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:002290022	Liver	HCC	electron transport chain	134/7958	175/18723	3.32e-20	4.68e-18	134
GO:000606621	Liver	HCC	alcohol metabolic process	208/7958	353/18723	2.80e-10	9.50e-09	208
GO:004218021	Liver	HCC	cellular ketone metabolic process	123/7958	211/18723	2.52e-06	3.37e-05	123
GO:19016571	Liver	HCC	glycosyl compound metabolic process	55/7958	88/18723	1.20e-04	1.01e-03	55
GO:000608112	Liver	HCC	cellular aldehyde metabolic process	39/7958	60/18723	3.61e-04	2.50e-03	39
GO:003063811	Liver	HCC	polyketide metabolic process	9/7958	10/18723	2.79e-03	1.31e-02	9
GO:004459811	Liver	HCC	doxorubicin metabolic process	9/7958	10/18723	2.79e-03	1.31e-02	9
GO:19016611	Liver	HCC	quinone metabolic process	26/7958	40/18723	3.40e-03	1.55e-02	26
GO:00161371	Liver	HCC	glycoside metabolic process	16/7958	22/18723	4.03e-03	1.76e-02	16
GO:003430812	Liver	HCC	primary alcohol metabolic process	55/7958	102/18723	1.30e-02	4.67e-02	55
GO:002290018	Oral cavity	OSCC	electron transport chain	126/7305	175/18723	6.65e-19	8.42e-17	126
GO:000609118	Oral cavity	OSCC	generation of precursor metabolites and energy	286/7305	490/18723	1.45e-18	1.71e-16	286
GO:19016613	Oral cavity	OSCC	quinone metabolic process	32/7305	40/18723	1.40e-07	2.34e-06	32
GO:00060667	Oral cavity	OSCC	alcohol metabolic process	179/7305	353/18723	4.54e-06	5.21e-05	179
GO:00421804	Oral cavity	OSCC	cellular ketone metabolic process	111/7305	211/18723	3.94e-05	3.45e-04	111
GO:19016573	Oral cavity	OSCC	glycosyl compound metabolic process	52/7305	88/18723	1.06e-04	7.84e-04	52
GO:00060817	Oral cavity	OSCC	cellular aldehyde metabolic process	36/7305	60/18723	7.94e-04	4.27e-03	36
GO:00306385	Oral cavity	OSCC	polyketide metabolic process	8/7305	10/18723	1.03e-02	3.53e-02	8
GO:00306475	Oral cavity	OSCC	aminoglycoside antibiotic metabolic process	8/7305	10/18723	1.03e-02	3.53e-02	8
GO:00445985	Oral cavity	OSCC	doxorubicin metabolic process	8/7305	10/18723	1.03e-02	3.53e-02	8

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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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