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: COX4I1

Gene summary for COX4I1

Gene summary.

Gene information	Species	Human
	Gene symbol	COX4I1
	Gene ID	1327
	Gene name	cytochrome c oxidase subunit 4I1
	Gene Alias	COX IV-1
	Cytomap	16q24.1
	Gene Type	protein-coding
	GO ID	GO:0006091
	UniProtAcc	P13073

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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
1327	COX4I1	GSM4909280	Human	Breast	Precancer	9.85e-05	-6.43e-01	0.0305
1327	COX4I1	GSM4909286	Human	Breast	IDC	1.92e-52	-3.89e-01	0.1081
1327	COX4I1	GSM4909287	Human	Breast	IDC	3.37e-22	-5.05e-01	0.2057
1327	COX4I1	GSM4909290	Human	Breast	IDC	4.37e-10	-2.99e-01	0.2096
1327	COX4I1	GSM4909291	Human	Breast	IDC	2.45e-03	1.80e-01	0.1753
1327	COX4I1	GSM4909293	Human	Breast	IDC	4.43e-37	-3.85e-01	0.1581
1327	COX4I1	GSM4909294	Human	Breast	IDC	1.95e-04	-1.29e-01	0.2022
1327	COX4I1	GSM4909296	Human	Breast	IDC	1.09e-04	-4.90e-02	0.1524
1327	COX4I1	GSM4909297	Human	Breast	IDC	4.69e-33	-7.51e-01	0.1517
1327	COX4I1	GSM4909298	Human	Breast	IDC	1.63e-34	-3.15e-01	0.1551
1327	COX4I1	GSM4909302	Human	Breast	IDC	2.27e-20	-5.23e-01	0.1545
1327	COX4I1	GSM4909303	Human	Breast	IDC	3.74e-04	-3.53e-01	0.0438
1327	COX4I1	GSM4909304	Human	Breast	IDC	1.43e-06	-1.22e-01	0.1636
1327	COX4I1	GSM4909306	Human	Breast	IDC	6.81e-12	-2.06e-01	0.1564
1327	COX4I1	GSM4909308	Human	Breast	IDC	1.57e-13	-1.28e-01	0.158
1327	COX4I1	GSM4909311	Human	Breast	IDC	1.63e-51	-6.85e-01	0.1534
1327	COX4I1	GSM4909312	Human	Breast	IDC	3.05e-37	-6.75e-01	0.1552
1327	COX4I1	GSM4909316	Human	Breast	IDC	3.60e-04	1.32e-01	0.21
1327	COX4I1	GSM4909317	Human	Breast	IDC	7.00e-03	-1.17e-01	0.1355
1327	COX4I1	GSM4909319	Human	Breast	IDC	6.74e-73	-8.45e-01	0.1563

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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:00196463	Colorectum	MSI-H	aerobic electron transport chain	37/1319	87/18723	2.32e-20	1.43e-17	37
GO:00061193	Colorectum	MSI-H	oxidative phosphorylation	47/1319	141/18723	3.34e-20	1.86e-17	47
GO:00229043	Colorectum	MSI-H	respiratory electron transport chain	42/1319	114/18723	4.50e-20	2.27e-17	42
GO:00229003	Colorectum	MSI-H	electron transport chain	52/1319	175/18723	1.13e-19	5.21e-17	52
GO:00060913	Colorectum	MSI-H	generation of precursor metabolites and energy	93/1319	490/18723	7.35e-19	3.14e-16	93
GO:00453333	Colorectum	MSI-H	cellular respiration	59/1319	230/18723	1.08e-18	4.27e-16	59
GO:00159803	Colorectum	MSI-H	energy derivation by oxidation of organic compounds	67/1319	318/18723	2.97e-16	1.03e-13	67
GO:19026003	Colorectum	MSI-H	proton transmembrane transport	29/1319	157/18723	1.49e-06	9.75e-05	29
GO:00061233	Colorectum	MSI-H	mitochondrial electron transport, cytochrome c to oxygen	8/1319	21/18723	5.27e-05	1.85e-03	8
GO:00460344	Colorectum	FAP	ATP metabolic process	87/2622	277/18723	6.50e-14	6.63e-11	87
GO:00060914	Colorectum	FAP	generation of precursor metabolites and energy	128/2622	490/18723	5.58e-13	4.28e-10	128
GO:00159804	Colorectum	FAP	energy derivation by oxidation of organic compounds	85/2622	318/18723	1.36e-09	2.77e-07	85
GO:00090604	Colorectum	FAP	aerobic respiration	57/2622	189/18723	7.02e-09	1.02e-06	57
GO:00453334	Colorectum	FAP	cellular respiration	65/2622	230/18723	1.13e-08	1.33e-06	65
GO:00229004	Colorectum	FAP	electron transport chain	51/2622	175/18723	1.44e-07	9.03e-06	51
GO:00061194	Colorectum	FAP	oxidative phosphorylation	43/2622	141/18723	3.39e-07	1.86e-05	43
GO:00229044	Colorectum	FAP	respiratory electron transport chain	35/2622	114/18723	3.43e-06	1.23e-04	35
GO:00427734	Colorectum	FAP	ATP synthesis coupled electron transport	28/2622	95/18723	7.10e-05	1.32e-03	28
GO:00427754	Colorectum	FAP	mitochondrial ATP synthesis coupled electron transport	28/2622	95/18723	7.10e-05	1.32e-03	28
GO:00316673	Colorectum	FAP	response to nutrient levels	95/2622	474/18723	1.59e-04	2.43e-03	95

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501218	Breast	Precancer	Parkinson disease	99/684	266/8465	3.58e-42	5.65e-40	4.33e-40	99
hsa0502016	Breast	Precancer	Prion disease	95/684	273/8465	1.39e-37	1.46e-35	1.12e-35	95
hsa0501616	Breast	Precancer	Huntington disease	98/684	306/8465	2.85e-35	2.25e-33	1.72e-33	98
hsa0019016	Breast	Precancer	Oxidative phosphorylation	59/684	134/8465	6.15e-30	3.24e-28	2.48e-28	59
hsa0501016	Breast	Precancer	Alzheimer disease	103/684	384/8465	1.03e-29	4.66e-28	3.57e-28	103
hsa0501416	Breast	Precancer	Amyotrophic lateral sclerosis	98/684	364/8465	2.13e-28	8.41e-27	6.44e-27	98
hsa0502216	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0520818	Breast	Precancer	Chemical carcinogenesis - reactive oxygen species	68/684	223/8465	3.61e-23	1.14e-21	8.73e-22	68
hsa0493216	Breast	Precancer	Non-alcoholic fatty liver disease	48/684	155/8465	6.16e-17	1.50e-15	1.15e-15	48
hsa0426016	Breast	Precancer	Cardiac muscle contraction	22/684	87/8465	9.72e-07	1.62e-05	1.24e-05	22
hsa0501219	Breast	Precancer	Parkinson disease	99/684	266/8465	3.58e-42	5.65e-40	4.33e-40	99
hsa0502017	Breast	Precancer	Prion disease	95/684	273/8465	1.39e-37	1.46e-35	1.12e-35	95
hsa0501617	Breast	Precancer	Huntington disease	98/684	306/8465	2.85e-35	2.25e-33	1.72e-33	98
hsa0019017	Breast	Precancer	Oxidative phosphorylation	59/684	134/8465	6.15e-30	3.24e-28	2.48e-28	59
hsa0501017	Breast	Precancer	Alzheimer disease	103/684	384/8465	1.03e-29	4.66e-28	3.57e-28	103
hsa0501417	Breast	Precancer	Amyotrophic lateral sclerosis	98/684	364/8465	2.13e-28	8.41e-27	6.44e-27	98
hsa0502217	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0520819	Breast	Precancer	Chemical carcinogenesis - reactive oxygen species	68/684	223/8465	3.61e-23	1.14e-21	8.73e-22	68
hsa0493217	Breast	Precancer	Non-alcoholic fatty liver disease	48/684	155/8465	6.16e-17	1.50e-15	1.15e-15	48
hsa0426017	Breast	Precancer	Cardiac muscle contraction	22/684	87/8465	9.72e-07	1.62e-05	1.24e-05	22

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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

COX4I1

insertion

Frame_Shift_Ins

novel

c.252dupT

p.Lys85Ter

p.K85*

P13073

protein_coding

TCGA-A2-A04Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

COX4I1

insertion

Nonsense_Mutation

novel

c.421_422insTGGACTTCCTAGCCTGAGCTGGGTTTTCATCTCATTTCT

p.Gln141delinsLeuAspPheLeuAlaTerAlaGlyPheSerSerHisPheTer

p.Q141delinsLDFLA*AGFSSHF*

P13073

protein_coding

TCGA-A2-A04Y-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

COX4I1

SNV

Missense_Mutation

rs374125919

c.248G>A

p.Arg83His

p.R83H

P13073

protein_coding

tolerated(0.25)

benign(0.011)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

COX4I1

SNV

Missense_Mutation

c.53N>G

p.Ser18Cys

p.S18C

P13073

protein_coding

deleterious(0.03)

probably_damaging(0.997)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

COX4I1

SNV

Missense_Mutation

rs772180664

c.343N>A

p.Ala115Thr

p.A115T

P13073

protein_coding

tolerated(0.06)

benign(0.132)

TCGA-AA-3664-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

COX4I1

SNV

Missense_Mutation

rs201058411

c.101C>T

p.Ser34Leu

p.S34L

P13073

protein_coding

deleterious(0.01)

benign(0.029)

TCGA-CK-6746-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

COX4I1

SNV

Missense_Mutation

novel

c.371N>G

p.Tyr124Cys

p.Y124C

P13073

protein_coding

tolerated(0.06)

probably_damaging(0.929)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

COX4I1

SNV

Missense_Mutation

c.340N>G

p.Thr114Ala

p.T114A

P13073

protein_coding

tolerated(0.09)

benign(0.017)

TCGA-AP-A056-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

COX4I1

SNV

Missense_Mutation

c.258N>A

p.Phe86Leu

p.F86L

P13073

protein_coding

deleterious(0.01)

possibly_damaging(0.691)

TCGA-D1-A16F-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

COX4I1

SNV

Missense_Mutation

rs761492668

c.238G>A

p.Glu80Lys

p.E80K

P13073

protein_coding

tolerated(0.07)

benign(0.199)

TCGA-EY-A215-01

Endometrium

uterine corpus endometrioid carcinoma

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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