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: IL6ST

Gene summary for IL6ST

Gene summary.

Gene information	Species	Human
	Gene symbol	IL6ST
	Gene ID	3572
	Gene name	interleukin 6 cytokine family signal transducer
	Gene Alias	CD130
	Cytomap	5q11.2
	Gene Type	protein-coding
	GO ID	GO:0001503
	UniProtAcc	A0A0A0N0L2

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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
3572	IL6ST	GSM4909281	Human	Breast	IDC	1.28e-11	-3.41e-01	0.21
3572	IL6ST	GSM4909282	Human	Breast	IDC	2.60e-14	-3.48e-01	-0.0288
3572	IL6ST	GSM4909285	Human	Breast	IDC	2.52e-07	-2.89e-01	0.21
3572	IL6ST	GSM4909286	Human	Breast	IDC	5.51e-23	-3.87e-01	0.1081
3572	IL6ST	GSM4909291	Human	Breast	IDC	6.76e-06	-3.83e-01	0.1753
3572	IL6ST	GSM4909293	Human	Breast	IDC	2.05e-17	5.12e-01	0.1581
3572	IL6ST	GSM4909294	Human	Breast	IDC	1.14e-08	-2.99e-01	0.2022
3572	IL6ST	GSM4909296	Human	Breast	IDC	2.85e-09	-2.36e-01	0.1524
3572	IL6ST	GSM4909297	Human	Breast	IDC	8.23e-10	1.24e-01	0.1517
3572	IL6ST	GSM4909298	Human	Breast	IDC	1.70e-08	4.69e-01	0.1551
3572	IL6ST	GSM4909301	Human	Breast	IDC	4.31e-11	5.14e-01	0.1577
3572	IL6ST	GSM4909302	Human	Breast	IDC	2.81e-20	5.87e-01	0.1545
3572	IL6ST	GSM4909303	Human	Breast	IDC	6.51e-08	5.62e-01	0.0438
3572	IL6ST	GSM4909304	Human	Breast	IDC	1.66e-30	7.31e-01	0.1636
3572	IL6ST	GSM4909307	Human	Breast	IDC	7.55e-11	5.21e-01	0.1569
3572	IL6ST	GSM4909308	Human	Breast	IDC	4.12e-62	9.41e-01	0.158
3572	IL6ST	GSM4909311	Human	Breast	IDC	2.53e-26	-3.80e-01	0.1534
3572	IL6ST	GSM4909312	Human	Breast	IDC	8.18e-08	-1.29e-01	0.1552
3572	IL6ST	GSM4909313	Human	Breast	IDC	1.76e-03	2.54e-01	0.0391
3572	IL6ST	GSM4909319	Human	Breast	IDC	3.96e-28	-2.31e-01	0.1563

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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
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
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
Prostate		BPH: Benign Prostatic Hyperplasia
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:00507679	Oral cavity	OSCC	regulation of neurogenesis	179/7305	364/18723	4.49e-05	3.84e-04	179
GO:000164910	Oral cavity	OSCC	osteoblast differentiation	118/7305	229/18723	7.51e-05	5.85e-04	118
GO:00072196	Oral cavity	OSCC	Notch signaling pathway	92/7305	172/18723	7.84e-05	6.08e-04	92
GO:005086315	Oral cavity	OSCC	regulation of T cell activation	161/7305	329/18723	1.44e-04	1.02e-03	161
GO:00321037	Oral cavity	OSCC	positive regulation of response to external stimulus	203/7305	427/18723	1.79e-04	1.22e-03	203
GO:00192214	Oral cavity	OSCC	cytokine-mediated signaling pathway	222/7305	472/18723	2.02e-04	1.35e-03	222
GO:00519624	Oral cavity	OSCC	positive regulation of nervous system development	135/7305	272/18723	2.20e-04	1.44e-03	135
GO:000715916	Oral cavity	OSCC	leukocyte cell-cell adhesion	178/7305	371/18723	2.44e-04	1.57e-03	178
GO:190303715	Oral cavity	OSCC	regulation of leukocyte cell-cell adhesion	162/7305	336/18723	3.39e-04	2.08e-03	162
GO:00182123	Oral cavity	OSCC	peptidyl-tyrosine modification	180/7305	378/18723	3.63e-04	2.22e-03	180
GO:005087819	Oral cavity	OSCC	regulation of body fluid levels	179/7305	379/18723	6.19e-04	3.50e-03	179
GO:00085934	Oral cavity	OSCC	regulation of Notch signaling pathway	53/7305	95/18723	6.64e-04	3.72e-03	53
GO:0050730	Oral cavity	OSCC	regulation of peptidyl-tyrosine phosphorylation	129/7305	264/18723	6.70e-04	3.75e-03	129
GO:00181083	Oral cavity	OSCC	peptidyl-tyrosine phosphorylation	177/7305	375/18723	6.86e-04	3.83e-03	177
GO:0014015	Oral cavity	OSCC	positive regulation of gliogenesis	39/7305	66/18723	7.46e-04	4.07e-03	39
GO:004209816	Oral cavity	OSCC	T cell proliferation	100/7305	199/18723	7.93e-04	4.27e-03	100
GO:00519605	Oral cavity	OSCC	regulation of nervous system development	205/7305	443/18723	9.80e-04	5.11e-03	205
GO:002240917	Oral cavity	OSCC	positive regulation of cell-cell adhesion	136/7305	284/18723	1.35e-03	6.62e-03	136
GO:00100015	Oral cavity	OSCC	glial cell differentiation	110/7305	225/18723	1.56e-03	7.45e-03	110
GO:000181910	Oral cavity	OSCC	positive regulation of cytokine production	213/7305	467/18723	1.93e-03	8.96e-03	213

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0517118	Breast	Precancer	Coronavirus disease - COVID-19	81/684	232/8465	3.74e-32	2.36e-30	1.81e-30	81
hsa0516718	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa052036	Breast	Precancer	Viral carcinogenesis	27/684	204/8465	7.19e-03	4.06e-02	3.11e-02	27
hsa0517119	Breast	Precancer	Coronavirus disease - COVID-19	81/684	232/8465	3.74e-32	2.36e-30	1.81e-30	81
hsa0516719	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0520312	Breast	Precancer	Viral carcinogenesis	27/684	204/8465	7.19e-03	4.06e-02	3.11e-02	27
hsa0517124	Breast	IDC	Coronavirus disease - COVID-19	86/867	232/8465	1.50e-28	9.72e-27	7.27e-27	86
hsa0516723	Breast	IDC	Kaposi sarcoma-associated herpesvirus infection	38/867	194/8465	5.87e-05	5.96e-04	4.46e-04	38
hsa0520322	Breast	IDC	Viral carcinogenesis	34/867	204/8465	2.82e-03	1.86e-02	1.39e-02	34
hsa0517134	Breast	IDC	Coronavirus disease - COVID-19	86/867	232/8465	1.50e-28	9.72e-27	7.27e-27	86
hsa0516733	Breast	IDC	Kaposi sarcoma-associated herpesvirus infection	38/867	194/8465	5.87e-05	5.96e-04	4.46e-04	38
hsa0520332	Breast	IDC	Viral carcinogenesis	34/867	204/8465	2.82e-03	1.86e-02	1.39e-02	34
hsa0517144	Breast	DCIS	Coronavirus disease - COVID-19	86/846	232/8465	2.42e-29	1.56e-27	1.15e-27	86
hsa0516743	Breast	DCIS	Kaposi sarcoma-associated herpesvirus infection	38/846	194/8465	3.43e-05	3.69e-04	2.72e-04	38
hsa0520341	Breast	DCIS	Viral carcinogenesis	34/846	204/8465	1.88e-03	1.27e-02	9.33e-03	34
hsa0517154	Breast	DCIS	Coronavirus disease - COVID-19	86/846	232/8465	2.42e-29	1.56e-27	1.15e-27	86
hsa0516753	Breast	DCIS	Kaposi sarcoma-associated herpesvirus infection	38/846	194/8465	3.43e-05	3.69e-04	2.72e-04	38
hsa052035	Breast	DCIS	Viral carcinogenesis	34/846	204/8465	1.88e-03	1.27e-02	9.33e-03	34
hsa05171	Colorectum	AD	Coronavirus disease - COVID-19	113/2092	232/8465	9.90e-16	2.55e-14	1.63e-14	113
hsa051711	Colorectum	AD	Coronavirus disease - COVID-19	113/2092	232/8465	9.90e-16	2.55e-14	1.63e-14	113

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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
OSM	LIFR_IL6ST	OSM_LIFR_IL6ST	OSM	Breast	DCIS
OSM	OSMR_IL6ST	OSM_OSMR_IL6ST	OSM	Breast	DCIS
IL6	IL6R_IL6ST	IL6_IL6R_IL6ST	IL6	Breast	Healthy
LIF	LIFR_IL6ST	LIF_LIFR_IL6ST	LIFR	Breast	Healthy
OSM	LIFR_IL6ST	OSM_LIFR_IL6ST	OSM	Breast	Healthy
OSM	OSMR_IL6ST	OSM_OSMR_IL6ST	OSM	Breast	Healthy
LIF	LIFR_IL6ST	LIF_LIFR_IL6ST	LIFR	Cervix	ADJ
IL6	IL6R_IL6ST	IL6_IL6R_IL6ST	IL6	Cervix	ADJ
OSM	LIFR_IL6ST	OSM_LIFR_IL6ST	OSM	Cervix	CC
OSM	OSMR_IL6ST	OSM_OSMR_IL6ST	OSM	Cervix	CC
IL6	IL6R_IL6ST	IL6_IL6R_IL6ST	IL6	Cervix	CC
LIF	LIFR_IL6ST	LIF_LIFR_IL6ST	LIFR	Cervix	CC
OSM	OSMR_IL6ST	OSM_OSMR_IL6ST	OSM	Cervix	Healthy
OSM	LIFR_IL6ST	OSM_LIFR_IL6ST	OSM	Cervix	Precancer
OSM	OSMR_IL6ST	OSM_OSMR_IL6ST	OSM	Cervix	Precancer
LIF	LIFR_IL6ST	LIF_LIFR_IL6ST	LIFR	Endometrium	ADJ
OSM	LIFR_IL6ST	OSM_LIFR_IL6ST	OSM	Endometrium	ADJ
OSM	OSMR_IL6ST	OSM_OSMR_IL6ST	OSM	Endometrium	ADJ
LIF	LIFR_IL6ST	LIF_LIFR_IL6ST	LIFR	Endometrium	AEH
OSM	LIFR_IL6ST	OSM_LIFR_IL6ST	OSM	Endometrium	AEH

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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

IL6ST

SNV

Missense_Mutation

novel

c.1768N>A

p.Val590Ile

p.V590I

P40189

protein_coding

tolerated(0.08)

possibly_damaging(0.682)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IL6ST

SNV

Missense_Mutation

rs764426398

c.412N>A

p.Glu138Lys

p.E138K

P40189

protein_coding

tolerated(0.06)

possibly_damaging(0.465)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IL6ST

SNV

Missense_Mutation

rs750312883

c.1435C>T

p.Arg479Cys

p.R479C

P40189

protein_coding

deleterious(0.02)

benign(0.37)

TCGA-AN-A0XW-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

IL6ST

SNV

Missense_Mutation

c.413N>C

p.Glu138Ala

p.E138A

P40189

protein_coding

tolerated(0.06)

possibly_damaging(0.542)

TCGA-AR-A251-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

IL6ST

SNV

Missense_Mutation

c.836N>G

p.Ser279Cys

p.S279C

P40189

protein_coding

deleterious(0)

possibly_damaging(0.773)

TCGA-BH-A0WA-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

IL6ST

SNV

Missense_Mutation

c.1136A>G

p.Asn379Ser

p.N379S

P40189

protein_coding

tolerated(0.85)

benign(0.003)

TCGA-C8-A12X-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

IL6ST

SNV

Missense_Mutation

c.1520N>G

p.Pro507Arg

p.P507R

P40189

protein_coding

tolerated(0.11)

benign(0.268)

TCGA-GI-A2C8-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

Adriamycin

IL6ST

SNV

Missense_Mutation

rs755797298

c.1436G>A

p.Arg479His

p.R479H

P40189

protein_coding

tolerated(0.14)

benign(0)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

IL6ST

SNV

Missense_Mutation

rs747379809

c.703N>A

p.Glu235Lys

p.E235K

P40189

protein_coding

tolerated(0.23)

possibly_damaging(0.695)

TCGA-C5-A901-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

IL6ST

SNV

Missense_Mutation

c.2471N>T

p.Ser824Phe

p.S824F

P40189

protein_coding

tolerated(0.4)

benign(0)

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
3572	IL6ST	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, KINASE		BAZEDOXIFENE	BAZEDOXIFENE	24456369
3572	IL6ST	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, KINASE		RALOXIFENE	RALOXIFENE	24456369
3572	IL6ST	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, KINASE	antagonist	CHEMBL3833307	SATRALIZUMAB

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