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: CACNB4

Gene summary for CACNB4

Gene summary.

Gene information	Species	Human
	Gene symbol	CACNB4
	Gene ID	785
	Gene name	calcium voltage-gated channel auxiliary subunit beta 4
	Gene Alias	CAB4
	Cytomap	2q23.3
	Gene Type	protein-coding
	GO ID	GO:0006810
	UniProtAcc	O00305

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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
785	CACNB4	RNA-P10T2-P10T2-3	Human	Lung	AAH	1.05e-04	8.72e-01	-0.1408
785	CACNB4	RNA-P10T2-P10T2-4	Human	Lung	AAH	2.92e-04	8.16e-01	-0.138
785	CACNB4	RNA-P25T1-P25T1-1	Human	Lung	AIS	5.42e-23	1.05e+00	-0.2116
785	CACNB4	RNA-P25T1-P25T1-2	Human	Lung	AIS	2.40e-10	9.97e-01	-0.1941
785	CACNB4	RNA-P25T1-P25T1-3	Human	Lung	AIS	1.33e-07	8.88e-01	-0.2107
785	CACNB4	RNA-P25T1-P25T1-4	Human	Lung	AIS	2.23e-19	1.10e+00	-0.2119
785	CACNB4	RNA-P6T1-P6T1-1	Human	Lung	MIAC	5.19e-04	1.13e+00	-0.0238
785	CACNB4	RNA-P6T1-P6T1-2	Human	Lung	MIAC	5.12e-05	1.23e+00	-0.0186
785	CACNB4	RNA-P6T1-P6T1-3	Human	Lung	MIAC	2.49e-03	1.24e+00	-0.0296
785	CACNB4	RNA-P6T1-P6T1-4	Human	Lung	MIAC	3.01e-06	1.19e+00	-0.0263
785	CACNB4	RNA-P6T2-P6T2-1	Human	Lung	IAC	1.01e-11	5.45e-01	-0.0166
785	CACNB4	RNA-P6T2-P6T2-2	Human	Lung	IAC	1.62e-15	5.89e-01	-0.0132
785	CACNB4	RNA-P6T2-P6T2-3	Human	Lung	IAC	5.67e-16	6.22e-01	-0.013
785	CACNB4	RNA-P6T2-P6T2-4	Human	Lung	IAC	1.46e-13	5.78e-01	-0.0121
785	CACNB4	RNA-P7T1-P7T1-1	Human	Lung	AIS	1.80e-05	6.97e-01	-0.0961
785	CACNB4	RNA-P7T1-P7T1-2	Human	Lung	AIS	1.19e-05	6.76e-01	-0.0876
785	CACNB4	RNA-P7T1-P7T1-3	Human	Lung	AIS	1.45e-06	7.41e-01	-0.0822
785	CACNB4	RNA-P7T1-P7T1-4	Human	Lung	AIS	4.72e-06	7.37e-01	-0.0809
785	CACNB4	047563_1562-all-cells	Human	Prostate	BPH	5.64e-13	2.70e-01	0.0791
785	CACNB4	048752_1579-all-cells	Human	Prostate	BPH	4.13e-31	8.10e-01	0.1008

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Prostate		BPH: Benign Prostatic Hyperplasia

∗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:00324124	Lung	IAC	regulation of ion transmembrane transporter activity	45/2061	267/18723	2.43e-03	2.33e-02	45
GO:00228984	Lung	IAC	regulation of transmembrane transporter activity	46/2061	278/18723	3.16e-03	2.75e-02	46
GO:00508085	Lung	IAC	synapse organization	65/2061	426/18723	4.05e-03	3.31e-02	65
GO:00324095	Lung	IAC	regulation of transporter activity	49/2061	310/18723	5.93e-03	4.30e-02	49
GO:19040622	Lung	IAC	regulation of cation transmembrane transport	55/2061	357/18723	6.36e-03	4.52e-02	55
GO:00109595	Lung	IAC	regulation of metal ion transport	61/2061	406/18723	7.31e-03	4.98e-02	61
GO:005080811	Lung	AIS	synapse organization	63/1849	426/18723	7.39e-04	1.07e-02	63
GO:003241211	Lung	AIS	regulation of ion transmembrane transporter activity	42/1849	267/18723	1.65e-03	1.89e-02	42
GO:002289811	Lung	AIS	regulation of transmembrane transporter activity	43/1849	278/18723	2.04e-03	2.24e-02	43
GO:001095912	Lung	AIS	regulation of metal ion transport	58/1849	406/18723	2.63e-03	2.67e-02	58
GO:003240911	Lung	AIS	regulation of transporter activity	45/1849	310/18723	5.54e-03	4.71e-02	45
GO:0006816	Lung	AIS	calcium ion transport	58/1849	422/18723	6.08e-03	4.98e-02	58
GO:003241221	Lung	AAH	regulation of ion transmembrane transporter activity	19/613	267/18723	1.33e-03	3.62e-02	19
GO:002289821	Lung	AAH	regulation of transmembrane transporter activity	19/613	278/18723	2.11e-03	4.61e-02	19
GO:00508087	Prostate	BPH	synapse organization	103/3107	426/18723	3.19e-05	3.61e-04	103
GO:005080813	Prostate	Tumor	synapse organization	105/3246	426/18723	7.20e-05	7.62e-04	105

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa040108	Lung	IAC	MAPK signaling pathway	62/1053	302/8465	3.54e-05	6.38e-04	4.24e-04	62
hsa054126	Lung	IAC	Arrhythmogenic right ventricular cardiomyopathy	22/1053	77/8465	1.15e-04	1.49e-03	9.88e-04	22
hsa04921	Lung	IAC	Oxytocin signaling pathway	33/1053	154/8465	1.09e-03	7.82e-03	5.19e-03	33
hsa05410	Lung	IAC	Hypertrophic cardiomyopathy	20/1053	90/8465	6.44e-03	2.68e-02	1.78e-02	20
hsa05414	Lung	IAC	Dilated cardiomyopathy	20/1053	96/8465	1.33e-02	4.64e-02	3.08e-02	20
hsa0401011	Lung	IAC	MAPK signaling pathway	62/1053	302/8465	3.54e-05	6.38e-04	4.24e-04	62
hsa0541211	Lung	IAC	Arrhythmogenic right ventricular cardiomyopathy	22/1053	77/8465	1.15e-04	1.49e-03	9.88e-04	22
hsa049211	Lung	IAC	Oxytocin signaling pathway	33/1053	154/8465	1.09e-03	7.82e-03	5.19e-03	33
hsa054101	Lung	IAC	Hypertrophic cardiomyopathy	20/1053	90/8465	6.44e-03	2.68e-02	1.78e-02	20
hsa054141	Lung	IAC	Dilated cardiomyopathy	20/1053	96/8465	1.33e-02	4.64e-02	3.08e-02	20
hsa0401021	Lung	AIS	MAPK signaling pathway	57/961	302/8465	6.41e-05	9.43e-04	6.03e-04	57
hsa0541221	Lung	AIS	Arrhythmogenic right ventricular cardiomyopathy	21/961	77/8465	9.05e-05	1.18e-03	7.57e-04	21
hsa049212	Lung	AIS	Oxytocin signaling pathway	34/961	154/8465	9.12e-05	1.18e-03	7.57e-04	34
hsa054142	Lung	AIS	Dilated cardiomyopathy	22/961	96/8465	9.02e-04	7.11e-03	4.55e-03	22
hsa054102	Lung	AIS	Hypertrophic cardiomyopathy	20/961	90/8465	2.25e-03	1.37e-02	8.80e-03	20
hsa0401031	Lung	AIS	MAPK signaling pathway	57/961	302/8465	6.41e-05	9.43e-04	6.03e-04	57
hsa0541231	Lung	AIS	Arrhythmogenic right ventricular cardiomyopathy	21/961	77/8465	9.05e-05	1.18e-03	7.57e-04	21
hsa049213	Lung	AIS	Oxytocin signaling pathway	34/961	154/8465	9.12e-05	1.18e-03	7.57e-04	34
hsa054143	Lung	AIS	Dilated cardiomyopathy	22/961	96/8465	9.02e-04	7.11e-03	4.55e-03	22
hsa054103	Lung	AIS	Hypertrophic cardiomyopathy	20/961	90/8465	2.25e-03	1.37e-02	8.80e-03	20

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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

CACNB4

SNV

Missense_Mutation

c.883N>A

p.Glu295Lys

p.E295K

O00305

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CACNB4

SNV

Missense_Mutation

novel

c.1534N>C

p.Tyr512His

p.Y512H

O00305

protein_coding

tolerated_low_confidence(0.48)

possibly_damaging(0.726)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CACNB4

deletion

Frame_Shift_Del

c.988delN

p.Ile330LeufsTer5

p.I330Lfs*5

O00305

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

CACNB4

SNV

Missense_Mutation

c.659N>A

p.Arg220His

p.R220H

O00305

protein_coding

deleterious(0.01)

probably_damaging(0.997)

TCGA-C5-A2LX-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CACNB4

SNV

Missense_Mutation

novel

c.873N>C

p.Glu291Asp

p.E291D

O00305

protein_coding

deleterious(0.01)

probably_damaging(0.942)

TCGA-C5-A2LZ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Unknown

CACNB4

SNV

Missense_Mutation

novel

c.828N>C

p.Lys276Asn

p.K276N

O00305

protein_coding

deleterious(0.02)

probably_damaging(0.996)

TCGA-EA-A3HU-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CACNB4

SNV

Missense_Mutation

c.122N>T

p.Thr41Ile

p.T41I

O00305

protein_coding

deleterious_low_confidence(0.03)

probably_damaging(0.969)

TCGA-FU-A3EO-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

CACNB4

SNV

Missense_Mutation

c.1186N>C

p.Glu396Gln

p.E396Q

O00305

protein_coding

deleterious(0)

probably_damaging(0.991)

TCGA-IR-A3LK-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

cisplatin

CACNB4

SNV

Missense_Mutation

rs751883436

c.325N>A

p.Glu109Lys

p.E109K

O00305

protein_coding

deleterious(0.03)

probably_damaging(0.97)

TCGA-VS-A958-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

CACNB4

SNV

Missense_Mutation

c.659N>A

p.Arg220His

p.R220H

O00305

protein_coding

deleterious(0.01)

probably_damaging(0.997)

TCGA-A6-6649-01

Colorectum

colon adenocarcinoma

Male

>=65

III/IV

Chemotherapy

fluorouracil

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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
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL		VERAPAMIL	VERAPAMIL
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL	modulator	CHEMBL1059	PREGABALIN
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL		SAFINAMIDE	SAFINAMIDE
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL	modulator	CHEMBL1628502	GABAPENTIN ENACARBIL
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL	modulator	CHEMBL940	GABAPENTIN
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL	modulator	CHEMBL593430	ATAGABALIN
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL	blocker	CHEMBL1200382	BEPRIDIL HYDROCHLORIDE
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL	modulator	CHEMBL2103836	IMAGABALIN
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL		celecoxib	CELECOXIB	22336956
785	CACNB4	DRUGGABLE GENOME, ION CHANNEL		ARVERAPAMIL

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