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: AKR7A2

Gene summary for AKR7A2

Gene summary.

Gene information	Species	Human
	Gene symbol	AKR7A2
	Gene ID	8574
	Gene name	aldo-keto reductase family 7 member A2
	Gene Alias	AFAR
	Cytomap	1p36.13
	Gene Type	protein-coding
	GO ID	GO:0005975
	UniProtAcc	B4DZX4

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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
8574	AKR7A2	GSM4909281	Human	Breast	IDC	8.11e-05	1.51e-01	0.21
8574	AKR7A2	GSM4909282	Human	Breast	IDC	2.08e-16	3.95e-01	-0.0288
8574	AKR7A2	GSM4909288	Human	Breast	IDC	2.72e-02	4.07e-01	0.0988
8574	AKR7A2	GSM4909291	Human	Breast	IDC	1.78e-04	3.72e-01	0.1753
8574	AKR7A2	GSM4909293	Human	Breast	IDC	2.10e-05	1.85e-01	0.1581
8574	AKR7A2	GSM4909294	Human	Breast	IDC	1.32e-11	3.69e-01	0.2022
8574	AKR7A2	GSM4909298	Human	Breast	IDC	5.58e-05	1.15e-01	0.1551
8574	AKR7A2	GSM4909304	Human	Breast	IDC	4.08e-44	6.82e-01	0.1636
8574	AKR7A2	GSM4909305	Human	Breast	IDC	2.15e-03	2.86e-01	0.0436
8574	AKR7A2	GSM4909306	Human	Breast	IDC	5.10e-09	3.10e-01	0.1564
8574	AKR7A2	GSM4909318	Human	Breast	IDC	8.68e-06	5.27e-01	0.2031
8574	AKR7A2	GSM4909319	Human	Breast	IDC	7.36e-17	1.94e-01	0.1563
8574	AKR7A2	brca2	Human	Breast	Precancer	1.37e-03	6.67e-02	-0.024
8574	AKR7A2	brca3	Human	Breast	Precancer	1.46e-02	9.31e-02	-0.0263
8574	AKR7A2	NCCBC2	Human	Breast	DCIS	1.91e-02	1.46e-01	0.1554
8574	AKR7A2	P1	Human	Breast	IDC	2.98e-03	-5.54e-02	0.1527
8574	AKR7A2	DCIS2	Human	Breast	DCIS	9.30e-49	7.53e-02	0.0085
8574	AKR7A2	HTA11_3410_2000001011	Human	Colorectum	AD	1.06e-04	2.54e-01	0.0155
8574	AKR7A2	HTA11_2487_2000001011	Human	Colorectum	SER	2.21e-12	6.02e-01	-0.1808
8574	AKR7A2	HTA11_1938_2000001011	Human	Colorectum	AD	1.14e-08	5.49e-01	-0.0811

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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
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
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:00060918	Breast	Precancer	generation of precursor metabolites and energy	94/1080	490/18723	1.54e-25	1.64e-22	94
GO:00229008	Breast	Precancer	electron transport chain	42/1080	175/18723	1.37e-15	4.59e-13	42
GO:000609113	Breast	IDC	generation of precursor metabolites and energy	103/1434	490/18723	1.53e-21	1.74e-18	103
GO:002290013	Breast	IDC	electron transport chain	51/1434	175/18723	2.23e-17	8.43e-15	51
GO:000609123	Breast	DCIS	generation of precursor metabolites and energy	103/1390	490/18723	1.46e-22	1.65e-19	103
GO:002290023	Breast	DCIS	electron transport chain	51/1390	175/18723	6.01e-18	2.62e-15	51
GO:0006091	Colorectum	AD	generation of precursor metabolites and energy	209/3918	490/18723	3.17e-28	6.61e-25	209
GO:0022900	Colorectum	AD	electron transport chain	89/3918	175/18723	1.42e-18	8.91e-16	89
GO:0006066	Colorectum	AD	alcohol metabolic process	106/3918	353/18723	3.02e-05	5.57e-04	106
GO:0034308	Colorectum	AD	primary alcohol metabolic process	35/3918	102/18723	1.16e-03	1.05e-02	35
GO:0006081	Colorectum	AD	cellular aldehyde metabolic process	22/3918	60/18723	3.64e-03	2.60e-02	22
GO:00060911	Colorectum	SER	generation of precursor metabolites and energy	168/2897	490/18723	1.39e-25	1.70e-22	168
GO:00229001	Colorectum	SER	electron transport chain	77/2897	175/18723	1.77e-19	1.36e-16	77
GO:00060661	Colorectum	SER	alcohol metabolic process	79/2897	353/18723	3.50e-04	5.50e-03	79
GO:00343081	Colorectum	SER	primary alcohol metabolic process	26/2897	102/18723	5.87e-03	4.29e-02	26
GO:00060912	Colorectum	MSS	generation of precursor metabolites and energy	186/3467	490/18723	1.14e-24	2.15e-21	186
GO:00229002	Colorectum	MSS	electron transport chain	83/3467	175/18723	2.06e-18	1.17e-15	83
GO:00060662	Colorectum	MSS	alcohol metabolic process	92/3467	353/18723	2.57e-04	3.46e-03	92
GO:00060811	Colorectum	MSS	cellular aldehyde metabolic process	21/3467	60/18723	1.81e-03	1.60e-02	21
GO:00229003	Colorectum	MSI-H	electron transport chain	52/1319	175/18723	1.13e-19	5.21e-17	52

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

AKR7A2

SNV

Missense_Mutation

rs773248892

c.847G>A

p.Ala283Thr

p.A283T

O43488

protein_coding

tolerated(0.37)

benign(0.003)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

AKR7A2

SNV

Missense_Mutation

rs775556235

c.862N>A

p.Ala288Thr

p.A288T

O43488

protein_coding

tolerated(0.39)

benign(0.003)

TCGA-A5-A0G1-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

rs146046785

c.358N>T

p.Arg120Trp

p.R120W

O43488

protein_coding

deleterious(0)

probably_damaging(0.977)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

AKR7A2

SNV

Missense_Mutation

novel

c.798N>T

p.Lys266Asn

p.K266N

O43488

protein_coding

tolerated(0.26)

possibly_damaging(0.642)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

novel

c.142N>A

p.Gly48Arg

p.G48R

O43488

protein_coding

deleterious(0)

probably_damaging(0.99)

TCGA-AX-A1C4-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

rs150666132

c.472C>T

p.Arg158Trp

p.R158W

O43488

protein_coding

deleterious(0)

possibly_damaging(0.884)

TCGA-B5-A11E-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

novel

c.884C>A

p.Ala295Asp

p.A295D

O43488

protein_coding

deleterious(0)

probably_damaging(0.938)

TCGA-B5-A3FC-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

c.835G>A

p.Ala279Thr

p.A279T

O43488

protein_coding

tolerated(0.06)

benign(0.362)

TCGA-D1-A0ZO-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

c.1012N>A

p.Ala338Thr

p.A338T

O43488

protein_coding

tolerated(0.39)

benign(0.007)

TCGA-D1-A103-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

AKR7A2

SNV

Missense_Mutation

novel

c.374N>T

p.Thr125Met

p.T125M

O43488

protein_coding

deleterious(0.01)

benign(0.098)

TCGA-DF-A2KU-01

Endometrium

uterine corpus endometrioid carcinoma

Female

Unknown

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
8574	AKR7A2	DRUGGABLE GENOME, ENZYME		daunorubicin	DAUNORUBICIN	20837989
8574	AKR7A2	DRUGGABLE GENOME, ENZYME		doxorubicin	DOXORUBICIN	20837989

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