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: TLL1

Gene summary for TLL1

Gene summary.

Gene information	Species	Human
	Gene symbol	TLL1
	Gene ID	7092
	Gene name	tolloid like 1
	Gene Alias	ASD6
	Cytomap	4q32.3
	Gene Type	protein-coding
	GO ID	GO:0001501
	UniProtAcc	O43897

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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
7092	TLL1	P11T-E	Human	Esophagus	ESCC	2.96e-18	7.84e-01	0.1426
7092	TLL1	P37T-E	Human	Esophagus	ESCC	5.58e-28	5.46e-01	0.1371
7092	TLL1	P52T-E	Human	Esophagus	ESCC	7.04e-04	1.76e-01	0.1555
7092	TLL1	P89T-E	Human	Esophagus	ESCC	3.85e-03	2.94e-01	0.1752
7092	TLL1	P107T-E	Human	Esophagus	ESCC	6.90e-07	1.84e-01	0.171

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias

∗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:0034340	Colorectum	AD	response to type I interferon	22/3918	58/18723	2.23e-03	1.75e-02	22
GO:0060337	Colorectum	AD	type I interferon signaling pathway	19/3918	50/18723	4.23e-03	2.91e-02	19
GO:0007346	Colorectum	AD	regulation of mitotic cell cycle	119/3918	457/18723	4.60e-03	3.14e-02	119
GO:0071357	Colorectum	AD	cellular response to type I interferon	19/3918	52/18723	6.92e-03	4.26e-02	19
GO:00343401	Colorectum	SER	response to type I interferon	17/2897	58/18723	5.50e-03	4.07e-02	17
GO:00343402	Colorectum	MSS	response to type I interferon	20/3467	58/18723	2.82e-03	2.20e-02	20
GO:00073461	Colorectum	MSS	regulation of mitotic cell cycle	108/3467	457/18723	3.30e-03	2.50e-02	108
GO:000734615	Esophagus	ESCC	regulation of mitotic cell cycle	293/8552	457/18723	8.00e-16	5.64e-14	293
GO:000170119	Esophagus	ESCC	in utero embryonic development	243/8552	367/18723	1.00e-15	6.86e-14	243
GO:003434013	Esophagus	ESCC	response to type I interferon	48/8552	58/18723	6.18e-09	1.26e-07	48
GO:00603375	Esophagus	ESCC	type I interferon signaling pathway	41/8552	50/18723	1.35e-07	2.17e-06	41
GO:00713575	Esophagus	ESCC	cellular response to type I interferon	42/8552	52/18723	2.15e-07	3.30e-06	42
GO:000182412	Esophagus	ESCC	blastocyst development	73/8552	106/18723	1.13e-06	1.40e-05	73
GO:00028318	Esophagus	ESCC	regulation of response to biotic stimulus	191/8552	327/18723	2.12e-06	2.45e-05	191
GO:00607595	Esophagus	ESCC	regulation of response to cytokine stimulus	103/8552	162/18723	3.14e-06	3.53e-05	103
GO:000283212	Esophagus	ESCC	negative regulation of response to biotic stimulus	72/8552	108/18723	8.36e-06	8.11e-05	72
GO:00019595	Esophagus	ESCC	regulation of cytokine-mediated signaling pathway	95/8552	150/18723	9.48e-06	9.04e-05	95
GO:00603385	Esophagus	ESCC	regulation of type I interferon-mediated signaling pathway	29/8552	36/18723	1.91e-05	1.67e-04	29
GO:00991114	Esophagus	ESCC	microtubule-based transport	115/8552	190/18723	2.54e-05	2.15e-04	115
GO:00301984	Esophagus	ESCC	extracellular matrix organization	171/8552	301/18723	6.08e-05	4.67e-04	171

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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

TLL1

SNV

Missense_Mutation

c.1265N>C

p.Arg422Thr

p.R422T

O43897

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A04X-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

TLL1

SNV

Missense_Mutation

rs541756882

c.2890N>G

p.Arg964Gly

p.R964G

O43897

protein_coding

deleterious(0.03)

probably_damaging(0.997)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TLL1

SNV

Missense_Mutation

novel

c.1983G>T

p.Glu661Asp

p.E661D

O43897

protein_coding

tolerated(0.67)

benign(0.031)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TLL1

SNV

Missense_Mutation

c.343N>G

p.Ile115Val

p.I115V

O43897

protein_coding

tolerated(0.32)

benign(0.022)

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TLL1

SNV

Missense_Mutation

rs150329580

c.1331N>A

p.Arg444His

p.R444H

O43897

protein_coding

tolerated(0.07)

probably_damaging(1)

TCGA-OL-A5RU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

TLL1

SNV

Missense_Mutation

c.1112C>G

p.Ser371Cys

p.S371C

O43897

protein_coding

deleterious(0)

probably_damaging(0.956)

TCGA-OL-A66L-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TLL1

SNV

Missense_Mutation

novel

c.2173G>A

p.Ala725Thr

p.A725T

O43897

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

TLL1

SNV

Missense_Mutation

c.350N>A

p.Arg117Lys

p.R117K

O43897

protein_coding

tolerated(0.32)

benign(0.001)

TCGA-C5-A1BQ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

cisplatin

TLL1

SNV

Missense_Mutation

c.350G>A

p.Arg117Lys

p.R117K

O43897

protein_coding

tolerated(0.32)

benign(0.001)

TCGA-C5-A3HL-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

TLL1

SNV

Missense_Mutation

c.2919N>T

p.Glu973Asp

p.E973D

O43897

protein_coding

tolerated(0.37)

benign(0.325)

TCGA-FU-A3HZ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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

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