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: CHI3L1

Gene summary for CHI3L1

Gene summary.

Gene information	Species	Human
	Gene symbol	CHI3L1
	Gene ID	1116
	Gene name	chitinase 3 like 1
	Gene Alias	ASRT7
	Cytomap	1q32.1
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	A0A024R969

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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
1116	CHI3L1	GSM4909282	Human	Breast	IDC	3.58e-12	3.25e-01	-0.0288
1116	CHI3L1	GSM4909285	Human	Breast	IDC	4.46e-04	-2.30e-01	0.21
1116	CHI3L1	GSM4909286	Human	Breast	IDC	1.76e-12	-4.27e-01	0.1081
1116	CHI3L1	GSM4909290	Human	Breast	IDC	3.77e-08	-4.27e-01	0.2096
1116	CHI3L1	GSM4909291	Human	Breast	IDC	2.68e-08	-4.33e-01	0.1753
1116	CHI3L1	GSM4909293	Human	Breast	IDC	6.19e-04	-3.36e-01	0.1581
1116	CHI3L1	GSM4909294	Human	Breast	IDC	5.36e-13	-4.02e-01	0.2022
1116	CHI3L1	GSM4909296	Human	Breast	IDC	5.75e-12	-4.29e-01	0.1524
1116	CHI3L1	GSM4909297	Human	Breast	IDC	9.60e-13	-4.12e-01	0.1517
1116	CHI3L1	GSM4909298	Human	Breast	IDC	1.81e-04	-3.44e-01	0.1551
1116	CHI3L1	GSM4909299	Human	Breast	IDC	8.97e-06	5.51e-01	0.035
1116	CHI3L1	GSM4909301	Human	Breast	IDC	2.12e-16	-4.33e-01	0.1577
1116	CHI3L1	GSM4909302	Human	Breast	IDC	1.05e-08	-3.98e-01	0.1545
1116	CHI3L1	GSM4909304	Human	Breast	IDC	1.17e-02	-3.11e-01	0.1636
1116	CHI3L1	GSM4909308	Human	Breast	IDC	2.56e-06	-3.95e-01	0.158
1116	CHI3L1	GSM4909311	Human	Breast	IDC	3.34e-08	-3.63e-01	0.1534
1116	CHI3L1	GSM4909312	Human	Breast	IDC	1.44e-09	-4.16e-01	0.1552
1116	CHI3L1	GSM4909313	Human	Breast	IDC	2.89e-02	4.26e-01	0.0391
1116	CHI3L1	GSM4909315	Human	Breast	IDC	4.80e-16	-4.31e-01	0.21
1116	CHI3L1	GSM4909316	Human	Breast	IDC	2.04e-03	-4.33e-01	0.21

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
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
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:00018196	Breast	Precancer	positive regulation of cytokine production	52/1080	467/18723	4.18e-06	1.29e-04	52
GO:00713568	Breast	Precancer	cellular response to tumor necrosis factor	28/1080	229/18723	1.42e-04	2.45e-03	28
GO:0045766	Breast	Precancer	positive regulation of angiogenesis	23/1080	181/18723	3.09e-04	4.43e-03	23
GO:1904018	Breast	Precancer	positive regulation of vasculature development	23/1080	181/18723	3.09e-04	4.43e-03	23
GO:00346128	Breast	Precancer	response to tumor necrosis factor	29/1080	253/18723	3.32e-04	4.70e-03	29
GO:0045765	Breast	Precancer	regulation of angiogenesis	35/1080	342/18723	7.35e-04	8.80e-03	35
GO:1901342	Breast	Precancer	regulation of vasculature development	35/1080	348/18723	1.00e-03	1.12e-02	35
GO:00434912	Breast	Precancer	protein kinase B signaling	23/1080	211/18723	2.53e-03	2.30e-02	23
GO:00336749	Breast	Precancer	positive regulation of kinase activity	42/1080	467/18723	2.94e-03	2.54e-02	42
GO:00096126	Breast	Precancer	response to mechanical stimulus	23/1080	216/18723	3.41e-03	2.85e-02	23
GO:000181911	Breast	IDC	positive regulation of cytokine production	61/1434	467/18723	2.81e-05	6.58e-04	61
GO:000961211	Breast	IDC	response to mechanical stimulus	34/1434	216/18723	4.59e-05	1.03e-03	34
GO:007135613	Breast	IDC	cellular response to tumor necrosis factor	35/1434	229/18723	6.64e-05	1.35e-03	35
GO:00303244	Breast	IDC	lung development	28/1434	177/18723	1.90e-04	3.15e-03	28
GO:003461213	Breast	IDC	response to tumor necrosis factor	36/1434	253/18723	2.29e-04	3.64e-03	36
GO:00457651	Breast	IDC	regulation of angiogenesis	45/1434	342/18723	2.57e-04	3.98e-03	45
GO:00303234	Breast	IDC	respiratory tube development	28/1434	181/18723	2.78e-04	4.26e-03	28
GO:19013421	Breast	IDC	regulation of vasculature development	45/1434	348/18723	3.78e-04	5.38e-03	45
GO:00605412	Breast	IDC	respiratory system development	30/1434	203/18723	3.85e-04	5.40e-03	30
GO:00703713	Breast	IDC	ERK1 and ERK2 cascade	43/1434	330/18723	4.28e-04	5.84e-03	43

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

CHI3L1

SNV

Missense_Mutation

c.113N>T

p.Asp38Val

p.D38V

P36222

protein_coding

tolerated(0.4)

benign(0.007)

TCGA-AN-A0XN-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

CHI3L1

SNV

Missense_Mutation

c.139G>A

p.Asp47Asn

p.D47N

P36222

protein_coding

deleterious(0.03)

possibly_damaging(0.811)

TCGA-AR-A24H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

CHI3L1

SNV

Missense_Mutation

c.217N>A

p.Asp73Asn

p.D73N

P36222

protein_coding

deleterious(0.01)

probably_damaging(0.995)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

CHI3L1

SNV

Missense_Mutation

rs376864309

c.267C>A

p.Asn89Lys

p.N89K

P36222

protein_coding

tolerated(0.95)

benign(0.007)

TCGA-BH-A8FZ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CHI3L1

SNV

Missense_Mutation

c.620N>G

p.Asp207Gly

p.D207G

P36222

protein_coding

deleterious(0)

probably_damaging(0.96)

TCGA-C8-A135-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

CHI3L1

SNV

Missense_Mutation

c.379N>G

p.Leu127Val

p.L127V

P36222

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-E2-A15E-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CHI3L1

SNV

Missense_Mutation

rs762736598

c.185N>A

p.Ser62Asn

p.S62N

P36222

protein_coding

tolerated(0.86)

benign(0.033)

TCGA-E9-A22E-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphane

CHI3L1

insertion

Nonsense_Mutation

novel

c.779_780insTAGGCACCTGGGATAGCCCTCTGGCTATGGGGCTGAGGTC

p.Phe261ArgfsTer5

p.F261Rfs*5

P36222

protein_coding

TCGA-A8-A07U-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

CHI3L1

insertion

Nonsense_Mutation

novel

c.502_503insAGCTGCTATGAAAGTATTTTGGAAAGGGAAGT

p.Gly168GlufsTer4

p.G168Efs*4

P36222

protein_coding

TCGA-B6-A0IA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CHI3L1

insertion

Frame_Shift_Ins

novel

c.225_226insG

p.Leu76AlafsTer58

p.L76Afs*58

P36222

protein_coding

TCGA-E2-A1LK-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

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
1116	CHI3L1	CELL SURFACE, DRUGGABLE GENOME		ANTI-INFLAMMATORY DRUGS		16035398
1116	CHI3L1	CELL SURFACE, DRUGGABLE GENOME		CHEMOKINES		15015934

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