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: BMP4

Gene summary for BMP4

Gene summary.

Gene information	Species	Human
	Gene symbol	BMP4
	Gene ID	652
	Gene name	bone morphogenetic protein 4
	Gene Alias	BMP2B
	Cytomap	14q22.2
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P12644

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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
652	BMP4	HTA11_3410_2000001011	Human	Colorectum	AD	1.92e-09	2.49e-01	0.0155
652	BMP4	HTA11_2487_2000001011	Human	Colorectum	SER	1.14e-02	1.51e-01	-0.1808
652	BMP4	HTA11_1938_2000001011	Human	Colorectum	AD	4.00e-12	3.59e-01	-0.0811
652	BMP4	HTA11_78_2000001011	Human	Colorectum	AD	2.35e-06	2.68e-01	-0.1088
652	BMP4	HTA11_3361_2000001011	Human	Colorectum	AD	5.46e-03	1.78e-01	-0.1207
652	BMP4	HTA11_696_2000001011	Human	Colorectum	AD	9.56e-07	2.03e-01	-0.1464
652	BMP4	HTA11_1391_2000001011	Human	Colorectum	AD	7.00e-13	4.29e-01	-0.059
652	BMP4	HTA11_866_3004761011	Human	Colorectum	AD	1.47e-27	8.76e-01	0.096
652	BMP4	HTA11_4255_2000001011	Human	Colorectum	SER	2.17e-09	5.36e-01	0.0446
652	BMP4	HTA11_8622_2000001021	Human	Colorectum	SER	1.49e-06	4.55e-01	0.0528
652	BMP4	HTA11_10711_2000001011	Human	Colorectum	AD	1.91e-07	4.51e-01	0.0338
652	BMP4	HTA11_6818_2000001021	Human	Colorectum	AD	4.64e-16	5.83e-01	0.0588
652	BMP4	HTA11_99999970781_79442	Human	Colorectum	MSS	4.78e-48	1.06e+00	0.294
652	BMP4	HTA11_99999965062_69753	Human	Colorectum	MSI-H	1.40e-05	5.83e-01	0.3487
652	BMP4	HTA11_99999965104_69814	Human	Colorectum	MSS	3.26e-04	2.22e-01	0.281
652	BMP4	HTA11_99999971662_82457	Human	Colorectum	MSS	3.40e-53	1.37e+00	0.3859
652	BMP4	HTA11_99999973899_84307	Human	Colorectum	MSS	1.05e-12	5.16e-01	0.2585
652	BMP4	HTA11_99999974143_84620	Human	Colorectum	MSS	1.92e-35	7.10e-01	0.3005
652	BMP4	A001-C-104	Human	Colorectum	FAP	1.92e-04	1.90e-01	0.0184
652	BMP4	A001-C-007	Human	Colorectum	CRC	5.46e-03	2.28e-01	0.1899

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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:00018383	Colorectum	CRC	embryonic epithelial tube formation	24/2078	121/18723	3.33e-03	2.85e-02	24
GO:00603952	Colorectum	CRC	SMAD protein signal transduction	18/2078	82/18723	3.37e-03	2.88e-02	18
GO:00703041	Colorectum	CRC	positive regulation of stress-activated protein kinase signaling cascade	25/2078	128/18723	3.44e-03	2.92e-02	25
GO:00031584	Colorectum	CRC	endothelium development	26/2078	136/18723	3.91e-03	3.24e-02	26
GO:19001805	Colorectum	CRC	regulation of protein localization to nucleus	26/2078	136/18723	3.91e-03	3.24e-02	26
GO:00032791	Colorectum	CRC	cardiac septum development	21/2078	103/18723	4.15e-03	3.40e-02	21
GO:00032811	Colorectum	CRC	ventricular septum development	16/2078	71/18723	4.22e-03	3.44e-02	16
GO:00308794	Colorectum	CRC	mammary gland development	26/2078	137/18723	4.32e-03	3.47e-02	26
GO:00025733	Colorectum	CRC	myeloid leukocyte differentiation	36/2078	208/18723	4.57e-03	3.57e-02	36
GO:00336734	Colorectum	CRC	negative regulation of kinase activity	40/2078	237/18723	4.58e-03	3.57e-02	40
GO:00550061	Colorectum	CRC	cardiac cell development	19/2078	91/18723	4.74e-03	3.67e-02	19
GO:0043410	Colorectum	CRC	positive regulation of MAPK cascade	72/2078	480/18723	4.85e-03	3.74e-02	72
GO:00454463	Colorectum	CRC	endothelial cell differentiation	23/2078	118/18723	5.01e-03	3.85e-02	23
GO:2000027	Colorectum	CRC	regulation of animal organ morphogenesis	24/2078	125/18723	5.12e-03	3.92e-02	24
GO:00485683	Colorectum	CRC	embryonic organ development	65/2078	427/18723	5.15e-03	3.94e-02	65
GO:00603903	Colorectum	CRC	regulation of SMAD protein signal transduction	9/2078	31/18723	5.21e-03	3.97e-02	9
GO:0060541	Colorectum	CRC	respiratory system development	35/2078	203/18723	5.45e-03	4.12e-02	35
GO:00328741	Colorectum	CRC	positive regulation of stress-activated MAPK cascade	24/2078	126/18723	5.68e-03	4.26e-02	24
GO:00032051	Colorectum	CRC	cardiac chamber development	29/2078	161/18723	5.82e-03	4.32e-02	29
GO:0002062	Colorectum	CRC	chondrocyte differentiation	21/2078	106/18723	5.87e-03	4.33e-02	21

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04919	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa05418	Colorectum	AD	Fluid shear stress and atherosclerosis	54/2092	139/8465	1.41e-04	1.16e-03	7.37e-04	54
hsa049191	Colorectum	AD	Thyroid hormone signaling pathway	51/2092	121/8465	1.71e-05	1.73e-04	1.10e-04	51
hsa054181	Colorectum	AD	Fluid shear stress and atherosclerosis	54/2092	139/8465	1.41e-04	1.16e-03	7.37e-04	54
hsa049192	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa054182	Colorectum	SER	Fluid shear stress and atherosclerosis	40/1580	139/8465	2.28e-03	1.75e-02	1.27e-02	40
hsa049193	Colorectum	SER	Thyroid hormone signaling pathway	40/1580	121/8465	1.02e-04	1.06e-03	7.67e-04	40
hsa054183	Colorectum	SER	Fluid shear stress and atherosclerosis	40/1580	139/8465	2.28e-03	1.75e-02	1.27e-02	40
hsa049194	Colorectum	MSS	Thyroid hormone signaling pathway	46/1875	121/8465	5.04e-05	4.97e-04	3.05e-04	46
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
hsa049195	Colorectum	MSS	Thyroid hormone signaling pathway	46/1875	121/8465	5.04e-05	4.97e-04	3.05e-04	46
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
hsa054186	Colorectum	MSI-H	Fluid shear stress and atherosclerosis	25/797	139/8465	1.11e-03	1.20e-02	1.01e-02	25
hsa049196	Colorectum	MSI-H	Thyroid hormone signaling pathway	21/797	121/8465	4.18e-03	4.10e-02	3.44e-02	21
hsa054187	Colorectum	MSI-H	Fluid shear stress and atherosclerosis	25/797	139/8465	1.11e-03	1.20e-02	1.01e-02	25
hsa049197	Colorectum	MSI-H	Thyroid hormone signaling pathway	21/797	121/8465	4.18e-03	4.10e-02	3.44e-02	21
hsa049198	Colorectum	FAP	Thyroid hormone signaling pathway	41/1404	121/8465	2.28e-06	4.28e-05	2.60e-05	41
hsa054188	Colorectum	FAP	Fluid shear stress and atherosclerosis	45/1404	139/8465	3.05e-06	4.63e-05	2.81e-05	45

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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
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	AD
BMP4	BMPR1A_ACVR2A	BMP4_BMPR1A_ACVR2A	BMP	CRC	ADJ
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	ADJ
BMP4	BMPR1A_ACVR2A	BMP4_BMPR1A_ACVR2A	BMP	CRC	MSI-H
BMP4	BMPR1A_ACVR2B	BMP4_BMPR1A_ACVR2B	BMP	CRC	MSI-H
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	MSI-H
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	CRC	SER
BMP4	BMPR1A_ACVR2B	BMP4_BMPR1A_ACVR2B	BMP	Esophagus	ESCC
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	HNSCC	Precancer
BMP4	BMPR1A_ACVR2A	BMP4_BMPR1A_ACVR2A	BMP	Liver	Precancer
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	Liver	Precancer
BMP4	BMPR1B_ACVR2A	BMP4_BMPR1B_ACVR2A	BMP	Liver	Precancer
BMP4	BMPR1B_BMPR2	BMP4_BMPR1B_BMPR2	BMP	Liver	Precancer
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	Lung	AAH
BMP4	BMPR1B_BMPR2	BMP4_BMPR1B_BMPR2	BMP	Lung	AAH
BMP4	BMPR1A_ACVR2A	BMP4_BMPR1A_ACVR2A	BMP	THCA	ADJ
BMP4	BMPR1A_BMPR2	BMP4_BMPR1A_BMPR2	BMP	THCA	ADJ

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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

BMP4

SNV

Missense_Mutation

c.404A>T

p.Asn135Ile

p.N135I

P12644

protein_coding

tolerated(0.12)

benign(0.1)

TCGA-AN-A0AR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

BMP4

SNV

Missense_Mutation

rs747238009

c.340N>T

p.Ala114Ser

p.A114S

P12644

protein_coding

deleterious(0.04)

probably_damaging(0.999)

TCGA-E9-A295-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

BMP4

deletion

Frame_Shift_Del

novel

c.179delN

p.Thr60AsnfsTer58

p.T60Nfs*58

P12644

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

BMP4

SNV

Missense_Mutation

rs750868626

c.1223N>A

p.Arg408His

p.R408H

P12644

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

BMP4

SNV

Missense_Mutation

rs773416502

c.484N>T

p.Arg162Trp

p.R162W

P12644

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

BMP4

SNV

Missense_Mutation

novel

c.646N>C

p.Asp216His

p.D216H

P12644

protein_coding

deleterious(0)

probably_damaging(0.946)

TCGA-C5-A2LZ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Unknown

BMP4

SNV

Missense_Mutation

c.464N>G

p.Ser155Cys

p.S155C

P12644

protein_coding

deleterious(0.01)

probably_damaging(0.976)

TCGA-IR-A3LL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

BMP4

SNV

Missense_Mutation

c.313N>C

p.Glu105Gln

p.E105Q

P12644

protein_coding

tolerated(0.7)

benign(0.015)

TCGA-UC-A7PF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

BMP4

SNV

Missense_Mutation

novel

c.239N>T

p.Pro80Leu

p.P80L

P12644

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-VS-A959-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Unknown

BMP4

SNV

Missense_Mutation

novel

c.1154A>G

p.Tyr385Cys

p.Y385C

P12644

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AA-3811-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

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

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