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: SMO

Gene summary for SMO

Gene summary.

Gene information	Species	Human
	Gene symbol	SMO
	Gene ID	6608
	Gene name	smoothened, frizzled class receptor
	Gene Alias	CRJS
	Cytomap	7q32.1
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	Q99835

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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
6608	SMO	HCC1_Meng	Human	Liver	HCC	1.01e-15	3.25e-02	0.0246
6608	SMO	HCC1	Human	Liver	HCC	9.29e-16	3.51e+00	0.5336
6608	SMO	HCC2	Human	Liver	HCC	8.74e-14	2.00e+00	0.5341

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		NAFLD: Non-alcoholic fatty liver disease

∗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:00016497	Cervix	CC	osteoblast differentiation	47/2311	229/18723	2.88e-04	3.11e-03	47
GO:0045667	Cervix	CC	regulation of osteoblast differentiation	29/2311	132/18723	1.32e-03	1.05e-02	29
GO:00015037	Cervix	CC	ossification	71/2311	408/18723	1.67e-03	1.28e-02	71
GO:00487365	Cervix	CC	appendage development	35/2311	172/18723	1.88e-03	1.39e-02	35
GO:00601735	Cervix	CC	limb development	35/2311	172/18723	1.88e-03	1.39e-02	35
GO:0150063	Cervix	CC	visual system development	63/2311	375/18723	6.58e-03	3.65e-02	63
GO:0030198	Cervix	CC	extracellular matrix organization	52/2311	301/18723	7.43e-03	3.98e-02	52
GO:0001654	Cervix	CC	eye development	62/2311	371/18723	7.83e-03	4.13e-02	62
GO:0043062	Cervix	CC	extracellular structure organization	52/2311	302/18723	7.92e-03	4.17e-02	52
GO:0045229	Cervix	CC	external encapsulating structure organization	52/2311	304/18723	9.00e-03	4.57e-02	52
GO:0048880	Cervix	CC	sensory system development	63/2311	381/18723	9.29e-03	4.66e-02	63
GO:0051052	Colorectum	AD	regulation of DNA metabolic process	116/3918	359/18723	2.47e-07	1.00e-05	116
GO:0051054	Colorectum	AD	positive regulation of DNA metabolic process	73/3918	201/18723	3.27e-07	1.29e-05	73
GO:0042060	Colorectum	AD	wound healing	128/3918	422/18723	2.73e-06	7.89e-05	128
GO:2000278	Colorectum	AD	regulation of DNA biosynthetic process	41/3918	106/18723	2.17e-05	4.33e-04	41
GO:0001667	Colorectum	AD	ameboidal-type cell migration	137/3918	475/18723	2.17e-05	4.33e-04	137
GO:2000573	Colorectum	AD	positive regulation of DNA biosynthetic process	28/3918	66/18723	6.35e-05	1.05e-03	28
GO:0090132	Colorectum	AD	epithelium migration	105/3918	360/18723	1.18e-04	1.73e-03	105
GO:0010632	Colorectum	AD	regulation of epithelial cell migration	88/3918	292/18723	1.19e-04	1.75e-03	88
GO:0010631	Colorectum	AD	epithelial cell migration	104/3918	357/18723	1.33e-04	1.90e-03	104

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0520521	Liver	HCC	Proteoglycans in cancer	121/4020	205/8465	5.22e-04	2.18e-03	1.21e-03	121
hsa0520531	Liver	HCC	Proteoglycans in cancer	121/4020	205/8465	5.22e-04	2.18e-03	1.21e-03	121

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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

SMO

SNV

Missense_Mutation

novel

c.1702N>G

p.Met568Val

p.M568V

Q99835

protein_coding

tolerated(0.42)

possibly_damaging(0.824)

TCGA-AC-A3YI-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

cytoxan

SMO

SNV

Missense_Mutation

c.1315N>A

p.Glu439Lys

p.E439K

Q99835

protein_coding

tolerated(0.11)

possibly_damaging(0.675)

TCGA-B6-A0IK-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

SMO

SNV

Missense_Mutation

c.2302C>T

p.Pro768Ser

p.P768S

Q99835

protein_coding

tolerated_low_confidence(0.07)

benign(0.003)

TCGA-BH-A0B8-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

SMO

SNV

Missense_Mutation

c.1244N>C

p.Gly415Ala

p.G415A

Q99835

protein_coding

tolerated(0.05)

possibly_damaging(0.739)

TCGA-D8-A1JA-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

SMO

SNV

Missense_Mutation

c.645N>G

p.Ile215Met

p.I215M

Q99835

protein_coding

deleterious(0)

benign(0.372)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SMO

insertion

Nonsense_Mutation

novel

c.1044_1045insGAGACTGTCTAAAAAAAGAAAGAAAAAAAGAAAGAAAGAAAGAAGTGGGG

p.Thr349GlufsTer4

p.T349Efs*4

Q99835

protein_coding

TCGA-A8-A08H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SMO

insertion

Frame_Shift_Ins

novel

c.917_918insAAGATTGTGCCATTGCACTGCAGCCTGGGCGACAGAGCCAGACT

p.Thr307ArgfsTer34

p.T307Rfs*34

Q99835

protein_coding

TCGA-B6-A0I6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SMO

SNV

Missense_Mutation

novel

c.847N>T

p.Ala283Ser

p.A283S

Q99835

protein_coding

deleterious(0.02)

probably_damaging(0.975)

TCGA-EA-A410-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

SMO

SNV

Missense_Mutation

c.859G>C

p.Asp287His

p.D287H

Q99835

protein_coding

deleterious(0.03)

probably_damaging(0.944)

TCGA-IR-A3LA-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SMO

SNV

Missense_Mutation

novel

c.1375N>T

p.Ala459Ser

p.A459S

Q99835

protein_coding

tolerated(0.1)

probably_damaging(0.998)

TCGA-A6-3809-01

Colorectum

colon adenocarcinoma

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
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR	antagonist	178103554	VISMODEGIB
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		PMID25726713-Compound-20
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		Imidazo bicyclic iminium derivative 4
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR	allosteric modulator	381745007
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		PMID25726713-Compound-29
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		Isoflavone derivative 5
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		Cyclic sulfonamide derivative 3
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		PMID25726713-Compound-48
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR		PMID25726713-Compound-34
6608	SMO	DRUG RESISTANCE, DRUGGABLE GENOME, CLINICALLY ACTIONABLE, G PROTEIN COUPLED RECEPTOR	inhibitor	CHEMBL3137317	SONIDEGIB PHOSPHATE

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