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: AKR1A1

Gene summary for AKR1A1

Gene summary.

Gene information	Species	Human
	Gene symbol	AKR1A1
	Gene ID	10327
	Gene name	aldo-keto reductase family 1 member A1
	Gene Alias	ALDR1
	Cytomap	1p34.1
	Gene Type	protein-coding
	GO ID	GO:0005975
	UniProtAcc	P14550

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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
10327	AKR1A1	HTA11_3410_2000001011	Human	Colorectum	AD	1.74e-04	3.03e-01	0.0155
10327	AKR1A1	HTA11_2487_2000001011	Human	Colorectum	SER	3.80e-12	7.95e-01	-0.1808
10327	AKR1A1	HTA11_1938_2000001011	Human	Colorectum	AD	2.71e-08	6.59e-01	-0.0811
10327	AKR1A1	HTA11_78_2000001011	Human	Colorectum	AD	3.62e-10	5.87e-01	-0.1088
10327	AKR1A1	HTA11_347_2000001011	Human	Colorectum	AD	3.75e-25	7.72e-01	-0.1954
10327	AKR1A1	HTA11_411_2000001011	Human	Colorectum	SER	9.27e-07	1.08e+00	-0.2602
10327	AKR1A1	HTA11_2112_2000001011	Human	Colorectum	SER	4.64e-02	7.11e-01	-0.2196
10327	AKR1A1	HTA11_3361_2000001011	Human	Colorectum	AD	6.09e-06	5.16e-01	-0.1207
10327	AKR1A1	HTA11_83_2000001011	Human	Colorectum	SER	3.78e-04	5.00e-01	-0.1526
10327	AKR1A1	HTA11_696_2000001011	Human	Colorectum	AD	7.06e-32	9.37e-01	-0.1464
10327	AKR1A1	HTA11_866_2000001011	Human	Colorectum	AD	2.60e-07	4.27e-01	-0.1001
10327	AKR1A1	HTA11_1391_2000001011	Human	Colorectum	AD	6.15e-19	9.36e-01	-0.059
10327	AKR1A1	HTA11_2992_2000001011	Human	Colorectum	SER	4.45e-06	7.77e-01	-0.1706
10327	AKR1A1	HTA11_5216_2000001011	Human	Colorectum	SER	1.43e-02	6.40e-01	-0.1462
10327	AKR1A1	HTA11_546_2000001011	Human	Colorectum	AD	1.26e-09	7.45e-01	-0.0842
10327	AKR1A1	HTA11_7862_2000001011	Human	Colorectum	AD	1.22e-03	5.12e-01	-0.0179
10327	AKR1A1	HTA11_866_3004761011	Human	Colorectum	AD	1.59e-19	6.16e-01	0.096
10327	AKR1A1	HTA11_8622_2000001021	Human	Colorectum	SER	4.56e-04	6.80e-01	0.0528
10327	AKR1A1	HTA11_7663_2000001011	Human	Colorectum	SER	1.42e-07	9.50e-01	0.0131
10327	AKR1A1	HTA11_10711_2000001011	Human	Colorectum	AD	1.76e-07	6.15e-01	0.0338

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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:00060063	Colorectum	FAP	glucose metabolic process	48/2622	196/18723	5.90e-05	1.16e-03	48
GO:00059963	Colorectum	FAP	monosaccharide metabolic process	59/2622	257/18723	6.79e-05	1.28e-03	59
GO:00723293	Colorectum	FAP	monocarboxylic acid catabolic process	32/2622	122/18723	2.57e-04	3.53e-03	32
GO:00442823	Colorectum	FAP	small molecule catabolic process	77/2622	376/18723	3.25e-04	4.16e-03	77
GO:00060663	Colorectum	FAP	alcohol metabolic process	69/2622	353/18723	2.29e-03	1.85e-02	69
GO:00160543	Colorectum	FAP	organic acid catabolic process	50/2622	240/18723	2.30e-03	1.85e-02	50
GO:00096363	Colorectum	FAP	response to toxic substance	53/2622	262/18723	3.35e-03	2.46e-02	53
GO:00463951	Colorectum	FAP	carboxylic acid catabolic process	48/2622	236/18723	4.53e-03	3.08e-02	48
GO:000609110	Endometrium	AEH	generation of precursor metabolites and energy	121/2100	490/18723	1.65e-17	8.23e-15	121
GO:002290010	Endometrium	AEH	electron transport chain	60/2100	175/18723	4.37e-16	1.75e-13	60
GO:009723710	Endometrium	AEH	cellular response to toxic substance	34/2100	124/18723	5.02e-07	1.97e-05	34
GO:199074810	Endometrium	AEH	cellular detoxification	30/2100	116/18723	8.40e-06	1.98e-04	30
GO:000963610	Endometrium	AEH	response to toxic substance	52/2100	262/18723	2.89e-05	5.40e-04	52
GO:009875410	Endometrium	AEH	detoxification	31/2100	152/18723	6.85e-04	6.62e-03	31
GO:000609115	Endometrium	EEC	generation of precursor metabolites and energy	125/2168	490/18723	3.76e-18	1.88e-15	125
GO:002290015	Endometrium	EEC	electron transport chain	61/2168	175/18723	4.60e-16	1.84e-13	61
GO:009723715	Endometrium	EEC	cellular response to toxic substance	35/2168	124/18723	3.44e-07	1.37e-05	35
GO:199074815	Endometrium	EEC	cellular detoxification	31/2168	116/18723	5.54e-06	1.36e-04	31
GO:000963615	Endometrium	EEC	response to toxic substance	54/2168	262/18723	1.65e-05	3.18e-04	54
GO:009875415	Endometrium	EEC	detoxification	32/2168	152/18723	5.52e-04	5.52e-03	32

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05208	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa00620	Colorectum	AD	Pyruvate metabolism	28/2092	47/8465	3.71e-07	5.41e-06	3.45e-06	28
hsa00010	Colorectum	AD	Glycolysis / Gluconeogenesis	34/2092	67/8465	3.63e-06	4.34e-05	2.77e-05	34
hsa00561	Colorectum	AD	Glycerolipid metabolism	24/2092	63/8465	1.25e-02	4.54e-02	2.90e-02	24
hsa052081	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa006201	Colorectum	AD	Pyruvate metabolism	28/2092	47/8465	3.71e-07	5.41e-06	3.45e-06	28
hsa000101	Colorectum	AD	Glycolysis / Gluconeogenesis	34/2092	67/8465	3.63e-06	4.34e-05	2.77e-05	34
hsa005611	Colorectum	AD	Glycerolipid metabolism	24/2092	63/8465	1.25e-02	4.54e-02	2.90e-02	24
hsa006202	Colorectum	SER	Pyruvate metabolism	22/1580	47/8465	9.62e-06	1.33e-04	9.67e-05	22
hsa000102	Colorectum	SER	Glycolysis / Gluconeogenesis	24/1580	67/8465	6.62e-04	5.36e-03	3.89e-03	24
hsa006203	Colorectum	SER	Pyruvate metabolism	22/1580	47/8465	9.62e-06	1.33e-04	9.67e-05	22
hsa000103	Colorectum	SER	Glycolysis / Gluconeogenesis	24/1580	67/8465	6.62e-04	5.36e-03	3.89e-03	24
hsa052084	Colorectum	MSS	Chemical carcinogenesis - reactive oxygen species	118/1875	223/8465	2.71e-24	4.54e-22	2.78e-22	118
hsa006204	Colorectum	MSS	Pyruvate metabolism	24/1875	47/8465	1.25e-05	1.35e-04	8.27e-05	24
hsa000104	Colorectum	MSS	Glycolysis / Gluconeogenesis	28/1875	67/8465	2.36e-04	1.81e-03	1.11e-03	28
hsa005612	Colorectum	MSS	Glycerolipid metabolism	23/1875	63/8465	6.55e-03	2.64e-02	1.62e-02	23
hsa052085	Colorectum	MSS	Chemical carcinogenesis - reactive oxygen species	118/1875	223/8465	2.71e-24	4.54e-22	2.78e-22	118
hsa006205	Colorectum	MSS	Pyruvate metabolism	24/1875	47/8465	1.25e-05	1.35e-04	8.27e-05	24
hsa000105	Colorectum	MSS	Glycolysis / Gluconeogenesis	28/1875	67/8465	2.36e-04	1.81e-03	1.11e-03	28
hsa005613	Colorectum	MSS	Glycerolipid metabolism	23/1875	63/8465	6.55e-03	2.64e-02	1.62e-02	23

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
AKR1A1	M2MAC	Cervix	ADJ	PRDX1,CAPG,TMEM176B, etc.	2.00e-01
AKR1A1	MAST	Cervix	ADJ	PRDX1,CAPG,TMEM176B, etc.	2.57e-01
AKR1A1	M2MAC	Cervix	HSIL_HPV	PRDX1,CAPG,TMEM176B, etc.	1.60e-01
AKR1A1	M2MAC	Endometrium	ADJ	CD81,PRDX1,CAPG, etc.	2.90e-01
AKR1A1	M2MAC	Endometrium	AEH	CD81,PRDX1,CAPG, etc.	2.73e-01
AKR1A1	M2MAC	Endometrium	EEC	CD81,PRDX1,CAPG, etc.	3.82e-01
AKR1A1	M2MAC	Endometrium	Healthy	CD81,PRDX1,CAPG, etc.	4.34e-01
AKR1A1	cDC	Skin	ADJ	PRDX1,HLA-DQB2,FCGBP, etc.	5.26e-02
AKR1A1	LC	Skin	ADJ	PRDX1,HLA-DQB2,FCGBP, etc.	4.18e-01
AKR1A1	M2MAC	Skin	ADJ	PRDX1,HLA-DQB2,FCGBP, etc.	2.06e-01

∗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

AKR1A1

SNV

Missense_Mutation

novel

c.631N>T

p.Ser211Cys

p.S211C

P14550

protein_coding

deleterious(0.05)

probably_damaging(0.996)

TCGA-S3-AA0Z-01

Breast

breast invasive carcinoma

Female

<65

I/II

Ancillary

neulasta

AKR1A1

deletion

Frame_Shift_Del

novel

c.945delG

p.His316IlefsTer24

p.H316Ifs*24

P14550

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

AKR1A1

SNV

Missense_Mutation

rs767717870

c.106G>A

p.Ala36Thr

p.A36T

P14550

protein_coding

deleterious(0.01)

probably_damaging(0.977)

TCGA-DS-A1OB-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

carboplatin

AKR1A1

SNV

Missense_Mutation

novel

c.733C>G

p.Pro245Ala

p.P245A

P14550

protein_coding

tolerated(0.2)

benign(0.232)

TCGA-DS-A1OB-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

carboplatin

AKR1A1

SNV

Missense_Mutation

c.147C>G

p.Ile49Met

p.I49M

P14550

protein_coding

tolerated(0.05)

benign(0.011)

TCGA-EK-A2RA-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

AKR1A1

SNV

Missense_Mutation

novel

c.107C>T

p.Ala36Val

p.A36V

P14550

protein_coding

deleterious(0.01)

probably_damaging(0.98)

TCGA-AA-A00N-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

AKR1A1

SNV

Missense_Mutation

novel

c.125N>A

p.Arg42His

p.R42H

P14550

protein_coding

deleterious(0.01)

probably_damaging(0.997)

TCGA-AJ-A3EL-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

AKR1A1

SNV

Missense_Mutation

rs757813969

c.950C>T

p.Pro317Leu

p.P317L

P14550

protein_coding

deleterious(0)

probably_damaging(0.989)

TCGA-AP-A051-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

AKR1A1

SNV

Missense_Mutation

novel

c.8N>A

p.Ala3Asp

p.A3D

P14550

protein_coding

deleterious(0)

benign(0.034)

TCGA-AP-A059-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

AKR1A1

SNV

Missense_Mutation

novel

c.825N>T

p.Lys275Asn

p.K275N

P14550

protein_coding

tolerated(0.27)

benign(0.001)

TCGA-AP-A1DV-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
10327	AKR1A1	ENZYME, DRUGGABLE GENOME		doxorubicin	DOXORUBICIN	21048526

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