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: ESR1

Gene summary for ESR1

Gene summary.

Gene information	Species	Human
	Gene symbol	ESR1
	Gene ID	2099
	Gene name	estrogen receptor 1
	Gene Alias	ER
	Cytomap	6q25.1-q25.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	G4XH65

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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
2099	ESR1	GSM4909281	Human	Breast	IDC	8.07e-06	-1.24e-01	0.21
2099	ESR1	GSM4909282	Human	Breast	IDC	8.07e-06	-1.24e-01	-0.0288
2099	ESR1	GSM4909286	Human	Breast	IDC	8.07e-06	-1.24e-01	0.1081
2099	ESR1	GSM4909293	Human	Breast	IDC	2.72e-51	8.64e-01	0.1581
2099	ESR1	GSM4909298	Human	Breast	IDC	7.24e-24	5.37e-01	0.1551
2099	ESR1	GSM4909301	Human	Breast	IDC	3.41e-52	1.05e+00	0.1577
2099	ESR1	GSM4909302	Human	Breast	IDC	2.79e-16	4.64e-01	0.1545
2099	ESR1	GSM4909303	Human	Breast	IDC	9.93e-07	4.06e-01	0.0438
2099	ESR1	GSM4909304	Human	Breast	IDC	2.08e-37	7.65e-01	0.1636
2099	ESR1	GSM4909305	Human	Breast	IDC	1.41e-04	2.31e-01	0.0436
2099	ESR1	GSM4909306	Human	Breast	IDC	3.30e-44	8.47e-01	0.1564
2099	ESR1	GSM4909307	Human	Breast	IDC	2.30e-36	8.59e-01	0.1569
2099	ESR1	GSM4909308	Human	Breast	IDC	1.86e-81	1.07e+00	0.158
2099	ESR1	GSM4909309	Human	Breast	IDC	2.26e-02	1.95e-01	0.0483
2099	ESR1	GSM4909311	Human	Breast	IDC	5.95e-08	1.49e-01	0.1534
2099	ESR1	GSM4909312	Human	Breast	IDC	6.30e-23	6.37e-01	0.1552
2099	ESR1	GSM4909313	Human	Breast	IDC	2.26e-13	4.81e-01	0.0391
2099	ESR1	GSM4909317	Human	Breast	IDC	1.44e-14	3.79e-01	0.1355
2099	ESR1	GSM4909318	Human	Breast	IDC	3.20e-03	4.62e-01	0.2031
2099	ESR1	GSM4909319	Human	Breast	IDC	1.25e-10	9.73e-03	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
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma

∗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:00016554	Lung	IAC	urogenital system development	59/2061	338/18723	2.27e-04	3.93e-03	59
GO:1903799	Lung	IAC	negative regulation of production of miRNAs involved in gene silencing by miRNA	7/2061	15/18723	5.60e-04	7.76e-03	7
GO:0060969	Lung	IAC	negative regulation of gene silencing	10/2061	29/18723	7.11e-04	9.50e-03	10
GO:00097557	Lung	IAC	hormone-mediated signaling pathway	36/2061	190/18723	7.95e-04	1.02e-02	36
GO:1903798	Lung	IAC	regulation of production of miRNAs involved in gene silencing by miRNA	9/2061	25/18723	9.19e-04	1.13e-02	9
GO:00488633	Lung	IAC	stem cell differentiation	38/2061	206/18723	9.79e-04	1.18e-02	38
GO:00432548	Lung	IAC	regulation of protein-containing complex assembly	68/2061	428/18723	1.20e-03	1.38e-02	68
GO:00313348	Lung	IAC	positive regulation of protein-containing complex assembly	42/2061	237/18723	1.25e-03	1.44e-02	42
GO:0070920	Lung	IAC	regulation of production of small RNA involved in gene silencing by RNA	9/2061	26/18723	1.27e-03	1.45e-02	9
GO:00611382	Lung	IAC	morphogenesis of a branching epithelium	34/2061	182/18723	1.41e-03	1.54e-02	34
GO:00487328	Lung	IAC	gland development	68/2061	436/18723	1.94e-03	1.97e-02	68
GO:00506735	Lung	IAC	epithelial cell proliferation	68/2061	437/18723	2.05e-03	2.05e-02	68
GO:00323554	Lung	IAC	response to estradiol	27/2061	141/18723	2.89e-03	2.60e-02	27
GO:00027643	Lung	IAC	immune response-regulating signaling pathway	70/2061	468/18723	4.79e-03	3.72e-02	70
GO:00305204	Lung	IAC	intracellular estrogen receptor signaling pathway	13/2061	54/18723	4.89e-03	3.78e-02	13
GO:00606882	Lung	IAC	regulation of morphogenesis of a branching structure	12/2061	50/18723	6.91e-03	4.75e-02	12
GO:004851112	Lung	AIS	rhythmic process	61/1849	298/18723	2.63e-08	3.40e-06	61
GO:006056012	Lung	AIS	developmental growth involved in morphogenesis	51/1849	234/18723	4.43e-08	5.24e-06	51
GO:000206413	Lung	AIS	epithelial cell development	48/1849	220/18723	1.06e-07	1.18e-05	48
GO:003052213	Lung	AIS	intracellular receptor signaling pathway	53/1849	265/18723	4.57e-07	3.55e-05	53

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0491518	Breast	Precancer	Estrogen signaling pathway	28/684	138/8465	4.10e-06	5.39e-05	4.13e-05	28
hsa0520514	Breast	Precancer	Proteoglycans in cancer	30/684	205/8465	1.00e-03	7.18e-03	5.50e-03	30
hsa0496110	Breast	Precancer	Endocrine and other factor-regulated calcium reabsorption	11/684	53/8465	2.92e-03	1.81e-02	1.39e-02	11
hsa0491519	Breast	Precancer	Estrogen signaling pathway	28/684	138/8465	4.10e-06	5.39e-05	4.13e-05	28
hsa0520515	Breast	Precancer	Proteoglycans in cancer	30/684	205/8465	1.00e-03	7.18e-03	5.50e-03	30
hsa0496111	Breast	Precancer	Endocrine and other factor-regulated calcium reabsorption	11/684	53/8465	2.92e-03	1.81e-02	1.39e-02	11
hsa0491523	Breast	IDC	Estrogen signaling pathway	35/867	138/8465	2.55e-07	5.18e-06	3.88e-06	35
hsa0520523	Breast	IDC	Proteoglycans in cancer	42/867	205/8465	7.69e-06	9.99e-05	7.48e-05	42
hsa0491916	Breast	IDC	Thyroid hormone signaling pathway	23/867	121/8465	2.45e-03	1.69e-02	1.27e-02	23
hsa0496121	Breast	IDC	Endocrine and other factor-regulated calcium reabsorption	12/867	53/8465	6.29e-03	3.30e-02	2.47e-02	12
hsa0491533	Breast	IDC	Estrogen signaling pathway	35/867	138/8465	2.55e-07	5.18e-06	3.88e-06	35
hsa0520533	Breast	IDC	Proteoglycans in cancer	42/867	205/8465	7.69e-06	9.99e-05	7.48e-05	42
hsa0491917	Breast	IDC	Thyroid hormone signaling pathway	23/867	121/8465	2.45e-03	1.69e-02	1.27e-02	23
hsa0496131	Breast	IDC	Endocrine and other factor-regulated calcium reabsorption	12/867	53/8465	6.29e-03	3.30e-02	2.47e-02	12
hsa0491542	Breast	DCIS	Estrogen signaling pathway	35/846	138/8465	1.40e-07	2.51e-06	1.85e-06	35
hsa0520542	Breast	DCIS	Proteoglycans in cancer	39/846	205/8465	5.36e-05	5.58e-04	4.11e-04	39
hsa0491922	Breast	DCIS	Thyroid hormone signaling pathway	23/846	121/8465	1.78e-03	1.22e-02	9.00e-03	23
hsa0491552	Breast	DCIS	Estrogen signaling pathway	35/846	138/8465	1.40e-07	2.51e-06	1.85e-06	35
hsa0520552	Breast	DCIS	Proteoglycans in cancer	39/846	205/8465	5.36e-05	5.58e-04	4.11e-04	39
hsa0491932	Breast	DCIS	Thyroid hormone signaling pathway	23/846	121/8465	1.78e-03	1.22e-02	9.00e-03	23

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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
ESR1	STM	Endometrium	ADJ	NPAS3,VWA8,EYA2, etc.	6.34e-01
ESR1	LC	Lung	MIAC	RBPJ,SSR4,FKBP11, etc.	1.79e-01
ESR1	M2MAC	Lung	MIAC	RBPJ,SSR4,FKBP11, etc.	3.28e-01
ESR1	M1MAC	Lung	MIAC	RBPJ,SSR4,FKBP11, etc.	3.01e-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

ESR1

SNV

Missense_Mutation

novel

c.51N>C

p.Gln17His

p.Q17H

P03372

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.997)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

ESR1

SNV

Missense_Mutation

novel

c.1778C>A

p.Ala593Asp

p.A593D

P03372

protein_coding

tolerated_low_confidence(0.2)

benign(0.012)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ESR1

SNV

Missense_Mutation

c.1138N>C

p.Glu380Gln

p.E380Q

P03372

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-AO-A0JC-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

fluorouracil

ESR1

SNV

Missense_Mutation

c.664N>T

p.Pro222Ser

p.P222S

P03372

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0DS-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

cyclophosphamide

ESR1

SNV

Missense_Mutation

c.1110N>C

p.Leu370Phe

p.L370F

P03372

protein_coding

deleterious(0.01)

probably_damaging(1)

TCGA-BH-A1F8-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

ESR1

SNV

Missense_Mutation

c.1138N>C

p.Glu380Gln

p.E380Q

P03372

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ESR1

insertion

Frame_Shift_Ins

novel

c.993_994insAGTATTTACACCATGAAAACTGCTACAAATA

p.Asp332SerfsTer18

p.D332Sfs*18

P03372

protein_coding

TCGA-A2-A04Q-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

ESR1

insertion

Nonsense_Mutation

novel

c.1029_1030insCCTTTTAATTTACTATTAAAAGAATATTCCTAGCAGAAGTAGTCTT

p.Gly344ProfsTer11

p.G344Pfs*11

P03372

protein_coding

TCGA-A2-A0CP-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ESR1

insertion

Frame_Shift_Ins

novel

c.1553_1553+1insTAACAAA

p.Gly521Ter

p.G521*

P03372

protein_coding

TCGA-LL-A5YM-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unspecific

letrozole

ESR1

SNV

Missense_Mutation

novel

c.894N>G

p.Ile298Met

p.I298M

P03372

protein_coding

tolerated(0.14)

benign(0.101)

TCGA-C5-A8XJ-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
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		Premarin/Pravachol
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR	agonist	384403649	STANOZOLOL
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		Exemestane	EXEMESTANE
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		GTx-758	GTX-758
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR	agonist,antagonist	135651233	TAMOXIFEN
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		TTC-352
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		METHOXSALEN	METHOXSALEN
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		ZERANOL	ZERANOL
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		Palbociclib	PALBOCICLIB
2099	ESR1	DRUG RESISTANCE, DRUGGABLE GENOME, NUCLEAR HORMONE RECEPTOR, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR COMPLEX, KINASE, TRANSCRIPTION FACTOR		4-(1,1-DIETHYLPROPYL)PHENOL	CHEMBL2313444	23214428

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