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: BMPR2

Gene summary for BMPR2

Gene summary.

Gene information	Species	Human
	Gene symbol	BMPR2
	Gene ID	659
	Gene name	bone morphogenetic protein receptor type 2
	Gene Alias	BMPR-II
	Cytomap	2q33.1-q33.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	Q13873

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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
659	BMPR2	CA_HPV_1	Human	Cervix	CC	6.32e-03	-9.49e-02	0.0264
659	BMPR2	CCI_2	Human	Cervix	CC	4.14e-16	2.38e+00	0.5249
659	BMPR2	CCI_3	Human	Cervix	CC	3.67e-18	1.16e+00	0.516
659	BMPR2	HTA11_347_2000001011	Human	Colorectum	AD	1.55e-08	4.68e-01	-0.1954
659	BMPR2	HTA11_411_2000001011	Human	Colorectum	SER	1.07e-03	7.34e-01	-0.2602
659	BMPR2	HTA11_99999970781_79442	Human	Colorectum	MSS	3.08e-13	-4.45e-01	0.294
659	BMPR2	A001-C-207	Human	Colorectum	FAP	8.95e-03	-2.21e-01	0.1278
659	BMPR2	A015-C-203	Human	Colorectum	FAP	7.53e-28	-3.18e-01	-0.1294
659	BMPR2	A015-C-204	Human	Colorectum	FAP	5.41e-05	-1.89e-01	-0.0228
659	BMPR2	A014-C-040	Human	Colorectum	FAP	4.43e-07	-6.78e-01	-0.1184
659	BMPR2	A002-C-201	Human	Colorectum	FAP	3.96e-14	-3.40e-01	0.0324
659	BMPR2	A001-C-119	Human	Colorectum	FAP	1.22e-05	9.59e-03	-0.1557
659	BMPR2	A001-C-108	Human	Colorectum	FAP	1.62e-16	-1.65e-01	-0.0272
659	BMPR2	A002-C-205	Human	Colorectum	FAP	2.27e-23	-3.29e-01	-0.1236
659	BMPR2	A015-C-005	Human	Colorectum	FAP	8.29e-06	-4.12e-01	-0.0336
659	BMPR2	A015-C-006	Human	Colorectum	FAP	3.59e-16	-3.71e-01	-0.0994
659	BMPR2	A015-C-106	Human	Colorectum	FAP	1.46e-10	-2.28e-01	-0.0511
659	BMPR2	A002-C-114	Human	Colorectum	FAP	1.91e-19	-3.39e-01	-0.1561
659	BMPR2	A015-C-104	Human	Colorectum	FAP	5.89e-32	-4.30e-01	-0.1899
659	BMPR2	A001-C-014	Human	Colorectum	FAP	6.04e-15	-2.88e-01	0.0135

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Colorectum (GSE201348)		FAP: Familial adenomatous polyposis
		CRC: Colorectal cancer
Colorectum (HTA11)		AD: Adenomas
		SER: Sessile serrated lesions
		MSI-H: Microsatellite-high colorectal cancer
		MSS: Microsatellite stable colorectal cancer
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
Thyroid		ATC: Anaplastic thyroid cancer
		HT: Hashimoto's thyroiditis
		PTC: Papillary thyroid cancer

∗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:00614484	Thyroid	ATC	connective tissue development	112/6293	252/18723	2.08e-04	1.38e-03	112
GO:000315825	Thyroid	ATC	endothelium development	66/6293	136/18723	2.16e-04	1.42e-03	66
GO:003210324	Thyroid	ATC	positive regulation of response to external stimulus	178/6293	427/18723	2.61e-04	1.67e-03	178
GO:000317912	Thyroid	ATC	heart valve morphogenesis	31/6293	55/18723	4.33e-04	2.59e-03	31
GO:00509206	Thyroid	ATC	regulation of chemotaxis	99/6293	223/18723	4.91e-04	2.86e-03	99
GO:001059431	Thyroid	ATC	regulation of endothelial cell migration	102/6293	232/18723	6.17e-04	3.51e-03	102
GO:190401921	Thyroid	ATC	epithelial cell apoptotic process	58/6293	121/18723	7.47e-04	4.14e-03	58
GO:000318111	Thyroid	ATC	atrioventricular valve morphogenesis	16/6293	24/18723	9.46e-04	5.07e-03	16
GO:000328121	Thyroid	ATC	ventricular septum development	37/6293	71/18723	9.80e-04	5.21e-03	37
GO:003300214	Thyroid	ATC	muscle cell proliferation	107/6293	248/18723	1.03e-03	5.47e-03	107
GO:000189321	Thyroid	ATC	maternal placenta development	21/6293	35/18723	1.22e-03	6.41e-03	21
GO:004544623	Thyroid	ATC	endothelial cell differentiation	56/6293	118/18723	1.23e-03	6.44e-03	56
GO:000323111	Thyroid	ATC	cardiac ventricle development	58/6293	123/18723	1.23e-03	6.46e-03	58
GO:000320612	Thyroid	ATC	cardiac chamber morphogenesis	57/6293	121/18723	1.39e-03	7.20e-03	57
GO:00487715	Thyroid	ATC	tissue remodeling	78/6293	175/18723	1.60e-03	8.04e-03	78
GO:006041111	Thyroid	ATC	cardiac septum morphogenesis	35/6293	68/18723	1.76e-03	8.71e-03	35
GO:00608401	Thyroid	ATC	artery development	48/6293	100/18723	1.97e-03	9.52e-03	48
GO:0003197	Thyroid	ATC	endocardial cushion development	25/6293	45/18723	2.00e-03	9.59e-03	25
GO:004865916	Thyroid	ATC	smooth muscle cell proliferation	81/6293	184/18723	2.02e-03	9.60e-03	81
GO:0061298	Thyroid	ATC	retina vasculature development in camera-type eye	12/6293	17/18723	2.02e-03	9.60e-03	12

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0541820	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa043609	Cervix	CC	Axon guidance	47/1267	182/8465	8.13e-05	5.38e-04	3.18e-04	47
hsa043908	Cervix	CC	Hippo signaling pathway	40/1267	157/8465	3.64e-04	1.82e-03	1.07e-03	40
hsa05418110	Cervix	CC	Fluid shear stress and atherosclerosis	50/1267	139/8465	5.71e-10	1.32e-08	7.81e-09	50
hsa0436012	Cervix	CC	Axon guidance	47/1267	182/8465	8.13e-05	5.38e-04	3.18e-04	47
hsa0439013	Cervix	CC	Hippo signaling pathway	40/1267	157/8465	3.64e-04	1.82e-03	1.07e-03	40
hsa05418	Colorectum	AD	Fluid shear stress and atherosclerosis	54/2092	139/8465	1.41e-04	1.16e-03	7.37e-04	54
hsa04360	Colorectum	AD	Axon guidance	61/2092	182/8465	4.36e-03	2.17e-02	1.38e-02	61
hsa054181	Colorectum	AD	Fluid shear stress and atherosclerosis	54/2092	139/8465	1.41e-04	1.16e-03	7.37e-04	54
hsa043601	Colorectum	AD	Axon guidance	61/2092	182/8465	4.36e-03	2.17e-02	1.38e-02	61
hsa054182	Colorectum	SER	Fluid shear stress and atherosclerosis	40/1580	139/8465	2.28e-03	1.75e-02	1.27e-02	40
hsa04350	Colorectum	SER	TGF-beta signaling pathway	31/1580	108/8465	7.00e-03	3.77e-02	2.74e-02	31
hsa054183	Colorectum	SER	Fluid shear stress and atherosclerosis	40/1580	139/8465	2.28e-03	1.75e-02	1.27e-02	40
hsa043501	Colorectum	SER	TGF-beta signaling pathway	31/1580	108/8465	7.00e-03	3.77e-02	2.74e-02	31
hsa054184	Colorectum	MSS	Fluid shear stress and atherosclerosis	51/1875	139/8465	6.06e-05	5.80e-04	3.55e-04	51
hsa04390	Colorectum	MSS	Hippo signaling pathway	48/1875	157/8465	8.32e-03	3.10e-02	1.90e-02	48
hsa043602	Colorectum	MSS	Axon guidance	54/1875	182/8465	1.03e-02	3.69e-02	2.26e-02	54
hsa054185	Colorectum	MSS	Fluid shear stress and atherosclerosis	51/1875	139/8465	6.06e-05	5.80e-04	3.55e-04	51
hsa043901	Colorectum	MSS	Hippo signaling pathway	48/1875	157/8465	8.32e-03	3.10e-02	1.90e-02	48
hsa043603	Colorectum	MSS	Axon guidance	54/1875	182/8465	1.03e-02	3.69e-02	2.26e-02	54

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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
BMP7	ACVR1_BMPR2	BMP7_ACVR1_BMPR2	BMP	Cervix	CC
BMP7	BMPR1A_BMPR2	BMP7_BMPR1A_BMPR2	BMP	Cervix	CC
BMP7	BMPR1B_BMPR2	BMP7_BMPR1B_BMPR2	BMP	Cervix	CC
BMP2	BMPR1A_BMPR2	BMP2_BMPR1A_BMPR2	BMP	CRC	AD
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	AD
BMP5	BMPR1A_BMPR2	BMP5_BMPR1A_BMPR2	BMP	CRC	AD
BMP6	BMPR1A_BMPR2	BMP6_BMPR1A_BMPR2	BMP	CRC	AD
BMP2	BMPR1A_BMPR2	BMP2_BMPR1A_BMPR2	BMP	CRC	ADJ
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	ADJ
BMP5	BMPR1A_BMPR2	BMP5_BMPR1A_BMPR2	BMP	CRC	ADJ
BMP6	BMPR1A_BMPR2	BMP6_BMPR1A_BMPR2	BMP	CRC	ADJ
BMP5	BMPR1A_BMPR2	BMP5_BMPR1A_BMPR2	BMP	CRC	CRC
BMP2	BMPR1A_BMPR2	BMP2_BMPR1A_BMPR2	BMP	CRC	FAP
BMP5	BMPR1A_BMPR2	BMP5_BMPR1A_BMPR2	BMP	CRC	FAP
BMP6	BMPR1A_BMPR2	BMP6_BMPR1A_BMPR2	BMP	CRC	FAP
BMP2	BMPR1A_BMPR2	BMP2_BMPR1A_BMPR2	BMP	CRC	Healthy
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	MSI-H
BMP6	ACVR1_BMPR2	BMP6_ACVR1_BMPR2	BMP	CRC	MSI-H
BMP6	BMPR1A_BMPR2	BMP6_BMPR1A_BMPR2	BMP	CRC	MSI-H
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	SER

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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

BMPR2

SNV

Missense_Mutation

rs777889469

c.440N>A

p.Arg147Gln

p.R147Q

Q13873

protein_coding

tolerated(0.25)

benign(0.007)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

BMPR2

SNV

Missense_Mutation

novel

c.704C>T

p.Ala235Val

p.A235V

Q13873

protein_coding

deleterious(0.04)

benign(0.073)

TCGA-B6-A0RE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

BMPR2

SNV

Missense_Mutation

novel

c.2798N>A

p.Arg933Lys

p.R933K

Q13873

protein_coding

tolerated(0.13)

benign(0.005)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

BMPR2

SNV

Missense_Mutation

c.1957C>G

p.Pro653Ala

p.P653A

Q13873

protein_coding

deleterious(0.01)

possibly_damaging(0.696)

TCGA-EW-A1PB-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

BMPR2

SNV

Missense_Mutation

c.1010N>A

p.Arg337Lys

p.R337K

Q13873

protein_coding

deleterious(0.01)

benign(0.25)

TCGA-LQ-A4E4-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

BMPR2

SNV

Missense_Mutation

novel

c.2093C>A

p.Pro698Gln

p.P698Q

Q13873

protein_coding

tolerated(0.06)

possibly_damaging(0.809)

TCGA-OL-A6VO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

BMPR2

deletion

Frame_Shift_Del

rs772920507

c.1742delN

p.Asn583ThrfsTer44

p.N583Tfs*44

Q13873

protein_coding

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

BMPR2

SNV

Missense_Mutation

rs200960921

c.776G>A

p.Arg259His

p.R259H

Q13873

protein_coding

tolerated(0.09)

benign(0.007)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

BMPR2

SNV

Missense_Mutation

rs201781338

c.2618N>A

p.Arg873Gln

p.R873Q

Q13873

protein_coding

deleterious(0.05)

benign(0.205)

TCGA-C5-A1BK-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

BMPR2

SNV

Missense_Mutation

rs370120266

c.71C>A

p.Ala24Glu

p.A24E

Q13873

protein_coding

tolerated(0.09)

benign(0.02)

TCGA-EK-A3GK-01

Cervix

cervical & endocervical cancer

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
659	BMPR2	KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, CELL SURFACE	inhibitor	249565835
659	BMPR2	KINASE, DRUGGABLE GENOME, SERINE THREONINE KINASE, CELL SURFACE	inhibitor	385612192

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