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: IL4R

Gene summary for IL4R

Gene summary.

Gene information	Species	Human
	Gene symbol	IL4R
	Gene ID	3566
	Gene name	interleukin 4 receptor
	Gene Alias	CD124
	Cytomap	16p12.1
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P24394

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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
3566	IL4R	HTA11_2487_2000001011	Human	Colorectum	SER	6.94e-04	3.52e-01	-0.1808
3566	IL4R	HTA11_1938_2000001011	Human	Colorectum	AD	4.52e-04	3.69e-01	-0.0811
3566	IL4R	HTA11_347_2000001011	Human	Colorectum	AD	3.79e-06	4.35e-01	-0.1954
3566	IL4R	HTA11_411_2000001011	Human	Colorectum	SER	4.79e-02	8.04e-01	-0.2602
3566	IL4R	HTA11_696_2000001011	Human	Colorectum	AD	2.20e-16	7.02e-01	-0.1464
3566	IL4R	HTA11_866_2000001011	Human	Colorectum	AD	9.17e-14	5.35e-01	-0.1001
3566	IL4R	HTA11_1391_2000001011	Human	Colorectum	AD	5.40e-04	4.98e-01	-0.059
3566	IL4R	HTA11_546_2000001011	Human	Colorectum	AD	4.59e-02	5.66e-01	-0.0842
3566	IL4R	A015-C-203	Human	Colorectum	FAP	3.30e-08	-2.53e-02	-0.1294
3566	IL4R	A001-C-108	Human	Colorectum	FAP	1.10e-02	-5.08e-02	-0.0272
3566	IL4R	A002-C-205	Human	Colorectum	FAP	1.60e-06	-1.07e-01	-0.1236
3566	IL4R	A015-C-006	Human	Colorectum	FAP	1.19e-04	-1.90e-01	-0.0994
3566	IL4R	A002-C-114	Human	Colorectum	FAP	1.54e-04	-2.28e-02	-0.1561
3566	IL4R	A015-C-104	Human	Colorectum	FAP	3.58e-07	-4.01e-02	-0.1899
3566	IL4R	A002-C-016	Human	Colorectum	FAP	8.07e-03	-1.20e-01	0.0521
3566	IL4R	A015-C-002	Human	Colorectum	FAP	2.69e-02	-6.17e-02	-0.0763
3566	IL4R	A002-C-116	Human	Colorectum	FAP	4.05e-06	-8.45e-02	-0.0452
3566	IL4R	A014-C-008	Human	Colorectum	FAP	2.82e-02	-1.63e-02	-0.191
3566	IL4R	A018-E-020	Human	Colorectum	FAP	1.83e-05	-1.13e-01	-0.2034
3566	IL4R	F034	Human	Colorectum	FAP	2.98e-04	-1.46e-01	-0.0665

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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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
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

∗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:00026984	Oral cavity	EOLP	negative regulation of immune effector process	26/2218	110/18723	3.94e-04	3.53e-03	26
GO:00508681	Oral cavity	EOLP	negative regulation of T cell activation	28/2218	122/18723	4.03e-04	3.58e-03	28
GO:0046638	Oral cavity	EOLP	positive regulation of alpha-beta T cell differentiation	15/2218	50/18723	4.75e-04	4.16e-03	15
GO:0042093	Oral cavity	EOLP	T-helper cell differentiation	18/2218	66/18723	4.94e-04	4.31e-03	18
GO:00026974	Oral cavity	EOLP	regulation of immune effector process	61/2218	339/18723	5.48e-04	4.68e-03	61
GO:00022864	Oral cavity	EOLP	T cell activation involved in immune response	26/2218	114/18723	7.06e-04	5.78e-03	26
GO:0002294	Oral cavity	EOLP	CD4-positive, alpha-beta T cell differentiation involved in immune response	18/2218	68/18723	7.29e-04	5.94e-03	18
GO:0002287	Oral cavity	EOLP	alpha-beta T cell activation involved in immune response	18/2218	69/18723	8.79e-04	6.75e-03	18
GO:0002293	Oral cavity	EOLP	alpha-beta T cell differentiation involved in immune response	18/2218	69/18723	8.79e-04	6.75e-03	18
GO:0002292	Oral cavity	EOLP	T cell differentiation involved in immune response	19/2218	75/18723	9.43e-04	7.15e-03	19
GO:007135321	Oral cavity	EOLP	cellular response to interleukin-4	11/2218	33/18723	1.01e-03	7.54e-03	11
GO:0046636	Oral cavity	EOLP	negative regulation of alpha-beta T cell activation	13/2218	43/18723	1.03e-03	7.63e-03	13
GO:20005161	Oral cavity	EOLP	positive regulation of CD4-positive, alpha-beta T cell activation	12/2218	39/18723	1.34e-03	9.33e-03	12
GO:00456203	Oral cavity	EOLP	negative regulation of lymphocyte differentiation	15/2218	55/18723	1.42e-03	9.62e-03	15
GO:00024433	Oral cavity	EOLP	leukocyte mediated immunity	73/2218	440/18723	1.78e-03	1.16e-02	73
GO:0046639	Oral cavity	EOLP	negative regulation of alpha-beta T cell differentiation	9/2218	26/18723	2.14e-03	1.34e-02	9
GO:00456212	Oral cavity	EOLP	positive regulation of lymphocyte differentiation	23/2218	104/18723	2.14e-03	1.34e-02	23
GO:007067021	Oral cavity	EOLP	response to interleukin-4	11/2218	36/18723	2.24e-03	1.39e-02	11
GO:00068874	Oral cavity	EOLP	exocytosis	60/2218	352/18723	2.32e-03	1.43e-02	60
GO:00455811	Oral cavity	EOLP	negative regulation of T cell differentiation	13/2218	47/18723	2.52e-03	1.53e-02	13

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04151	Colorectum	FAP	PI3K-Akt signaling pathway	75/1404	354/8465	1.23e-02	4.19e-02	2.55e-02	75
hsa041511	Colorectum	FAP	PI3K-Akt signaling pathway	75/1404	354/8465	1.23e-02	4.19e-02	2.55e-02	75
hsa046599	Esophagus	ESCC	Th17 cell differentiation	68/4205	108/8465	3.53e-03	9.30e-03	4.76e-03	68
hsa046585	Esophagus	ESCC	Th1 and Th2 cell differentiation	58/4205	92/8465	6.49e-03	1.60e-02	8.19e-03	58
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0465914	Esophagus	ESCC	Th17 cell differentiation	68/4205	108/8465	3.53e-03	9.30e-03	4.76e-03	68
hsa0465812	Esophagus	ESCC	Th1 and Th2 cell differentiation	58/4205	92/8465	6.49e-03	1.60e-02	8.19e-03	58
hsa0415114	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa046598	Oral cavity	OSCC	Th17 cell differentiation	65/3704	108/8465	4.02e-04	1.25e-03	6.35e-04	65
hsa041516	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa046584	Oral cavity	OSCC	Th1 and Th2 cell differentiation	53/3704	92/8465	5.00e-03	1.20e-02	6.13e-03	53
hsa0465913	Oral cavity	OSCC	Th17 cell differentiation	65/3704	108/8465	4.02e-04	1.25e-03	6.35e-04	65
hsa0415113	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185
hsa0465811	Oral cavity	OSCC	Th1 and Th2 cell differentiation	53/3704	92/8465	5.00e-03	1.20e-02	6.13e-03	53
hsa0465923	Oral cavity	EOLP	Th17 cell differentiation	41/1218	108/8465	9.84e-10	3.18e-08	1.87e-08	41
hsa0465821	Oral cavity	EOLP	Th1 and Th2 cell differentiation	31/1218	92/8465	2.27e-06	1.79e-05	1.05e-05	31
hsa053214	Oral cavity	EOLP	Inflammatory bowel disease	20/1218	65/8465	5.49e-04	2.16e-03	1.28e-03	20
hsa0415123	Oral cavity	EOLP	PI3K-Akt signaling pathway	73/1218	354/8465	7.03e-04	2.69e-03	1.59e-03	73
hsa04630	Oral cavity	EOLP	JAK-STAT signaling pathway	35/1218	166/8465	1.15e-02	3.07e-02	1.81e-02	35
hsa0465933	Oral cavity	EOLP	Th17 cell differentiation	41/1218	108/8465	9.84e-10	3.18e-08	1.87e-08	41

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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

IL4R

SNV

Missense_Mutation

c.971C>A

p.Pro324His

p.P324H

P24394

protein_coding

tolerated(0.21)

benign(0.187)

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

IL4R

SNV

Missense_Mutation

novel

c.352A>C

p.Ser118Arg

p.S118R

P24394

protein_coding

deleterious(0.04)

probably_damaging(0.993)

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IL4R

SNV

Missense_Mutation

novel

c.353G>C

p.Ser118Thr

p.S118T

P24394

protein_coding

deleterious(0.04)

possibly_damaging(0.578)

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IL4R

SNV

Missense_Mutation

c.293N>T

p.Asn98Ile

p.N98I

P24394

protein_coding

tolerated(0.29)

benign(0.003)

TCGA-A8-A091-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

IL4R

SNV

Missense_Mutation

c.761N>A

p.Ser254Asn

p.S254N

P24394

protein_coding

deleterious(0.02)

possibly_damaging(0.462)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IL4R

SNV

Missense_Mutation

novel

c.2143N>C

p.Ala715Pro

p.A715P

P24394

protein_coding

deleterious(0.01)

probably_damaging(0.946)

TCGA-AO-A1KT-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

fluorouracil

IL4R

SNV

Missense_Mutation

c.2462A>G

p.Tyr821Cys

p.Y821C

P24394

protein_coding

tolerated(0.37)

benign(0)

TCGA-AR-A24S-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

anastrozole

IL4R

SNV

Missense_Mutation

novel

c.1805N>C

p.Gly602Ala

p.G602A

P24394

protein_coding

tolerated(0.05)

benign(0.07)

TCGA-B6-A0I8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

IL4R

SNV

Missense_Mutation

c.731T>A

p.Ile244Asn

p.I244N

P24394

protein_coding

deleterious(0)

probably_damaging(0.95)

TCGA-B6-A0IJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

IL4R

SNV

Missense_Mutation

c.2260N>T

p.Pro754Ser

p.P754S

P24394

protein_coding

tolerated(0.32)

benign(0.211)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

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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
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		Hepatitis vaccines		21111021
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		PRX-321	PRX-321
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		CHEMBL2108583	CINTREDEKIN BESUDOTOX
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		AIR645
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		SAR-156597	ROMILKIMAB
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		Aerovant
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		CINTREDEKIN BESUDOTOX
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		AER001,AEROVANT
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE	antibody	223365910	DUPILUMAB
3566	IL4R	DRUGGABLE GENOME, EXTERNAL SIDE OF PLASMA MEMBRANE		pitrakinra	PITRAKINRA

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