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: IDE

Gene summary for IDE

Gene summary.

Gene information	Species	Human
	Gene symbol	IDE
	Gene ID	3416
	Gene name	insulin degrading enzyme
	Gene Alias	INSULYSIN
	Cytomap	10q23.33
	Gene Type	protein-coding
	GO ID	GO:0002376
	UniProtAcc	P14735

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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
3416	IDE	GSM6177620_NYU_UCEC1_lib1_lib1	Human	Endometrium	EEC	5.08e-04	8.42e-02	-0.1869
3416	IDE	GSM6177620_NYU_UCEC1_lib2_lib2	Human	Endometrium	EEC	1.54e-03	-4.53e-02	-0.1875
3416	IDE	GSM6177620_NYU_UCEC1_lib3_lib3	Human	Endometrium	EEC	2.34e-05	2.31e-02	-0.1883
3416	IDE	GSM6177622_NYU_UCEC3_lib1_lib1	Human	Endometrium	EEC	2.30e-04	7.48e-02	-0.1917
3416	IDE	GSM6177622_NYU_UCEC3_lib2_lib2	Human	Endometrium	EEC	3.14e-02	-4.75e-03	-0.1916
3416	IDE	NAFLD1	Human	Liver	NAFLD	3.13e-04	4.99e-01	-0.04
3416	IDE	HCC1_Meng	Human	Liver	HCC	7.67e-24	-2.30e-02	0.0246
3416	IDE	HCC2_Meng	Human	Liver	HCC	2.31e-13	2.42e-02	0.0107
3416	IDE	HCC1	Human	Liver	HCC	3.08e-05	4.35e+00	0.5336
3416	IDE	HCC2	Human	Liver	HCC	1.68e-20	4.15e+00	0.5341
3416	IDE	S014	Human	Liver	HCC	2.81e-02	2.43e-01	0.2254
3416	IDE	S015	Human	Liver	HCC	1.41e-03	2.94e-01	0.2375
3416	IDE	S016	Human	Liver	HCC	1.28e-03	2.93e-01	0.2243
3416	IDE	S027	Human	Liver	HCC	2.08e-10	7.66e-01	0.2446
3416	IDE	S028	Human	Liver	HCC	9.59e-19	7.93e-01	0.2503
3416	IDE	S029	Human	Liver	HCC	2.30e-19	8.31e-01	0.2581
3416	IDE	C04	Human	Oral cavity	OSCC	7.63e-03	1.79e-01	0.2633
3416	IDE	C21	Human	Oral cavity	OSCC	9.30e-11	2.67e-01	0.2678
3416	IDE	C30	Human	Oral cavity	OSCC	1.18e-05	3.13e-01	0.3055
3416	IDE	C38	Human	Oral cavity	OSCC	1.92e-07	5.93e-01	0.172

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
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
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:000756815	Endometrium	EEC	aging	66/2168	339/18723	1.46e-05	2.87e-04	66
GO:003209213	Endometrium	EEC	positive regulation of protein binding	24/2168	85/18723	2.29e-05	4.08e-04	24
GO:190165314	Endometrium	EEC	cellular response to peptide	68/2168	359/18723	2.75e-05	4.83e-04	68
GO:004800216	Endometrium	EEC	antigen processing and presentation of peptide antigen	19/2168	62/18723	4.65e-05	7.48e-04	19
GO:004343416	Endometrium	EEC	response to peptide hormone	74/2168	414/18723	9.11e-05	1.28e-03	74
GO:004345713	Endometrium	EEC	regulation of cellular respiration	15/2168	49/18723	2.90e-04	3.27e-03	15
GO:001988217	Endometrium	EEC	antigen processing and presentation	25/2168	106/18723	3.71e-04	3.97e-03	25
GO:000248317	Endometrium	EEC	antigen processing and presentation of endogenous peptide antigen	8/2168	19/18723	7.41e-04	7.01e-03	8
GO:007137513	Endometrium	EEC	cellular response to peptide hormone stimulus	52/2168	290/18723	8.77e-04	8.01e-03	52
GO:003286914	Endometrium	EEC	cellular response to insulin stimulus	39/2168	203/18723	9.93e-04	8.79e-03	39
GO:000828613	Endometrium	EEC	insulin receptor signaling pathway	25/2168	116/18723	1.50e-03	1.21e-02	25
GO:001988316	Endometrium	EEC	antigen processing and presentation of endogenous antigen	9/2168	26/18723	1.82e-03	1.41e-02	9
GO:009724211	Endometrium	EEC	amyloid-beta clearance	11/2168	38/18723	3.00e-03	2.10e-02	11
GO:003286814	Endometrium	EEC	response to insulin	46/2168	264/18723	3.01e-03	2.10e-02	46
GO:0097193111	Esophagus	ESCC	intrinsic apoptotic signaling pathway	222/8552	288/18723	5.87e-28	2.02e-25	222
GO:0045862111	Esophagus	ESCC	positive regulation of proteolysis	256/8552	372/18723	7.88e-20	9.43e-18	256
GO:0010821110	Esophagus	ESCC	regulation of mitochondrion organization	107/8552	144/18723	2.31e-12	9.41e-11	107
GO:0031667111	Esophagus	ESCC	response to nutrient levels	289/8552	474/18723	9.25e-12	3.47e-10	289
GO:0008630110	Esophagus	ESCC	intrinsic apoptotic signaling pathway in response to DNA damage	78/8552	99/18723	1.43e-11	5.08e-10	78
GO:0008637110	Esophagus	ESCC	apoptotic mitochondrial changes	83/8552	107/18723	1.43e-11	5.08e-10	83

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501025	Endometrium	EEC	Alzheimer disease	126/1237	384/8465	2.25e-20	7.40e-19	5.52e-19	126
hsa0501035	Endometrium	EEC	Alzheimer disease	126/1237	384/8465	2.25e-20	7.40e-19	5.52e-19	126
hsa0501022	Liver	HCC	Alzheimer disease	254/4020	384/8465	3.75e-14	8.97e-13	4.99e-13	254
hsa0501032	Liver	HCC	Alzheimer disease	254/4020	384/8465	3.75e-14	8.97e-13	4.99e-13	254
hsa0501028	Oral cavity	OSCC	Alzheimer disease	244/3704	384/8465	1.18e-15	3.60e-14	1.83e-14	244
hsa05010112	Oral cavity	OSCC	Alzheimer disease	244/3704	384/8465	1.18e-15	3.60e-14	1.83e-14	244
hsa0501029	Oral cavity	LP	Alzheimer disease	197/2418	384/8465	6.66e-22	3.69e-20	2.38e-20	197
hsa0501037	Oral cavity	LP	Alzheimer disease	197/2418	384/8465	6.66e-22	3.69e-20	2.38e-20	197
hsa0501045	Oral cavity	EOLP	Alzheimer disease	87/1218	384/8465	5.79e-06	3.67e-05	2.16e-05	87
hsa0501055	Oral cavity	EOLP	Alzheimer disease	87/1218	384/8465	5.79e-06	3.67e-05	2.16e-05	87

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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

IDE

SNV

Missense_Mutation

novel

c.2006C>T

p.Ser669Phe

p.S669F

P14735

protein_coding

deleterious(0.01)

benign(0.339)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

IDE

SNV

Missense_Mutation

c.2849G>T

p.Arg950Met

p.R950M

P14735

protein_coding

tolerated(0.19)

benign(0.003)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IDE

SNV

Missense_Mutation

c.1929N>C

p.Lys643Asn

p.K643N

P14735

protein_coding

tolerated(0.18)

benign(0.006)

TCGA-AR-A24Z-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

IDE

SNV

Missense_Mutation

c.706G>C

p.Asp236His

p.D236H

P14735

protein_coding

deleterious(0.01)

probably_damaging(0.91)

TCGA-AR-A256-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

IDE

SNV

Missense_Mutation

novel

c.2152N>G

p.Gln718Glu

p.Q718E

P14735

protein_coding

tolerated(0.26)

benign(0.019)

TCGA-BH-A0HP-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

doxorubicin

IDE

insertion

Frame_Shift_Ins

novel

c.2580_2581insTTTTTTTTTTT

p.Ser861PhefsTer11

p.S861Ffs*11

P14735

protein_coding

TCGA-BH-A0EB-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

IDE

SNV

Missense_Mutation

c.2062N>G

p.Leu688Val

p.L688V

P14735

protein_coding

tolerated(0.5)

benign(0.035)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

IDE

SNV

Missense_Mutation

c.1402N>A

p.Leu468Ile

p.L468I

P14735

protein_coding

tolerated(0.08)

possibly_damaging(0.486)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

IDE

SNV

Missense_Mutation

c.1384N>C

p.Asp462His

p.D462H

P14735

protein_coding

deleterious(0.01)

probably_damaging(0.967)

TCGA-IR-A3LH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

IDE

SNV

Missense_Mutation

rs766038121

c.2569C>A

p.His857Asn

p.H857N

P14735

protein_coding

tolerated(0.59)

benign(0.085)

TCGA-VS-A8Q8-01

Cervix

cervical & endocervical cancer

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
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE		CALMIDAZOLIUM CHLORIDE	CALMIDAZOLIUM CHLORIDE
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE	inhibitor	252166800
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE		Bacitracin	BACITRACIN
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE		OLEOYL DOPAMINE	OLEOYL DOPAMINE
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE		N-(4-NITROPHENYL)ANTHRANILIC ACID	CHEMBL1574420
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE	inhibitor	252166798
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE		BIOTIN	BIOTIN
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE	inhibitor	252166797
3416	IDE	DRUGGABLE GENOME, NEUTRAL ZINC METALLOPEPTIDASE, EXTERNAL SIDE OF PLASMA MEMBRANE, CELL SURFACE, ENZYME, PROTEASE		PRO-001

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