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:000906015	Endometrium	EEC	aerobic respiration	79/2168	189/18723	2.63e-26	3.95e-23	79
GO:004533315	Endometrium	EEC	cellular respiration	83/2168	230/18723	1.72e-22	2.06e-19	83
GO:001598015	Endometrium	EEC	energy derivation by oxidation of organic compounds	97/2168	318/18723	5.37e-20	3.58e-17	97
GO:001603217	Endometrium	EEC	viral process	112/2168	415/18723	2.48e-18	1.35e-15	112
GO:000609115	Endometrium	EEC	generation of precursor metabolites and energy	125/2168	490/18723	3.76e-18	1.88e-15	125
GO:004217617	Endometrium	EEC	regulation of protein catabolic process	103/2168	391/18723	3.54e-16	1.52e-13	103
GO:001905817	Endometrium	EEC	viral life cycle	86/2168	317/18723	1.63e-14	4.65e-12	86
GO:000989617	Endometrium	EEC	positive regulation of catabolic process	108/2168	492/18723	2.55e-11	3.64e-09	108
GO:004440317	Endometrium	EEC	biological process involved in symbiotic interaction	73/2168	290/18723	7.47e-11	9.95e-09	73
GO:005109817	Endometrium	EEC	regulation of binding	83/2168	363/18723	6.72e-10	6.61e-08	83
GO:005170117	Endometrium	EEC	biological process involved in interaction with host	54/2168	203/18723	2.67e-09	2.01e-07	54
GO:004573217	Endometrium	EEC	positive regulation of protein catabolic process	59/2168	231/18723	2.69e-09	2.01e-07	59
GO:005212617	Endometrium	EEC	movement in host environment	47/2168	175/18723	2.03e-08	1.23e-06	47
GO:005109917	Endometrium	EEC	positive regulation of binding	44/2168	173/18723	3.08e-07	1.27e-05	44
GO:004671817	Endometrium	EEC	viral entry into host cell	38/2168	144/18723	7.19e-07	2.58e-05	38
GO:004586117	Endometrium	EEC	negative regulation of proteolysis	72/2168	351/18723	8.46e-07	2.98e-05	72
GO:004440917	Endometrium	EEC	entry into host	39/2168	151/18723	9.34e-07	3.22e-05	39
GO:004339315	Endometrium	EEC	regulation of protein binding	46/2168	196/18723	1.94e-06	5.80e-05	46
GO:004346714	Endometrium	EEC	regulation of generation of precursor metabolites and energy	34/2168	130/18723	3.36e-06	9.13e-05	34
GO:190371513	Endometrium	EEC	regulation of aerobic respiration	14/2168	33/18723	7.17e-06	1.66e-04	14

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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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