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: COX6A1

Gene summary for COX6A1

Gene summary.

Gene information	Species	Human
	Gene symbol	COX6A1
	Gene ID	1337
	Gene name	cytochrome c oxidase subunit 6A1
	Gene Alias	CMTRID
	Cytomap	12q24.31
	Gene Type	protein-coding
	GO ID	GO:0006091
	UniProtAcc	H6SG15

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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
1337	COX6A1	GSM4909281	Human	Breast	IDC	8.34e-22	3.58e-01	0.21
1337	COX6A1	GSM4909286	Human	Breast	IDC	4.08e-02	1.09e-01	0.1081
1337	COX6A1	GSM4909287	Human	Breast	IDC	7.42e-12	-4.71e-01	0.2057
1337	COX6A1	GSM4909288	Human	Breast	IDC	1.27e-04	-4.10e-01	0.0988
1337	COX6A1	GSM4909294	Human	Breast	IDC	6.89e-21	-3.18e-01	0.2022
1337	COX6A1	GSM4909296	Human	Breast	IDC	1.03e-19	5.47e-02	0.1524
1337	COX6A1	GSM4909297	Human	Breast	IDC	2.52e-36	-9.39e-02	0.1517
1337	COX6A1	GSM4909298	Human	Breast	IDC	8.26e-05	2.48e-01	0.1551
1337	COX6A1	GSM4909301	Human	Breast	IDC	1.46e-23	3.71e-01	0.1577
1337	COX6A1	GSM4909302	Human	Breast	IDC	6.06e-06	6.80e-02	0.1545
1337	COX6A1	GSM4909306	Human	Breast	IDC	2.04e-37	4.69e-01	0.1564
1337	COX6A1	GSM4909309	Human	Breast	IDC	2.70e-16	2.01e-01	0.0483
1337	COX6A1	GSM4909311	Human	Breast	IDC	3.41e-62	-1.71e-01	0.1534
1337	COX6A1	GSM4909312	Human	Breast	IDC	1.15e-14	-1.60e-01	0.1552
1337	COX6A1	GSM4909313	Human	Breast	IDC	1.96e-08	1.43e-02	0.0391
1337	COX6A1	GSM4909315	Human	Breast	IDC	5.80e-07	8.68e-02	0.21
1337	COX6A1	GSM4909316	Human	Breast	IDC	1.52e-06	-1.50e-02	0.21
1337	COX6A1	GSM4909318	Human	Breast	IDC	1.30e-04	-6.08e-02	0.2031
1337	COX6A1	GSM4909319	Human	Breast	IDC	1.93e-83	-1.07e-01	0.1563
1337	COX6A1	GSM4909320	Human	Breast	IDC	3.93e-16	2.30e-01	0.1575

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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
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:0006119110	Oral cavity	LP	oxidative phosphorylation	81/4623	141/18723	9.70e-17	1.48e-14	81
GO:001598019	Oral cavity	LP	energy derivation by oxidation of organic compounds	145/4623	318/18723	2.44e-16	3.64e-14	145
GO:0046034110	Oral cavity	LP	ATP metabolic process	128/4623	277/18723	3.95e-15	5.38e-13	128
GO:004603426	Oral cavity	EOLP	ATP metabolic process	68/2218	277/18723	2.72e-09	1.71e-07	68
GO:001964625	Oral cavity	EOLP	aerobic electron transport chain	26/2218	87/18723	5.15e-06	1.04e-04	26
GO:004277325	Oral cavity	EOLP	ATP synthesis coupled electron transport	27/2218	95/18723	9.68e-06	1.75e-04	27
GO:004277525	Oral cavity	EOLP	mitochondrial ATP synthesis coupled electron transport	27/2218	95/18723	9.68e-06	1.75e-04	27
GO:000611925	Oral cavity	EOLP	oxidative phosphorylation	33/2218	141/18723	8.63e-05	1.02e-03	33
GO:002290425	Oral cavity	EOLP	respiratory electron transport chain	28/2218	114/18723	1.20e-04	1.33e-03	28
GO:000906025	Oral cavity	EOLP	aerobic respiration	40/2218	189/18723	1.76e-04	1.81e-03	40
GO:000612317	Oral cavity	EOLP	mitochondrial electron transport, cytochrome c to oxygen	9/2218	21/18723	3.49e-04	3.21e-03	9
GO:004533325	Oral cavity	EOLP	cellular respiration	44/2218	230/18723	8.67e-04	6.75e-03	44
GO:002290025	Oral cavity	EOLP	electron transport chain	35/2218	175/18723	1.26e-03	9.04e-03	35
GO:000609125	Oral cavity	EOLP	generation of precursor metabolites and energy	79/2218	490/18723	2.65e-03	1.59e-02	79
GO:001598025	Oral cavity	EOLP	energy derivation by oxidation of organic compounds	54/2218	318/18723	4.02e-03	2.23e-02	54
GO:004603433	Oral cavity	NEOLP	ATP metabolic process	71/2005	277/18723	1.44e-12	3.17e-10	71
GO:004277332	Oral cavity	NEOLP	ATP synthesis coupled electron transport	33/2005	95/18723	3.57e-10	3.07e-08	33
GO:004277532	Oral cavity	NEOLP	mitochondrial ATP synthesis coupled electron transport	33/2005	95/18723	3.57e-10	3.07e-08	33
GO:001964632	Oral cavity	NEOLP	aerobic electron transport chain	31/2005	87/18723	5.88e-10	4.59e-08	31
GO:000611932	Oral cavity	NEOLP	oxidative phosphorylation	40/2005	141/18723	4.88e-09	2.74e-07	40

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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
hsa0471418	Breast	Precancer	Thermogenesis	68/684	232/8465	4.40e-22	1.26e-20	9.69e-21	68
hsa0541518	Breast	Precancer	Diabetic cardiomyopathy	63/684	203/8465	5.63e-22	1.48e-20	1.14e-20	63
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

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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

COX6A1

SNV

Missense_Mutation

novel

c.31N>T

p.Arg11Trp

p.R11W

P12074

protein_coding

deleterious(0.04)

benign(0.328)

TCGA-AR-A2LE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

COX6A1

SNV

Missense_Mutation

c.43N>T

p.Arg15Trp

p.R15W

P12074

protein_coding

tolerated(0.14)

possibly_damaging(0.832)

TCGA-FU-A3HY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

COX6A1

SNV

Missense_Mutation

novel

c.247N>A

p.Pro83Thr

p.P83T

P12074

protein_coding

deleterious(0.02)

possibly_damaging(0.783)

TCGA-A5-A2K5-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

COX6A1

SNV

Missense_Mutation

novel

c.149N>C

p.Val50Ala

p.V50A

P12074

protein_coding

deleterious(0.02)

probably_damaging(0.96)

TCGA-AJ-A3I9-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

COX6A1

SNV

Missense_Mutation

c.37N>A

p.Leu13Met

p.L13M

P12074

protein_coding

deleterious(0.03)

probably_damaging(0.974)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

COX6A1

SNV

Missense_Mutation

rs377211866

c.254N>A

p.Pro85His

p.P85H

P12074

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BK-A13B-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

COX6A1

SNV

Missense_Mutation

c.194N>G

p.Glu65Gly

p.E65G

P12074

protein_coding

deleterious(0.03)

benign(0.049)

TCGA-D1-A17Q-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

COX6A1

SNV

Missense_Mutation

novel

c.322N>C

p.Asp108His

p.D108H

P12074

protein_coding

deleterious(0)

benign(0.334)

TCGA-63-A5MI-01

Lung

lung squamous cell carcinoma

Male

>=65

III/IV

Chemotherapy

vinorelbine

COX6A1

SNV

Missense_Mutation

novel

c.277N>A

p.Leu93Ile

p.L93I

P12074

protein_coding

deleterious(0.01)

probably_damaging(0.967)

TCGA-CX-7219-01

Oral cavity

head & neck squamous cell carcinoma

Male

<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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