Missense_Mutation

novel

c.1387C>T

p.Arg463Trp

p.R463W

O75306

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NDUFS2

SNV

Missense_Mutation

c.719T>G

p.Leu240Arg

p.L240R

O75306

protein_coding

deleterious(0)

probably_damaging(0.981)

TCGA-AR-A1AH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

NDUFS2

SNV

Missense_Mutation

c.1276G>A

p.Ala426Thr

p.A426T

O75306

protein_coding

deleterious(0.01)

possibly_damaging(0.859)

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NDUFS2

SNV

Missense_Mutation

c.934G>A

p.Asp312Asn

p.D312N

O75306

protein_coding

tolerated(0.08)

benign(0.077)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

NDUFS2

SNV

Missense_Mutation

novel

c.1216N>A

p.Glu406Lys

p.E406K

O75306

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-VS-A94Z-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

NDUFS2

SNV

Missense_Mutation

c.289N>A

p.Leu97Ile

p.L97I

O75306

protein_coding

deleterious(0)

probably_damaging(0.94)

TCGA-AY-4070-01

Colorectum

colon adenocarcinoma

Female

<65

III/IV

Chemotherapy

5-fu

NDUFS2

SNV

Missense_Mutation

c.328G>A

p.Asp110Asn

p.D110N

O75306

protein_coding

deleterious(0.01)

possibly_damaging(0.482)

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
4720	NDUFS2	ENZYME	inhibitor	CHEMBL3545135	NV-128
4720	NDUFS2	ENZYME	inhibitor	CHEMBL1703	METFORMIN HYDROCHLORIDE
4720	NDUFS2	ENZYME	inhibitor	CHEMBL3545320	ME-344

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