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: NR1D1

Gene summary for NR1D1

Gene summary.

Gene information	Species	Human
	Gene symbol	NR1D1
	Gene ID	9572
	Gene name	nuclear receptor subfamily 1 group D member 1
	Gene Alias	EAR1
	Cytomap	17q21.1
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	F1D8S3

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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
9572	NR1D1	LZE7T	Human	Esophagus	ESCC	3.93e-10	2.53e-01	0.0667
9572	NR1D1	LZE8T	Human	Esophagus	ESCC	1.80e-05	2.20e-01	0.067
9572	NR1D1	LZE24T	Human	Esophagus	ESCC	9.69e-04	3.82e-01	0.0596
9572	NR1D1	LZE6T	Human	Esophagus	ESCC	1.59e-06	1.65e-01	0.0845
9572	NR1D1	P1T-E	Human	Esophagus	ESCC	6.47e-05	5.37e-01	0.0875
9572	NR1D1	P2T-E	Human	Esophagus	ESCC	2.50e-07	2.43e-01	0.1177
9572	NR1D1	P4T-E	Human	Esophagus	ESCC	1.15e-08	-1.03e-02	0.1323
9572	NR1D1	P5T-E	Human	Esophagus	ESCC	2.11e-06	-3.29e-02	0.1327
9572	NR1D1	P8T-E	Human	Esophagus	ESCC	1.27e-06	1.00e-01	0.0889
9572	NR1D1	P9T-E	Human	Esophagus	ESCC	6.60e-04	-1.78e-02	0.1131
9572	NR1D1	P11T-E	Human	Esophagus	ESCC	1.29e-02	1.48e-01	0.1426
9572	NR1D1	P12T-E	Human	Esophagus	ESCC	3.95e-23	6.33e-01	0.1122
9572	NR1D1	P15T-E	Human	Esophagus	ESCC	1.88e-07	2.39e-01	0.1149
9572	NR1D1	P16T-E	Human	Esophagus	ESCC	3.48e-03	-5.01e-02	0.1153
9572	NR1D1	P19T-E	Human	Esophagus	ESCC	9.19e-03	1.36e-01	0.1662
9572	NR1D1	P20T-E	Human	Esophagus	ESCC	6.28e-11	6.59e-01	0.1124
9572	NR1D1	P21T-E	Human	Esophagus	ESCC	5.94e-16	6.77e-01	0.1617
9572	NR1D1	P23T-E	Human	Esophagus	ESCC	1.15e-17	8.03e-01	0.108
9572	NR1D1	P24T-E	Human	Esophagus	ESCC	1.62e-05	2.70e-01	0.1287
9572	NR1D1	P26T-E	Human	Esophagus	ESCC	5.65e-18	5.51e-01	0.1276

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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
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ

∗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:0010498111	Esophagus	ESCC	proteasomal protein catabolic process	369/8552	490/18723	1.13e-41	1.80e-38	369
GO:0031647111	Esophagus	ESCC	regulation of protein stability	223/8552	298/18723	5.76e-25	1.52e-22	223
GO:0006091110	Esophagus	ESCC	generation of precursor metabolites and energy	331/8552	490/18723	3.86e-23	8.45e-21	331
GO:0015980110	Esophagus	ESCC	energy derivation by oxidation of organic compounds	220/8552	318/18723	1.20e-17	1.09e-15	220
GO:0043122110	Esophagus	ESCC	regulation of I-kappaB kinase/NF-kappaB signaling	167/8552	249/18723	6.11e-12	2.32e-10	167
GO:000724919	Esophagus	ESCC	I-kappaB kinase/NF-kappaB signaling	183/8552	281/18723	3.02e-11	1.01e-09	183
GO:0030522110	Esophagus	ESCC	intracellular receptor signaling pathway	170/8552	265/18723	8.58e-10	2.09e-08	170
GO:0048545111	Esophagus	ESCC	response to steroid hormone	204/8552	339/18723	4.47e-08	8.11e-07	204
GO:0071383110	Esophagus	ESCC	cellular response to steroid hormone stimulus	127/8552	204/18723	1.26e-06	1.55e-05	127
GO:004340119	Esophagus	ESCC	steroid hormone mediated signaling pathway	87/8552	136/18723	1.25e-05	1.15e-04	87
GO:003461220	Esophagus	ESCC	response to tumor necrosis factor	149/8552	253/18723	1.47e-05	1.33e-04	149
GO:003292215	Esophagus	ESCC	circadian regulation of gene expression	48/8552	68/18723	2.76e-05	2.30e-04	48
GO:00454449	Esophagus	ESCC	fat cell differentiation	135/8552	229/18723	3.38e-05	2.78e-04	135
GO:00420636	Esophagus	ESCC	gliogenesis	172/8552	301/18723	3.75e-05	3.04e-04	172
GO:005076710	Esophagus	ESCC	regulation of neurogenesis	203/8552	364/18723	6.10e-05	4.68e-04	203
GO:003249619	Esophagus	ESCC	response to lipopolysaccharide	191/8552	343/18723	1.11e-04	7.73e-04	191
GO:005067318	Esophagus	ESCC	epithelial cell proliferation	238/8552	437/18723	1.19e-04	8.20e-04	238
GO:00442626	Esophagus	ESCC	cellular carbohydrate metabolic process	160/8552	283/18723	1.43e-04	9.66e-04	160
GO:007135620	Esophagus	ESCC	cellular response to tumor necrosis factor	132/8552	229/18723	1.69e-04	1.11e-03	132
GO:00463948	Esophagus	ESCC	carboxylic acid biosynthetic process	175/8552	314/18723	1.98e-04	1.26e-03	175

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa047105	Esophagus	ESCC	Circadian rhythm	24/4205	34/8465	1.09e-02	2.51e-02	1.29e-02	24
hsa0471012	Esophagus	ESCC	Circadian rhythm	24/4205	34/8465	1.09e-02	2.51e-02	1.29e-02	24

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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
NR1D1	INCAF	Cervix	N_HPV	SERTAD4-AS1,DBP,NR1D2, etc.	7.82e-01
NR1D1	SSC	Colorectum	Healthy	RNF2,PDP2,R3HDM4, etc.	1.04e-01
NR1D1	SURF	Endometrium	AEH	AL118506.1,ASH1L-AS1,AC015802.6, etc.	2.76e-01
NR1D1	TRANS	Esophagus	ADJ	GADD45B,MGLL,NR1D2, etc.	4.81e-01
NR1D1	TRANS	Esophagus	ESCC	GADD45B,MGLL,NR1D2, etc.	1.63e-01
NR1D1	TRANS	Esophagus	HGIN	GADD45B,MGLL,NR1D2, etc.	2.80e-01
NR1D1	MAIT	Oral cavity	ADJ	ZNF414,DBP,RP11-841O20.2, etc.	3.50e-02
NR1D1	TH17	Oral cavity	NEOLP	ZNF414,DBP,RP11-841O20.2, etc.	3.98e-02
NR1D1	CD8TCM	Oral cavity	NEOLP	ZNF414,DBP,RP11-841O20.2, etc.	1.45e-02
NR1D1	CD8TEXP	Prostate	ADJ	NUDT15,LINC00330,SQLE, etc.	3.63e-02

∗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

NR1D1

SNV

Missense_Mutation

c.1053N>A

p.His351Gln

p.H351Q

P20393

protein_coding

tolerated(0.27)

benign(0.413)

TCGA-A8-A07P-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

5-fluorouracil

NR1D1

SNV

Missense_Mutation

rs766624331

c.71C>A

p.Pro24Gln

p.P24Q

P20393

protein_coding

deleterious(0)

possibly_damaging(0.557)

TCGA-B6-A0IE-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

NR1D1

SNV

Missense_Mutation

rs760740974

c.611N>A

p.Arg204His

p.R204H

P20393

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-BH-A0HA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

NR1D1

SNV

Missense_Mutation

rs766624331

c.71N>A

p.Pro24Gln

p.P24Q

P20393

protein_coding

deleterious(0)

possibly_damaging(0.557)

TCGA-C8-A1HM-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

NR1D1

SNV

Missense_Mutation

novel

c.844N>C

p.Glu282Gln

p.E282Q

P20393

protein_coding

tolerated(0.11)

benign(0.315)

TCGA-C8-A8HP-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

5-fluorouracil

NR1D1

insertion

Frame_Shift_Ins

novel

c.126_127insAA

p.Ser43AsnfsTer3

p.S43Nfs*3

P20393

protein_coding

TCGA-BH-A0BV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

NR1D1

SNV

Missense_Mutation

c.570N>G

p.Phe190Leu

p.F190L

P20393

protein_coding

deleterious(0.03)

benign(0.436)

TCGA-C5-A7CL-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

NR1D1

SNV

Missense_Mutation

c.251C>T

p.Ser84Leu

p.S84L

P20393

protein_coding

tolerated(0.12)

benign(0.01)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

NR1D1

SNV

Missense_Mutation

novel

c.1055A>G

p.Asn352Ser

p.N352S

P20393

protein_coding

tolerated(0.27)

benign(0.005)

TCGA-MA-AA42-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

NR1D1

SNV

Missense_Mutation

rs766286236

c.263N>T

p.Ser88Leu

p.S88L

P20393

protein_coding

tolerated(0.21)

possibly_damaging(0.602)

TCGA-AA-3510-01

Colorectum

colon adenocarcinoma

Male

>=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
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		SR9011	SR9011	23656296
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME	agonist	135650323	GSK-4112
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME	antagonist	135651083
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME	agonist	310264681	SR9011
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		GSK-4112	GSK-4112	23656296
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME		lithium	LITHIUM	20348464
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME	agonist	178101166
9572	NR1D1	NUCLEAR HORMONE RECEPTOR, DRUGGABLE GENOME, TRANSCRIPTION FACTOR, ENZYME	agonist	310264682	SR9009

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