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:00485459	Breast	Precancer	response to steroid hormone	53/1080	339/18723	3.07e-11	3.66e-09	53
GO:00432549	Breast	Precancer	regulation of protein-containing complex assembly	50/1080	428/18723	1.63e-06	5.97e-05	50
GO:00075653	Breast	Precancer	female pregnancy	29/1080	193/18723	2.07e-06	7.31e-05	29
GO:00313349	Breast	Precancer	positive regulation of protein-containing complex assembly	33/1080	237/18723	2.39e-06	8.21e-05	33
GO:00447063	Breast	Precancer	multi-multicellular organism process	31/1080	220/18723	3.73e-06	1.19e-04	31
GO:00487329	Breast	Precancer	gland development	49/1080	436/18723	6.11e-06	1.73e-04	49
GO:0050727	Breast	Precancer	regulation of inflammatory response	44/1080	386/18723	1.26e-05	3.22e-04	44
GO:00713838	Breast	Precancer	cellular response to steroid hormone stimulus	28/1080	204/18723	1.78e-05	4.26e-04	28
GO:00436273	Breast	Precancer	response to estrogen	15/1080	75/18723	2.06e-05	4.83e-04	15
GO:00506736	Breast	Precancer	epithelial cell proliferation	46/1080	437/18723	6.02e-05	1.23e-03	46
GO:00335983	Breast	Precancer	mammary gland epithelial cell proliferation	8/1080	26/18723	7.33e-05	1.44e-03	8
GO:00486087	Breast	Precancer	reproductive structure development	43/1080	424/18723	2.36e-04	3.56e-03	43
GO:00614587	Breast	Precancer	reproductive system development	43/1080	427/18723	2.75e-04	4.00e-03	43
GO:00323555	Breast	Precancer	response to estradiol	19/1080	141/18723	4.81e-04	6.31e-03	19
GO:00305187	Breast	Precancer	intracellular steroid hormone receptor signaling pathway	16/1080	116/18723	1.01e-03	1.13e-02	16
GO:00481453	Breast	Precancer	regulation of fibroblast proliferation	12/1080	80/18723	2.03e-03	1.94e-02	12
GO:00481443	Breast	Precancer	fibroblast proliferation	12/1080	81/18723	2.26e-03	2.12e-02	12
GO:0060749	Breast	Precancer	mammary gland alveolus development	5/1080	18/18723	2.88e-03	2.49e-02	5
GO:0061377	Breast	Precancer	mammary gland lobule development	5/1080	18/18723	2.88e-03	2.49e-02	5
GO:00305228	Breast	Precancer	intracellular receptor signaling pathway	27/1080	265/18723	2.99e-03	2.57e-02	27

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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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