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: CRTC2

Gene summary for CRTC2

Gene summary.

Gene information	Species	Human
	Gene symbol	CRTC2
	Gene ID	200186
	Gene name	CREB regulated transcription coactivator 2
	Gene Alias	TORC-2
	Cytomap	1q21.3
	Gene Type	protein-coding
	GO ID	GO:0005975
	UniProtAcc	Q53ET0

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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
200186	CRTC2	LZE4T	Human	Esophagus	ESCC	5.77e-07	1.90e-01	0.0811
200186	CRTC2	LZE7T	Human	Esophagus	ESCC	2.21e-04	2.70e-01	0.0667
200186	CRTC2	LZE20T	Human	Esophagus	ESCC	6.06e-05	1.05e-01	0.0662
200186	CRTC2	LZE24T	Human	Esophagus	ESCC	3.62e-13	3.34e-01	0.0596
200186	CRTC2	LZE6T	Human	Esophagus	ESCC	9.67e-06	1.07e-01	0.0845
200186	CRTC2	P1T-E	Human	Esophagus	ESCC	1.07e-05	4.14e-01	0.0875
200186	CRTC2	P2T-E	Human	Esophagus	ESCC	3.32e-13	2.38e-01	0.1177
200186	CRTC2	P4T-E	Human	Esophagus	ESCC	2.57e-14	7.55e-02	0.1323
200186	CRTC2	P5T-E	Human	Esophagus	ESCC	5.15e-14	9.09e-02	0.1327
200186	CRTC2	P8T-E	Human	Esophagus	ESCC	6.46e-13	2.92e-01	0.0889
200186	CRTC2	P9T-E	Human	Esophagus	ESCC	9.38e-14	2.33e-01	0.1131
200186	CRTC2	P10T-E	Human	Esophagus	ESCC	2.59e-15	1.88e-01	0.116
200186	CRTC2	P11T-E	Human	Esophagus	ESCC	1.11e-13	3.47e-01	0.1426
200186	CRTC2	P12T-E	Human	Esophagus	ESCC	2.02e-12	1.66e-01	0.1122
200186	CRTC2	P15T-E	Human	Esophagus	ESCC	5.17e-18	3.95e-01	0.1149
200186	CRTC2	P16T-E	Human	Esophagus	ESCC	2.38e-14	1.39e-01	0.1153
200186	CRTC2	P17T-E	Human	Esophagus	ESCC	1.43e-06	2.03e-01	0.1278
200186	CRTC2	P20T-E	Human	Esophagus	ESCC	4.14e-17	3.09e-01	0.1124
200186	CRTC2	P21T-E	Human	Esophagus	ESCC	1.10e-16	2.29e-01	0.1617
200186	CRTC2	P22T-E	Human	Esophagus	ESCC	4.79e-15	1.41e-01	0.1236

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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
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:001657015	Esophagus	ESCC	histone modification	323/8552	463/18723	2.61e-26	7.88e-24	323
GO:001820514	Esophagus	ESCC	peptidyl-lysine modification	259/8552	376/18723	3.90e-20	5.26e-18	259
GO:001839413	Esophagus	ESCC	peptidyl-lysine acetylation	123/8552	169/18723	6.58e-13	2.94e-11	123
GO:004354313	Esophagus	ESCC	protein acylation	165/8552	243/18723	1.69e-12	7.14e-11	165
GO:000647313	Esophagus	ESCC	protein acetylation	140/8552	201/18723	4.37e-12	1.69e-10	140
GO:001839313	Esophagus	ESCC	internal peptidyl-lysine acetylation	114/8552	158/18723	1.16e-11	4.24e-10	114
GO:000647513	Esophagus	ESCC	internal protein amino acid acetylation	115/8552	160/18723	1.43e-11	5.08e-10	115
GO:00165735	Esophagus	ESCC	histone acetylation	110/8552	152/18723	1.95e-11	6.81e-10	110
GO:00059969	Esophagus	ESCC	monosaccharide metabolic process	159/8552	257/18723	1.11e-07	1.81e-06	159
GO:00193189	Esophagus	ESCC	hexose metabolic process	147/8552	237/18723	2.63e-07	3.94e-06	147
GO:00510908	Esophagus	ESCC	regulation of DNA-binding transcription factor activity	252/8552	440/18723	5.22e-07	6.97e-06	252
GO:00510918	Esophagus	ESCC	positive regulation of DNA-binding transcription factor activity	155/8552	260/18723	3.83e-06	4.14e-05	155
GO:00060069	Esophagus	ESCC	glucose metabolic process	119/8552	196/18723	1.51e-05	1.36e-04	119
GO:00439662	Esophagus	ESCC	histone H3 acetylation	43/8552	61/18723	7.57e-05	5.67e-04	43
GO:00160514	Esophagus	ESCC	carbohydrate biosynthetic process	117/8552	202/18723	2.96e-04	1.79e-03	117
GO:00463643	Esophagus	ESCC	monosaccharide biosynthetic process	52/8552	82/18723	9.03e-04	4.61e-03	52
GO:00512623	Esophagus	ESCC	protein tetramerization	54/8552	87/18723	1.50e-03	7.06e-03	54
GO:19019987	Esophagus	ESCC	toxin transport	28/8552	40/18723	1.61e-03	7.50e-03	28
GO:00193193	Esophagus	ESCC	hexose biosynthetic process	49/8552	78/18723	1.69e-03	7.81e-03	49
GO:00512592	Esophagus	ESCC	protein complex oligomerization	130/8552	238/18723	3.29e-03	1.36e-02	130

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05166211	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa0415210	Esophagus	ESCC	AMPK signaling pathway	80/4205	121/8465	1.73e-04	6.67e-04	3.42e-04	80
hsa049318	Esophagus	ESCC	Insulin resistance	69/4205	108/8465	1.92e-03	5.54e-03	2.84e-03	69
hsa041517	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0492214	Esophagus	ESCC	Glucagon signaling pathway	64/4205	107/8465	2.18e-02	4.80e-02	2.46e-02	64
hsa05166310	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa0415213	Esophagus	ESCC	AMPK signaling pathway	80/4205	121/8465	1.73e-04	6.67e-04	3.42e-04	80
hsa0493113	Esophagus	ESCC	Insulin resistance	69/4205	108/8465	1.92e-03	5.54e-03	2.84e-03	69
hsa0415114	Esophagus	ESCC	PI3K-Akt signaling pathway	197/4205	354/8465	1.24e-02	2.83e-02	1.45e-02	197
hsa0492215	Esophagus	ESCC	Glucagon signaling pathway	64/4205	107/8465	2.18e-02	4.80e-02	2.46e-02	64
hsa0493121	Liver	HCC	Insulin resistance	77/4020	108/8465	3.89e-07	4.46e-06	2.48e-06	77
hsa0516622	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0415241	Liver	HCC	AMPK signaling pathway	77/4020	121/8465	2.32e-04	1.11e-03	6.18e-04	77
hsa0492241	Liver	HCC	Glucagon signaling pathway	64/4020	107/8465	6.70e-03	1.87e-02	1.04e-02	64
hsa0493131	Liver	HCC	Insulin resistance	77/4020	108/8465	3.89e-07	4.46e-06	2.48e-06	77
hsa0516632	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0415251	Liver	HCC	AMPK signaling pathway	77/4020	121/8465	2.32e-04	1.11e-03	6.18e-04	77
hsa0492251	Liver	HCC	Glucagon signaling pathway	64/4020	107/8465	6.70e-03	1.87e-02	1.04e-02	64
hsa0516630	Oral cavity	OSCC	Human T-cell leukemia virus 1 infection	150/3704	222/8465	3.68e-13	7.26e-12	3.70e-12	150
hsa041516	Oral cavity	OSCC	PI3K-Akt signaling pathway	185/3704	354/8465	6.26e-04	1.86e-03	9.49e-04	185

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
CRTC2	cDC	Lung	AAH	SLC29A3,STX18,LTB, etc.	3.20e-02
CRTC2	M1MAC	Lung	AAH	SLC29A3,STX18,LTB, etc.	1.08e-02
CRTC2	M2MAC	Lung	AAH	SLC29A3,STX18,LTB, etc.	8.30e-03
CRTC2	NK	Lung	AAH	SLC29A3,STX18,LTB, etc.	6.46e-03

∗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

CRTC2

SNV

Missense_Mutation

c.1496N>T

p.Pro499Leu

p.P499L

Q53ET0

protein_coding

deleterious(0.03)

benign(0)

TCGA-A2-A04P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxol

CRTC2

SNV

Missense_Mutation

rs752412661

c.356N>A

p.Arg119His

p.R119H

Q53ET0

protein_coding

deleterious(0.04)

benign(0)

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

CRTC2

SNV

Missense_Mutation

c.434N>C

p.Arg145Thr

p.R145T

Q53ET0

protein_coding

deleterious(0)

probably_damaging(0.977)

TCGA-B6-A0RE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CRTC2

SNV

Missense_Mutation

c.856N>T

p.Pro286Ser

p.P286S

Q53ET0

protein_coding

deleterious(0.01)

probably_damaging(0.948)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

CRTC2

SNV

Missense_Mutation

c.518C>G

p.Ser173Cys

p.S173C

Q53ET0

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-BH-A0HW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

CRTC2

SNV

Missense_Mutation

novel

c.1789C>G

p.Pro597Ala

p.P597A

Q53ET0

protein_coding

tolerated(0.07)

benign(0.001)

TCGA-PL-A8LV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

CRTC2

deletion

Frame_Shift_Del

novel

c.1763_1764delNN

p.Glu588GlyfsTer28

p.E588Gfs*28

Q53ET0

protein_coding

TCGA-BH-A0DK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

CRTC2

SNV

Missense_Mutation

c.2032C>A

p.Leu678Met

p.L678M

Q53ET0

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CRTC2

SNV

Missense_Mutation

novel

c.1881C>A

p.Phe627Leu

p.F627L

Q53ET0

protein_coding

tolerated(1)

benign(0.037)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CRTC2

SNV

Missense_Mutation

novel

c.559A>G

p.Thr187Ala

p.T187A

Q53ET0

protein_coding

tolerated(0.83)

benign(0.072)

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
200186	CRTC2	KINASE		PKI-587	GEDATOLISIB
200186	CRTC2	KINASE		tacrolimus	TACROLIMUS	26644205
200186	CRTC2	KINASE		N/A
200186	CRTC2	KINASE		XL765
200186	CRTC2	KINASE		INK128	SAPANISERTIB
200186	CRTC2	KINASE		NVP-BEZ235	DACTOLISIB
200186	CRTC2	KINASE		cyclosporine	CYCLOSPORINE	26644205

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