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: CALM1

Gene summary for CALM1

Gene summary.

Gene information	Species	Human
	Gene symbol	CALM1
	Gene ID	801
	Gene name	calmodulin 1
	Gene Alias	CALML2
	Cytomap	14q32.11
	Gene Type	protein-coding
	GO ID	GO:0000086
	UniProtAcc	B4DJ51

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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
801	CALM1	GSM4909286	Human	Breast	IDC	1.90e-09	-3.30e-01	0.1081
801	CALM1	GSM4909294	Human	Breast	IDC	4.64e-30	5.06e-01	0.2022
801	CALM1	GSM4909296	Human	Breast	IDC	1.94e-09	-3.08e-02	0.1524
801	CALM1	GSM4909297	Human	Breast	IDC	1.06e-27	2.60e-02	0.1517
801	CALM1	GSM4909311	Human	Breast	IDC	7.21e-42	-6.00e-01	0.1534
801	CALM1	GSM4909312	Human	Breast	IDC	3.22e-14	-3.70e-01	0.1552
801	CALM1	GSM4909313	Human	Breast	IDC	3.98e-04	-4.36e-01	0.0391
801	CALM1	GSM4909315	Human	Breast	IDC	1.36e-16	3.87e-01	0.21
801	CALM1	GSM4909316	Human	Breast	IDC	2.62e-17	4.94e-01	0.21
801	CALM1	GSM4909317	Human	Breast	IDC	1.86e-19	5.26e-01	0.1355
801	CALM1	GSM4909318	Human	Breast	IDC	5.86e-11	6.04e-01	0.2031
801	CALM1	GSM4909319	Human	Breast	IDC	2.47e-53	-5.56e-01	0.1563
801	CALM1	GSM4909320	Human	Breast	IDC	3.63e-03	-1.40e-01	0.1575
801	CALM1	GSM4909321	Human	Breast	IDC	1.84e-15	-2.25e-01	0.1559
801	CALM1	brca1	Human	Breast	Precancer	1.63e-13	4.41e-01	-0.0338
801	CALM1	M1	Human	Breast	IDC	9.38e-04	3.05e-01	0.1577
801	CALM1	M2	Human	Breast	IDC	4.59e-08	4.15e-01	0.21
801	CALM1	NCCBC14	Human	Breast	DCIS	3.35e-15	2.53e-01	0.2021
801	CALM1	NCCBC5	Human	Breast	DCIS	4.62e-26	4.30e-01	0.2046
801	CALM1	P1	Human	Breast	IDC	2.33e-20	-7.89e-02	0.1527

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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
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
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:004338812	Breast	IDC	positive regulation of DNA binding	14/1434	56/18723	6.11e-05	1.27e-03	14
GO:007058513	Breast	IDC	protein localization to mitochondrion	23/1434	125/18723	6.92e-05	1.40e-03	23
GO:007265513	Breast	IDC	establishment of protein localization to mitochondrion	22/1434	120/18723	1.04e-04	1.97e-03	22
GO:003530414	Breast	IDC	regulation of protein dephosphorylation	18/1434	90/18723	1.39e-04	2.48e-03	18
GO:001095913	Breast	IDC	regulation of metal ion transport	52/1434	406/18723	1.76e-04	2.97e-03	52
GO:000700613	Breast	IDC	mitochondrial membrane organization	21/1434	116/18723	1.78e-04	3.00e-03	21
GO:009730514	Breast	IDC	response to alcohol	36/1434	253/18723	2.29e-04	3.64e-03	36
GO:005138511	Breast	IDC	response to mineralocorticoid	10/1434	36/18723	2.70e-04	4.18e-03	10
GO:008606511	Breast	IDC	cell communication involved in cardiac conduction	13/1434	58/18723	3.59e-04	5.18e-03	13
GO:008606411	Breast	IDC	cell communication by electrical coupling involved in cardiac conduction	8/1434	25/18723	3.85e-04	5.40e-03	8
GO:00459369	Breast	IDC	negative regulation of phosphate metabolic process	53/1434	441/18723	7.21e-04	8.79e-03	53
GO:00105639	Breast	IDC	negative regulation of phosphorus metabolic process	53/1434	442/18723	7.60e-04	9.25e-03	53
GO:003241111	Breast	IDC	positive regulation of transporter activity	20/1434	120/18723	7.64e-04	9.27e-03	20
GO:007259413	Breast	IDC	establishment of protein localization to organelle	51/1434	422/18723	7.94e-04	9.55e-03	51
GO:190184412	Breast	IDC	regulation of cell communication by electrical coupling involved in cardiac conduction	5/1434	11/18723	8.17e-04	9.64e-03	5
GO:00106491	Breast	IDC	regulation of cell communication by electrical coupling	6/1434	16/18723	8.18e-04	9.64e-03	6
GO:005141211	Breast	IDC	response to corticosterone	7/1434	22/18723	9.31e-04	1.06e-02	7
GO:00140751	Breast	IDC	response to amine	11/1434	49/18723	9.88e-04	1.11e-02	11
GO:00432703	Breast	IDC	positive regulation of ion transport	36/1434	275/18723	1.11e-03	1.22e-02	36
GO:004366613	Breast	IDC	regulation of phosphoprotein phosphatase activity	12/1434	58/18723	1.27e-03	1.35e-02	12

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501218	Breast	Precancer	Parkinson disease	99/684	266/8465	3.58e-42	5.65e-40	4.33e-40	99
hsa0501016	Breast	Precancer	Alzheimer disease	103/684	384/8465	1.03e-29	4.66e-28	3.57e-28	103
hsa0502216	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0516718	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0491518	Breast	Precancer	Estrogen signaling pathway	28/684	138/8465	4.10e-06	5.39e-05	4.13e-05	28
hsa0541818	Breast	Precancer	Fluid shear stress and atherosclerosis	28/684	139/8465	4.74e-06	6.00e-05	4.59e-05	28
hsa0541718	Breast	Precancer	Lipid and atherosclerosis	37/684	215/8465	7.64e-06	9.29e-05	7.12e-05	37
hsa042189	Breast	Precancer	Cellular senescence	29/684	156/8465	1.66e-05	1.69e-04	1.30e-04	29
hsa05031	Breast	Precancer	Amphetamine addiction	14/684	69/8465	1.05e-03	7.35e-03	5.63e-03	14
hsa0516316	Breast	Precancer	Human cytomegalovirus infection	32/684	225/8465	1.13e-03	7.57e-03	5.80e-03	32
hsa0497114	Breast	Precancer	Gastric acid secretion	13/684	76/8465	7.35e-03	4.07e-02	3.12e-02	13
hsa0501219	Breast	Precancer	Parkinson disease	99/684	266/8465	3.58e-42	5.65e-40	4.33e-40	99
hsa0501017	Breast	Precancer	Alzheimer disease	103/684	384/8465	1.03e-29	4.66e-28	3.57e-28	103
hsa0502217	Breast	Precancer	Pathways of neurodegeneration - multiple diseases	112/684	476/8465	6.96e-27	2.44e-25	1.87e-25	112
hsa0516719	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0491519	Breast	Precancer	Estrogen signaling pathway	28/684	138/8465	4.10e-06	5.39e-05	4.13e-05	28
hsa0541819	Breast	Precancer	Fluid shear stress and atherosclerosis	28/684	139/8465	4.74e-06	6.00e-05	4.59e-05	28
hsa0541719	Breast	Precancer	Lipid and atherosclerosis	37/684	215/8465	7.64e-06	9.29e-05	7.12e-05	37
hsa0421814	Breast	Precancer	Cellular senescence	29/684	156/8465	1.66e-05	1.69e-04	1.30e-04	29
hsa050311	Breast	Precancer	Amphetamine addiction	14/684	69/8465	1.05e-03	7.35e-03	5.63e-03	14

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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

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

CALM1

SNV

Missense_Mutation

c.400N>A

p.Asp134Asn

p.D134N

P62158

protein_coding

deleterious_low_confidence(0.03)

possibly_damaging(0.574)

TCGA-C5-A1BK-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CALM1

SNV

Missense_Mutation

c.241N>A

p.Asp81Asn

p.D81N

P62158

protein_coding

deleterious_low_confidence(0.03)

benign(0.043)

TCGA-C5-A1BQ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Chemotherapy

cisplatin

CALM1

SNV

Missense_Mutation

c.202G>A

p.Glu68Lys

p.E68K

P62158

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.932)

TCGA-AA-3977-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Unknown

CALM1

SNV

Missense_Mutation

c.202N>A

p.Glu68Lys

p.E68K

P62158

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.932)

TCGA-AP-A1DV-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

CALM1

SNV

Missense_Mutation

novel

c.169N>A

p.Asp57Asn

p.D57N

P62158

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.972)

TCGA-B5-A3FA-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

CALM1

SNV

Missense_Mutation

c.210N>T

p.Leu70Phe

p.L70F

P62158

protein_coding

deleterious_low_confidence(0.01)

possibly_damaging(0.67)

TCGA-05-4415-01

Lung

lung adenocarcinoma

Male

<65

III/IV

Unknown

CALM1

SNV

Missense_Mutation

novel

c.219N>T

p.Met73Ile

p.M73I

P62158

protein_coding

deleterious_low_confidence(0.02)

possibly_damaging(0.654)

TCGA-55-7907-01

Lung

lung adenocarcinoma

Male

>=65

I/II

Unknown

CALM1

SNV

Missense_Mutation

novel

c.17N>T

p.Thr6Ile

p.T6I

P62158

protein_coding

deleterious_low_confidence(0)

benign(0.272)

TCGA-60-2695-01

Lung

lung squamous cell carcinoma

Female

>=65

I/II

Unknown

CALM1

SNV

Missense_Mutation

novel

c.76N>T

p.Gly26Cys

p.G26C

P62158

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.918)

TCGA-85-8287-01

Lung

lung squamous cell carcinoma

Male

>=65

I/II

Unknown

CALM1

SNV

Missense_Mutation

novel

c.77N>T

p.Gly26Val

p.G26V

P62158

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.983)

TCGA-85-8287-01

Lung

lung squamous cell carcinoma

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
801	CALM1	ION CHANNEL, KINASE, ENZYME, DRUGGABLE GENOME		FLUNARIZINE	FLUNARIZINE
801	CALM1	ION CHANNEL, KINASE, ENZYME, DRUGGABLE GENOME		APRINDINE	APRINDINE
801	CALM1	ION CHANNEL, KINASE, ENZYME, DRUGGABLE GENOME		BEPRIDIL	BEPRIDIL

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