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:000609120	Esophagus	HGIN	generation of precursor metabolites and energy	145/2587	490/18723	3.41e-20	2.04e-17	145
GO:002290020	Esophagus	HGIN	electron transport chain	66/2587	175/18723	2.21e-15	4.73e-13	66
GO:199074820	Esophagus	HGIN	cellular detoxification	30/2587	116/18723	4.05e-04	6.15e-03	30
GO:00306386	Esophagus	HGIN	polyketide metabolic process	6/2587	10/18723	8.81e-04	1.13e-02	6
GO:00306476	Esophagus	HGIN	aminoglycoside antibiotic metabolic process	6/2587	10/18723	8.81e-04	1.13e-02	6
GO:00445986	Esophagus	HGIN	doxorubicin metabolic process	6/2587	10/18723	8.81e-04	1.13e-02	6
GO:009723720	Esophagus	HGIN	cellular response to toxic substance	30/2587	124/18723	1.32e-03	1.57e-02	30
GO:19016614	Esophagus	HGIN	quinone metabolic process	13/2587	40/18723	2.04e-03	2.13e-02	13
GO:0006091110	Esophagus	ESCC	generation of precursor metabolites and energy	331/8552	490/18723	3.86e-23	8.45e-21	331
GO:0022900110	Esophagus	ESCC	electron transport chain	133/8552	175/18723	2.18e-16	1.67e-14	133
GO:00059969	Esophagus	ESCC	monosaccharide metabolic process	159/8552	257/18723	1.11e-07	1.81e-06	159
GO:00193189	Esophagus	ESCC	hexose metabolic process	147/8552	237/18723	2.63e-07	3.94e-06	147
GO:00067906	Esophagus	ESCC	sulfur compound metabolic process	201/8552	339/18723	2.64e-07	3.94e-06	201
GO:190166112	Esophagus	ESCC	quinone metabolic process	34/8552	40/18723	3.00e-07	4.27e-06	34
GO:00442725	Esophagus	ESCC	sulfur compound biosynthetic process	96/8552	148/18723	1.86e-06	2.16e-05	96
GO:00060668	Esophagus	ESCC	alcohol metabolic process	202/8552	353/18723	7.32e-06	7.26e-05	202
GO:00060069	Esophagus	ESCC	glucose metabolic process	119/8552	196/18723	1.51e-05	1.36e-04	119
GO:000963620	Esophagus	ESCC	response to toxic substance	150/8552	262/18723	1.00e-04	7.12e-04	150
GO:00067671	Esophagus	ESCC	water-soluble vitamin metabolic process	41/8552	59/18723	1.84e-04	1.17e-03	41
GO:00463948	Esophagus	ESCC	carboxylic acid biosynthetic process	175/8552	314/18723	1.98e-04	1.26e-03	175

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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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