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: CYLD

Gene summary for CYLD

Gene summary.

Gene information	Species	Human
	Gene symbol	CYLD
	Gene ID	1540
	Gene name	CYLD lysine 63 deubiquitinase
	Gene Alias	BRSS
	Cytomap	16q12.1
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	A0A024R6T1

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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
1540	CYLD	EEC-subject1	Human	Endometrium	EEC	2.41e-03	1.71e-01	-0.2682
1540	CYLD	GSM5276934	Human	Endometrium	EEC	3.95e-24	6.50e-01	-0.0913
1540	CYLD	GSM5276937	Human	Endometrium	EEC	9.27e-13	4.54e-01	-0.0897
1540	CYLD	GSM6177620_NYU_UCEC1_lib1_lib1	Human	Endometrium	EEC	7.89e-04	9.23e-02	-0.1869
1540	CYLD	GSM6177620_NYU_UCEC1_lib2_lib2	Human	Endometrium	EEC	1.05e-05	9.46e-02	-0.1875
1540	CYLD	GSM6177620_NYU_UCEC1_lib3_lib3	Human	Endometrium	EEC	1.09e-04	6.48e-02	-0.1883
1540	CYLD	GSM6177621_NYU_UCEC2_lib1_lib1	Human	Endometrium	EEC	5.74e-06	1.57e-02	-0.1934
1540	CYLD	GSM6177622_NYU_UCEC3_lib1_lib1	Human	Endometrium	EEC	2.51e-12	4.44e-02	-0.1917
1540	CYLD	GSM6177622_NYU_UCEC3_lib2_lib2	Human	Endometrium	EEC	4.22e-04	-2.12e-02	-0.1916
1540	CYLD	LZE4T	Human	Esophagus	ESCC	1.89e-13	3.00e-01	0.0811
1540	CYLD	LZE7T	Human	Esophagus	ESCC	9.38e-07	2.58e-01	0.0667
1540	CYLD	LZE8T	Human	Esophagus	ESCC	1.69e-04	1.08e-01	0.067
1540	CYLD	LZE20T	Human	Esophagus	ESCC	1.72e-02	1.74e-01	0.0662
1540	CYLD	LZE24T	Human	Esophagus	ESCC	9.21e-14	2.63e-01	0.0596
1540	CYLD	P1T-E	Human	Esophagus	ESCC	1.78e-03	3.83e-01	0.0875
1540	CYLD	P2T-E	Human	Esophagus	ESCC	5.20e-17	8.87e-02	0.1177
1540	CYLD	P4T-E	Human	Esophagus	ESCC	2.68e-09	1.34e-01	0.1323
1540	CYLD	P5T-E	Human	Esophagus	ESCC	3.00e-14	1.77e-01	0.1327
1540	CYLD	P8T-E	Human	Esophagus	ESCC	1.66e-13	3.00e-01	0.0889
1540	CYLD	P10T-E	Human	Esophagus	ESCC	1.50e-09	-2.78e-02	0.116

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma

∗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:000276413	Oral cavity	EOLP	immune response-regulating signaling pathway	108/2218	468/18723	4.04e-12	7.34e-10	108
GO:00607592	Oral cavity	EOLP	regulation of response to cytokine stimulus	49/2218	162/18723	2.70e-10	2.45e-08	49
GO:00019592	Oral cavity	EOLP	regulation of cytokine-mediated signaling pathway	46/2218	150/18723	5.71e-10	4.44e-08	46
GO:200123525	Oral cavity	EOLP	positive regulation of apoptotic signaling pathway	41/2218	126/18723	6.68e-10	5.06e-08	41
GO:003052225	Oral cavity	EOLP	intracellular receptor signaling pathway	64/2218	265/18723	1.56e-08	7.06e-07	64
GO:200123625	Oral cavity	EOLP	regulation of extrinsic apoptotic signaling pathway	42/2218	151/18723	7.31e-08	2.61e-06	42
GO:009719125	Oral cavity	EOLP	extrinsic apoptotic signaling pathway	54/2218	219/18723	9.74e-08	3.36e-06	54
GO:000222113	Oral cavity	EOLP	pattern recognition receptor signaling pathway	45/2218	172/18723	1.82e-07	5.82e-06	45
GO:007135623	Oral cavity	EOLP	cellular response to tumor necrosis factor	55/2218	229/18723	1.90e-07	6.02e-06	55
GO:001922112	Oral cavity	EOLP	cytokine-mediated signaling pathway	94/2218	472/18723	2.36e-07	7.37e-06	94
GO:001605523	Oral cavity	EOLP	Wnt signaling pathway	89/2218	444/18723	3.66e-07	1.06e-05	89
GO:019873823	Oral cavity	EOLP	cell-cell signaling by wnt	89/2218	446/18723	4.49e-07	1.25e-05	89
GO:003461224	Oral cavity	EOLP	response to tumor necrosis factor	58/2218	253/18723	4.79e-07	1.32e-05	58
GO:003320922	Oral cavity	EOLP	tumor necrosis factor-mediated signaling pathway	30/2218	99/18723	7.19e-07	1.83e-05	30
GO:007042312	Oral cavity	EOLP	nucleotide-binding oligomerization domain containing signaling pathway	13/2218	25/18723	1.14e-06	2.78e-05	13
GO:003587212	Oral cavity	EOLP	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	13/2218	26/18723	2.03e-06	4.60e-05	13
GO:000275312	Oral cavity	EOLP	cytoplasmic pattern recognition receptor signaling pathway	21/2218	60/18723	2.55e-06	5.64e-05	21
GO:003011123	Oral cavity	EOLP	regulation of Wnt signaling pathway	67/2218	328/18723	5.11e-06	1.04e-04	67
GO:003247911	Oral cavity	EOLP	regulation of type I interferon production	27/2218	95/18723	9.68e-06	1.75e-04	27
GO:003260611	Oral cavity	EOLP	type I interferon production	27/2218	95/18723	9.68e-06	1.75e-04	27

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa046687	Endometrium	EEC	TNF signaling pathway	27/1237	114/8465	6.47e-03	3.22e-02	2.40e-02	27
hsa0466814	Endometrium	EEC	TNF signaling pathway	27/1237	114/8465	6.47e-03	3.22e-02	2.40e-02	27
hsa0466810	Esophagus	ESCC	TNF signaling pathway	89/4205	114/8465	3.36e-10	4.01e-09	2.06e-09	89
hsa046259	Esophagus	ESCC	C-type lectin receptor signaling pathway	73/4205	104/8465	1.57e-05	7.98e-05	4.09e-05	73
hsa040645	Esophagus	ESCC	NF-kappa B signaling pathway	67/4205	104/8465	1.62e-03	4.89e-03	2.50e-03	67
hsa0466817	Esophagus	ESCC	TNF signaling pathway	89/4205	114/8465	3.36e-10	4.01e-09	2.06e-09	89
hsa0462513	Esophagus	ESCC	C-type lectin receptor signaling pathway	73/4205	104/8465	1.57e-05	7.98e-05	4.09e-05	73
hsa0406412	Esophagus	ESCC	NF-kappa B signaling pathway	67/4205	104/8465	1.62e-03	4.89e-03	2.50e-03	67
hsa046684	Liver	HCC	TNF signaling pathway	73/4020	114/8465	2.53e-04	1.19e-03	6.63e-04	73
hsa0466811	Liver	HCC	TNF signaling pathway	73/4020	114/8465	2.53e-04	1.19e-03	6.63e-04	73
hsa046689	Oral cavity	OSCC	TNF signaling pathway	82/3704	114/8465	8.30e-10	9.59e-09	4.88e-09	82
hsa046258	Oral cavity	OSCC	C-type lectin receptor signaling pathway	73/3704	104/8465	3.83e-08	3.12e-07	1.59e-07	73
hsa040644	Oral cavity	OSCC	NF-kappa B signaling pathway	67/3704	104/8465	1.57e-05	6.75e-05	3.44e-05	67
hsa043806	Oral cavity	OSCC	Osteoclast differentiation	73/3704	128/8465	1.60e-03	4.44e-03	2.26e-03	73
hsa04622	Oral cavity	OSCC	RIG-I-like receptor signaling pathway	41/3704	71/8465	1.20e-02	2.63e-02	1.34e-02	41
hsa0466816	Oral cavity	OSCC	TNF signaling pathway	82/3704	114/8465	8.30e-10	9.59e-09	4.88e-09	82
hsa0462512	Oral cavity	OSCC	C-type lectin receptor signaling pathway	73/3704	104/8465	3.83e-08	3.12e-07	1.59e-07	73
hsa0406411	Oral cavity	OSCC	NF-kappa B signaling pathway	67/3704	104/8465	1.57e-05	6.75e-05	3.44e-05	67
hsa0438011	Oral cavity	OSCC	Osteoclast differentiation	73/3704	128/8465	1.60e-03	4.44e-03	2.26e-03	73
hsa046221	Oral cavity	OSCC	RIG-I-like receptor signaling pathway	41/3704	71/8465	1.20e-02	2.63e-02	1.34e-02	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

CYLD

SNV

Missense_Mutation

c.1787N>A

p.Gly596Asp

p.G596D

Q9NQC7

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AR-A1AY-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unspecific

Doxorubicin

CYLD

SNV

Missense_Mutation

c.815N>T

p.Pro272Leu

p.P272L

Q9NQC7

protein_coding

deleterious(0)

possibly_damaging(0.767)

TCGA-BH-A0B7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CYLD

SNV

Missense_Mutation

novel

c.590T>C

p.Val197Ala

p.V197A

Q9NQC7

protein_coding

tolerated(0.08)

probably_damaging(0.992)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CYLD

SNV

Missense_Mutation

c.1240N>C

p.Asn414His

p.N414H

Q9NQC7

protein_coding

deleterious(0.02)

possibly_damaging(0.832)

TCGA-EW-A1P4-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

docetaxel

CYLD

SNV

Missense_Mutation

rs538206791

c.100N>G

p.Gln34Glu

p.Q34E

Q9NQC7

protein_coding

tolerated_low_confidence(0.11)

benign(0.066)

TCGA-OL-A66I-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CYLD

insertion

Frame_Shift_Ins

novel

c.1584_1585insCCTGTTTTAATGCTTGTAGAAATGGTGCGGGAAAGCCCGTTTAACC

p.Lys529ProfsTer29

p.K529Pfs*29

Q9NQC7

protein_coding

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CYLD

insertion

Frame_Shift_Ins

novel

c.2766_2767insTGGTA

p.Leu923TrpfsTer32

p.L923Wfs*32

Q9NQC7

protein_coding

TCGA-BH-A0BV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

CYLD

insertion

Nonsense_Mutation

novel

c.2767_2768insAAGCACAAGTGACAGGAGATATCTAGTAAAGACTT

p.Leu923GlnfsTer9

p.L923Qfs*9

Q9NQC7

protein_coding

TCGA-BH-A0BV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

CYLD

SNV

Missense_Mutation

novel

c.1411G>C

p.Glu471Gln

p.E471Q

Q9NQC7

protein_coding

deleterious(0)

probably_damaging(0.986)

TCGA-EA-A3HU-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CYLD

SNV

Missense_Mutation

novel

c.280N>C

p.Glu94Gln

p.E94Q

Q9NQC7

protein_coding

tolerated(0.18)

probably_damaging(0.986)

TCGA-JW-A5VL-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

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