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: NDUFS4

Gene summary for NDUFS4

Gene summary.

Gene information	Species	Human
	Gene symbol	NDUFS4
	Gene ID	4724
	Gene name	NADH:ubiquinone oxidoreductase subunit S4
	Gene Alias	AQDQ
	Cytomap	5q11.2
	Gene Type	protein-coding
	GO ID	GO:0001932
	UniProtAcc	A0A0S2Z433

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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
4724	NDUFS4	LZE4T	Human	Esophagus	ESCC	1.95e-15	3.23e-01	0.0811
4724	NDUFS4	LZE8T	Human	Esophagus	ESCC	5.33e-07	3.88e-01	0.067
4724	NDUFS4	LZE20T	Human	Esophagus	ESCC	6.86e-03	5.72e-03	0.0662
4724	NDUFS4	LZE22D1	Human	Esophagus	HGIN	3.85e-04	-8.47e-02	0.0595
4724	NDUFS4	LZE24T	Human	Esophagus	ESCC	1.59e-13	7.13e-01	0.0596
4724	NDUFS4	LZE6T	Human	Esophagus	ESCC	2.06e-02	3.90e-01	0.0845
4724	NDUFS4	P1T-E	Human	Esophagus	ESCC	1.74e-05	6.49e-01	0.0875
4724	NDUFS4	P2T-E	Human	Esophagus	ESCC	3.04e-43	9.09e-01	0.1177
4724	NDUFS4	P4T-E	Human	Esophagus	ESCC	3.75e-38	1.05e+00	0.1323
4724	NDUFS4	P5T-E	Human	Esophagus	ESCC	1.72e-28	7.26e-01	0.1327
4724	NDUFS4	P8T-E	Human	Esophagus	ESCC	7.98e-21	4.03e-01	0.0889
4724	NDUFS4	P9T-E	Human	Esophagus	ESCC	1.79e-20	6.68e-01	0.1131
4724	NDUFS4	P10T-E	Human	Esophagus	ESCC	2.69e-32	5.41e-01	0.116
4724	NDUFS4	P11T-E	Human	Esophagus	ESCC	2.38e-11	8.93e-01	0.1426
4724	NDUFS4	P12T-E	Human	Esophagus	ESCC	6.33e-63	1.26e+00	0.1122
4724	NDUFS4	P15T-E	Human	Esophagus	ESCC	4.78e-36	9.09e-01	0.1149
4724	NDUFS4	P16T-E	Human	Esophagus	ESCC	3.04e-23	5.11e-01	0.1153
4724	NDUFS4	P17T-E	Human	Esophagus	ESCC	7.15e-05	4.50e-01	0.1278
4724	NDUFS4	P19T-E	Human	Esophagus	ESCC	4.35e-06	8.89e-01	0.1662
4724	NDUFS4	P20T-E	Human	Esophagus	ESCC	3.43e-28	7.90e-01	0.1124

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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:000611920	Esophagus	HGIN	oxidative phosphorylation	69/2587	141/18723	1.37e-23	2.05e-20	69
GO:000906020	Esophagus	HGIN	aerobic respiration	81/2587	189/18723	1.07e-22	9.26e-20	81
GO:004603427	Esophagus	HGIN	ATP metabolic process	101/2587	277/18723	1.53e-21	1.02e-18	101
GO:000609120	Esophagus	HGIN	generation of precursor metabolites and energy	145/2587	490/18723	3.41e-20	2.04e-17	145
GO:004533320	Esophagus	HGIN	cellular respiration	86/2587	230/18723	2.41e-19	1.20e-16	86
GO:001598020	Esophagus	HGIN	energy derivation by oxidation of organic compounds	105/2587	318/18723	1.16e-18	4.99e-16	105
GO:004277320	Esophagus	HGIN	ATP synthesis coupled electron transport	49/2587	95/18723	2.21e-18	7.36e-16	49
GO:004277520	Esophagus	HGIN	mitochondrial ATP synthesis coupled electron transport	49/2587	95/18723	2.21e-18	7.36e-16	49
GO:003310820	Esophagus	HGIN	mitochondrial respiratory chain complex assembly	47/2587	93/18723	3.15e-17	8.60e-15	47
GO:002290420	Esophagus	HGIN	respiratory electron transport chain	51/2587	114/18723	9.63e-16	2.41e-13	51
GO:001964620	Esophagus	HGIN	aerobic electron transport chain	43/2587	87/18723	1.98e-15	4.41e-13	43
GO:002290020	Esophagus	HGIN	electron transport chain	66/2587	175/18723	2.21e-15	4.73e-13	66
GO:001025720	Esophagus	HGIN	NADH dehydrogenase complex assembly	31/2587	57/18723	5.89e-13	8.62e-11	31
GO:003298120	Esophagus	HGIN	mitochondrial respiratory chain complex I assembly	31/2587	57/18723	5.89e-13	8.62e-11	31
GO:000612020	Esophagus	HGIN	mitochondrial electron transport, NADH to ubiquinone	28/2587	51/18723	5.72e-12	7.30e-10	28
GO:00481458	Esophagus	HGIN	regulation of fibroblast proliferation	23/2587	80/18723	3.71e-04	5.77e-03	23
GO:00481447	Esophagus	HGIN	fibroblast proliferation	23/2587	81/18723	4.52e-04	6.62e-03	23
GO:0006091110	Esophagus	ESCC	generation of precursor metabolites and energy	331/8552	490/18723	3.86e-23	8.45e-21	331
GO:0045333110	Esophagus	ESCC	cellular respiration	173/8552	230/18723	4.53e-20	5.99e-18	173
GO:0033108110	Esophagus	ESCC	mitochondrial respiratory chain complex assembly	83/8552	93/18723	9.56e-19	1.05e-16	83

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501239	Esophagus	HGIN	Parkinson disease	124/1383	266/8465	5.95e-32	9.70e-30	7.70e-30	124
hsa0501630	Esophagus	HGIN	Huntington disease	129/1383	306/8465	6.81e-28	7.41e-26	5.88e-26	129
hsa0502030	Esophagus	HGIN	Prion disease	117/1383	273/8465	4.15e-26	3.38e-24	2.69e-24	117
hsa0501430	Esophagus	HGIN	Amyotrophic lateral sclerosis	140/1383	364/8465	2.13e-25	1.16e-23	9.19e-24	140
hsa0019030	Esophagus	HGIN	Oxidative phosphorylation	68/1383	134/8465	1.73e-20	8.07e-19	6.41e-19	68
hsa0520839	Esophagus	HGIN	Chemical carcinogenesis - reactive oxygen species	92/1383	223/8465	2.41e-19	9.83e-18	7.80e-18	92
hsa0502230	Esophagus	HGIN	Pathways of neurodegeneration - multiple diseases	153/1383	476/8465	1.22e-18	4.41e-17	3.50e-17	153
hsa0501030	Esophagus	HGIN	Alzheimer disease	130/1383	384/8465	5.26e-18	1.71e-16	1.36e-16	130
hsa0471439	Esophagus	HGIN	Thermogenesis	91/1383	232/8465	1.97e-17	5.36e-16	4.25e-16	91
hsa0541530	Esophagus	HGIN	Diabetic cardiomyopathy	80/1383	203/8465	1.35e-15	3.38e-14	2.69e-14	80
hsa0493230	Esophagus	HGIN	Non-alcoholic fatty liver disease	66/1383	155/8465	5.21e-15	1.21e-13	9.64e-14	66
hsa0472327	Esophagus	HGIN	Retrograde endocannabinoid signaling	36/1383	148/8465	7.52e-03	4.63e-02	3.68e-02	36
hsa05012114	Esophagus	HGIN	Parkinson disease	124/1383	266/8465	5.95e-32	9.70e-30	7.70e-30	124
hsa05016113	Esophagus	HGIN	Huntington disease	129/1383	306/8465	6.81e-28	7.41e-26	5.88e-26	129
hsa05020113	Esophagus	HGIN	Prion disease	117/1383	273/8465	4.15e-26	3.38e-24	2.69e-24	117
hsa05014113	Esophagus	HGIN	Amyotrophic lateral sclerosis	140/1383	364/8465	2.13e-25	1.16e-23	9.19e-24	140
hsa00190113	Esophagus	HGIN	Oxidative phosphorylation	68/1383	134/8465	1.73e-20	8.07e-19	6.41e-19	68
hsa05208115	Esophagus	HGIN	Chemical carcinogenesis - reactive oxygen species	92/1383	223/8465	2.41e-19	9.83e-18	7.80e-18	92
hsa05022113	Esophagus	HGIN	Pathways of neurodegeneration - multiple diseases	153/1383	476/8465	1.22e-18	4.41e-17	3.50e-17	153
hsa05010113	Esophagus	HGIN	Alzheimer disease	130/1383	384/8465	5.26e-18	1.71e-16	1.36e-16	130

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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

NDUFS4

insertion

Nonsense_Mutation

novel

c.342_343insAGTTGTTAAATTTACAACTTTACAAAAAGGTTCA

p.Ala115SerfsTer3

p.A115Sfs*3

O43181

protein_coding

TCGA-B6-A0I8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

novel

c.494C>A

p.Ser165Tyr

p.S165Y

O43181

protein_coding

deleterious(0)

possibly_damaging(0.767)

TCGA-AG-A002-01

Colorectum

rectum adenocarcinoma

Male

<65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

c.210N>T

p.Glu70Asp

p.E70D

O43181

protein_coding

tolerated(0.08)

probably_damaging(0.984)

TCGA-AP-A051-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

c.43N>C

p.Trp15Arg

p.W15R

O43181

protein_coding

tolerated_low_confidence(0.35)

benign(0.014)

TCGA-AX-A0J0-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

c.521N>A

p.Thr174Lys

p.T174K

O43181

protein_coding

deleterious(0)

possibly_damaging(0.598)

TCGA-B5-A0JY-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

NDUFS4

SNV

Missense_Mutation

rs766855689

c.217N>C

p.Lys73Gln

p.K73Q

O43181

protein_coding

deleterious(0.03)

probably_damaging(0.995)

TCGA-E6-A1LX-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

novel

c.473N>C

p.Lys158Thr

p.K158T

O43181

protein_coding

deleterious(0)

possibly_damaging(0.716)

TCGA-EY-A548-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

novel

c.337G>T

p.Gly113Cys

p.G113C

O43181

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-EY-A5W2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

NDUFS4

SNV

Missense_Mutation

novel

c.148N>G

p.Thr50Ala

p.T50A

O43181

protein_coding

tolerated(0.3)

benign(0.003)

TCGA-FI-A2D0-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

NDUFS4

insertion

Frame_Shift_Ins

novel

c.331_332insATTTGCA

p.Leu111TyrfsTer11

p.L111Yfs*11

O43181

protein_coding

TCGA-D1-A0ZP-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

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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
4724	NDUFS4	ENZYME	inhibitor	CHEMBL3545320	ME-344
4724	NDUFS4	ENZYME	inhibitor	CHEMBL3545135	NV-128
4724	NDUFS4	ENZYME	inhibitor	CHEMBL1703	METFORMIN HYDROCHLORIDE

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