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: SMC6

Gene summary for SMC6

Gene summary.

Gene information	Species	Human
	Gene symbol	SMC6
	Gene ID	79677
	Gene name	structural maintenance of chromosomes 6
	Gene Alias	SMC-6
	Cytomap	2p24.2
	Gene Type	protein-coding
	GO ID	GO:0000722
	UniProtAcc	Q96SB8

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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
79677	SMC6	CA_HPV_1	Human	Cervix	CC	1.40e-05	1.93e-01	0.0264
79677	SMC6	CCI_1	Human	Cervix	CC	6.73e-03	8.19e-01	0.528
79677	SMC6	CCI_2	Human	Cervix	CC	5.15e-10	1.01e+00	0.5249
79677	SMC6	CCI_3	Human	Cervix	CC	4.28e-08	6.74e-01	0.516
79677	SMC6	sample3	Human	Cervix	CC	4.48e-03	2.44e-01	0.1387
79677	SMC6	T3	Human	Cervix	CC	4.49e-03	2.56e-01	0.1389
79677	SMC6	LZE4T	Human	Esophagus	ESCC	4.08e-15	4.42e-01	0.0811
79677	SMC6	LZE7T	Human	Esophagus	ESCC	8.22e-08	4.45e-01	0.0667
79677	SMC6	LZE8T	Human	Esophagus	ESCC	2.56e-12	1.29e-01	0.067
79677	SMC6	LZE20T	Human	Esophagus	ESCC	3.25e-07	3.09e-02	0.0662
79677	SMC6	LZE22D1	Human	Esophagus	HGIN	1.33e-02	-4.45e-02	0.0595
79677	SMC6	LZE22T	Human	Esophagus	ESCC	1.70e-03	2.01e-01	0.068
79677	SMC6	LZE24T	Human	Esophagus	ESCC	1.53e-13	4.31e-01	0.0596
79677	SMC6	LZE21T	Human	Esophagus	ESCC	1.86e-08	5.38e-01	0.0655
79677	SMC6	LZE6T	Human	Esophagus	ESCC	1.87e-05	3.19e-02	0.0845
79677	SMC6	P1T-E	Human	Esophagus	ESCC	1.25e-06	5.88e-01	0.0875
79677	SMC6	P2T-E	Human	Esophagus	ESCC	1.46e-32	7.12e-01	0.1177
79677	SMC6	P4T-E	Human	Esophagus	ESCC	2.55e-30	7.31e-01	0.1323
79677	SMC6	P5T-E	Human	Esophagus	ESCC	5.47e-13	2.89e-01	0.1327
79677	SMC6	P8T-E	Human	Esophagus	ESCC	4.19e-19	2.22e-01	0.0889

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
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:00075689	Cervix	CC	aging	75/2311	339/18723	2.75e-07	1.13e-05	75
GO:00075695	Cervix	CC	cell aging	34/2311	132/18723	1.92e-05	3.53e-04	34
GO:00903981	Cervix	CC	cellular senescence	25/2311	93/18723	1.11e-04	1.40e-03	25
GO:00007239	Cervix	CC	telomere maintenance	26/2311	131/18723	9.33e-03	4.66e-02	26
GO:004217627	Esophagus	HGIN	regulation of protein catabolic process	119/2587	391/18723	8.09e-18	2.43e-15	119
GO:001049826	Esophagus	HGIN	proteasomal protein catabolic process	139/2587	490/18723	1.20e-17	3.41e-15	139
GO:004586227	Esophagus	HGIN	positive regulation of proteolysis	107/2587	372/18723	2.61e-14	4.60e-12	107
GO:004316126	Esophagus	HGIN	proteasome-mediated ubiquitin-dependent protein catabolic process	114/2587	412/18723	7.00e-14	1.20e-11	114
GO:190336227	Esophagus	HGIN	regulation of cellular protein catabolic process	81/2587	255/18723	1.16e-13	1.93e-11	81
GO:003497625	Esophagus	HGIN	response to endoplasmic reticulum stress	81/2587	256/18723	1.47e-13	2.32e-11	81
GO:000989626	Esophagus	HGIN	positive regulation of catabolic process	126/2587	492/18723	1.46e-12	2.09e-10	126
GO:003133126	Esophagus	HGIN	positive regulation of cellular catabolic process	112/2587	427/18723	5.15e-12	6.72e-10	112
GO:190305027	Esophagus	HGIN	regulation of proteolysis involved in cellular protein catabolic process	70/2587	221/18723	6.21e-12	7.76e-10	70
GO:006113627	Esophagus	HGIN	regulation of proteasomal protein catabolic process	60/2587	187/18723	1.10e-10	1.12e-08	60
GO:004573227	Esophagus	HGIN	positive regulation of protein catabolic process	69/2587	231/18723	1.66e-10	1.64e-08	69
GO:190336427	Esophagus	HGIN	positive regulation of cellular protein catabolic process	51/2587	155/18723	1.01e-09	8.15e-08	51
GO:190180020	Esophagus	HGIN	positive regulation of proteasomal protein catabolic process	41/2587	114/18723	2.25e-09	1.67e-07	41
GO:190305219	Esophagus	HGIN	positive regulation of proteolysis involved in cellular protein catabolic process	45/2587	133/18723	3.55e-09	2.53e-07	45
GO:003133425	Esophagus	HGIN	positive regulation of protein-containing complex assembly	61/2587	237/18723	7.10e-07	3.00e-05	61
GO:004325427	Esophagus	HGIN	regulation of protein-containing complex assembly	94/2587	428/18723	2.39e-06	8.55e-05	94

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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

SMC6

SNV

Missense_Mutation

novel

c.179N>T

p.Ser60Leu

p.S60L

Q96SB8

protein_coding

deleterious(0.01)

possibly_damaging(0.783)

TCGA-5L-AAT0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

SMC6

SNV

Missense_Mutation

rs376248274

c.2819N>A

p.Arg940Gln

p.R940Q

Q96SB8

protein_coding

tolerated(0.22)

possibly_damaging(0.596)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SMC6

SNV

Missense_Mutation

rs373857118

c.745N>T

p.Arg249Cys

p.R249C

Q96SB8

protein_coding

deleterious(0)

benign(0.133)

TCGA-AR-A0TS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

SMC6

SNV

Missense_Mutation

novel

c.1570N>A

p.Glu524Lys

p.E524K

Q96SB8

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

SMC6

SNV

Missense_Mutation

c.2240A>G

p.Glu747Gly

p.E747G

Q96SB8

protein_coding

deleterious(0)

possibly_damaging(0.745)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SMC6

SNV

Missense_Mutation

c.1694C>T

p.Ser565Phe

p.S565F

Q96SB8

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-EW-A1PB-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

SMC6

SNV

Missense_Mutation

novel

c.1041N>T

p.Met347Ile

p.M347I

Q96SB8

protein_coding

tolerated(1)

benign(0)

TCGA-S3-A6ZH-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

SMC6

insertion

Frame_Shift_Ins

novel

c.1867_1868insATCTTCTAAGTCAT

p.Val623AspfsTer6

p.V623Dfs*6

Q96SB8

protein_coding

TCGA-AQ-A04H-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxotere

SMC6

SNV

Missense_Mutation

novel

c.2837A>G

p.Asp946Gly

p.D946G

Q96SB8

protein_coding

deleterious(0.02)

benign(0.092)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SMC6

SNV

Missense_Mutation

novel

c.2482A>G

p.Thr828Ala

p.T828A

Q96SB8

protein_coding

tolerated(0.45)

benign(0.05)

TCGA-2W-A8YY-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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