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: CACNA1C

Gene summary for CACNA1C

Gene summary.

Gene information	Species	Human
	Gene symbol	CACNA1C
	Gene ID	775
	Gene name	calcium voltage-gated channel subunit alpha1 C
	Gene Alias	CACH2
	Cytomap	12p13.33
	Gene Type	protein-coding
	GO ID	GO:0001508
	UniProtAcc	Q13936

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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
775	CACNA1C	HTA11_99999965104_69814	Human	Colorectum	MSS	2.45e-10	7.81e-01	0.281
775	CACNA1C	A002-C-021	Human	Colorectum	FAP	1.14e-03	2.42e-01	0.1171
775	CACNA1C	CRC-1-8810	Human	Colorectum	CRC	2.35e-12	5.68e-01	0.6257
775	CACNA1C	C21	Human	Oral cavity	OSCC	2.20e-02	-3.07e-01	0.2678
775	CACNA1C	C43	Human	Oral cavity	OSCC	2.01e-07	-3.07e-01	0.1704
775	CACNA1C	C46	Human	Oral cavity	OSCC	1.43e-05	-3.07e-01	0.1673
775	CACNA1C	C57	Human	Oral cavity	OSCC	3.97e-03	-3.07e-01	0.1679
775	CACNA1C	C08	Human	Oral cavity	OSCC	2.29e-06	-2.80e-01	0.1919
775	CACNA1C	EOLP-1	Human	Oral cavity	EOLP	6.30e-14	6.62e-01	-0.0202
775	CACNA1C	NEOLP-1	Human	Oral cavity	NEOLP	3.69e-11	6.66e-01	-0.0194
775	CACNA1C	NEOLP-2	Human	Oral cavity	NEOLP	5.49e-10	4.97e-01	-0.0196
775	CACNA1C	NEOLP-3	Human	Oral cavity	NEOLP	1.46e-13	6.47e-01	-0.0191
775	CACNA1C	SYSMH1	Human	Oral cavity	OSCC	1.96e-09	-3.06e-01	0.1127
775	CACNA1C	SYSMH2	Human	Oral cavity	OSCC	4.27e-09	-3.05e-01	0.2326
775	CACNA1C	SYSMH3	Human	Oral cavity	OSCC	9.25e-09	-3.07e-01	0.2442
775	CACNA1C	SYSMH4	Human	Oral cavity	OSCC	4.33e-08	-3.04e-01	0.1226
775	CACNA1C	SYSMH5	Human	Oral cavity	OSCC	6.29e-07	-3.02e-01	0.0647
775	CACNA1C	SYSMH6	Human	Oral cavity	OSCC	1.79e-07	-3.00e-01	0.1275
775	CACNA1C	HTA12-15-2	Human	Pancreas	PDAC	2.53e-12	6.96e-01	0.2315
775	CACNA1C	HTA12-16-2	Human	Pancreas	PDAC	1.71e-02	6.40e-01	0.0535

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
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:00329702	Colorectum	MSS	regulation of actin filament-based process	128/3467	397/18723	2.47e-11	3.49e-09	128
GO:00300482	Colorectum	MSS	actin filament-based movement	44/3467	127/18723	1.11e-05	2.64e-04	44
GO:00989012	Colorectum	MSS	regulation of cardiac muscle cell action potential	15/3467	27/18723	1.81e-05	3.95e-04	15
GO:00989112	Colorectum	MSS	regulation of ventricular cardiac muscle cell action potential	9/3467	12/18723	3.24e-05	6.37e-04	9
GO:00860042	Colorectum	MSS	regulation of cardiac muscle cell contraction	15/3467	34/18723	5.22e-04	5.99e-03	15
GO:0086001	Colorectum	MSS	cardiac muscle cell action potential	26/3467	76/18723	8.18e-04	8.59e-03	26
GO:0086065	Colorectum	MSS	cell communication involved in cardiac conduction	21/3467	58/18723	1.11e-03	1.09e-02	21
GO:00902572	Colorectum	MSS	regulation of muscle system process	66/3467	252/18723	1.55e-03	1.41e-02	66
GO:00487362	Colorectum	MSS	appendage development	48/3467	172/18723	1.61e-03	1.46e-02	48
GO:00601732	Colorectum	MSS	limb development	48/3467	172/18723	1.61e-03	1.46e-02	48
GO:00516512	Colorectum	MSS	maintenance of location in cell	57/3467	214/18723	2.07e-03	1.76e-02	57
GO:0086005	Colorectum	MSS	ventricular cardiac muscle cell action potential	14/3467	35/18723	2.50e-03	2.01e-02	14
GO:0086091	Colorectum	MSS	regulation of heart rate by cardiac conduction	15/3467	39/18723	2.80e-03	2.19e-02	15
GO:1903115	Colorectum	MSS	regulation of actin filament-based movement	15/3467	39/18723	2.80e-03	2.19e-02	15
GO:0086064	Colorectum	MSS	cell communication by electrical coupling involved in cardiac conduction	11/3467	25/18723	2.96e-03	2.28e-02	11
GO:0070252	Colorectum	MSS	actin-mediated cell contraction	29/3467	97/18723	4.38e-03	3.10e-02	29
GO:0051349	Colorectum	MSS	positive regulation of lyase activity	10/3467	23/18723	5.06e-03	3.47e-02	10
GO:0086003	Colorectum	MSS	cardiac muscle cell contraction	23/3467	73/18723	5.22e-03	3.57e-02	23
GO:00030121	Colorectum	MSS	muscle system process	105/3467	452/18723	6.39e-03	4.26e-02	105
GO:00329704	Colorectum	FAP	regulation of actin filament-based process	105/2622	397/18723	3.15e-11	1.38e-08	105

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa050104	Colorectum	MSS	Alzheimer disease	169/1875	384/8465	1.21e-22	1.01e-20	6.21e-21	169
hsa050204	Colorectum	MSS	Prion disease	129/1875	273/8465	1.04e-20	5.00e-19	3.06e-19	129
hsa050224	Colorectum	MSS	Pathways of neurodegeneration - multiple diseases	192/1875	476/8465	2.79e-20	1.04e-18	6.36e-19	192
hsa047234	Colorectum	MSS	Retrograde endocannabinoid signaling	61/1875	148/8465	1.21e-07	1.93e-06	1.18e-06	61
hsa049124	Colorectum	MSS	GnRH signaling pathway	35/1875	93/8465	4.81e-04	3.43e-03	2.10e-03	35
hsa04935	Colorectum	MSS	Growth hormone synthesis, secretion and action	42/1875	120/8465	8.17e-04	5.16e-03	3.16e-03	42
hsa047284	Colorectum	MSS	Dopaminergic synapse	45/1875	132/8465	1.02e-03	5.94e-03	3.64e-03	45
hsa042604	Colorectum	MSS	Cardiac muscle contraction	31/1875	87/8465	2.73e-03	1.32e-02	8.12e-03	31
hsa04022	Colorectum	MSS	cGMP-PKG signaling pathway	51/1875	167/8465	6.83e-03	2.73e-02	1.67e-02	51
hsa047204	Colorectum	MSS	Long-term potentiation	24/1875	67/8465	7.27e-03	2.83e-02	1.73e-02	24
hsa04713	Colorectum	MSS	Circadian entrainment	32/1875	97/8465	8.84e-03	3.25e-02	1.99e-02	32
hsa04725	Colorectum	MSS	Cholinergic synapse	36/1875	113/8465	1.05e-02	3.69e-02	2.26e-02	36
hsa050105	Colorectum	MSS	Alzheimer disease	169/1875	384/8465	1.21e-22	1.01e-20	6.21e-21	169
hsa050205	Colorectum	MSS	Prion disease	129/1875	273/8465	1.04e-20	5.00e-19	3.06e-19	129
hsa050225	Colorectum	MSS	Pathways of neurodegeneration - multiple diseases	192/1875	476/8465	2.79e-20	1.04e-18	6.36e-19	192
hsa047235	Colorectum	MSS	Retrograde endocannabinoid signaling	61/1875	148/8465	1.21e-07	1.93e-06	1.18e-06	61
hsa049125	Colorectum	MSS	GnRH signaling pathway	35/1875	93/8465	4.81e-04	3.43e-03	2.10e-03	35
hsa049351	Colorectum	MSS	Growth hormone synthesis, secretion and action	42/1875	120/8465	8.17e-04	5.16e-03	3.16e-03	42
hsa047285	Colorectum	MSS	Dopaminergic synapse	45/1875	132/8465	1.02e-03	5.94e-03	3.64e-03	45
hsa042605	Colorectum	MSS	Cardiac muscle contraction	31/1875	87/8465	2.73e-03	1.32e-02	8.12e-03	31

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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

CACNA1C

SNV

Missense_Mutation

c.1258N>C

p.Asp420His

p.D420H

Q13936

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A0SY-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

arimidex

CACNA1C

SNV

Missense_Mutation

c.2699N>T

p.Thr900Met

p.T900M

Q13936

protein_coding

tolerated(0.07)

possibly_damaging(0.828)

TCGA-A8-A06Q-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

CACNA1C

SNV

Missense_Mutation

c.4011N>T

p.Leu1337Phe

p.L1337F

Q13936

protein_coding

deleterious(0.01)

probably_damaging(0.997)

TCGA-A8-A09G-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

CACNA1C

SNV

Missense_Mutation

novel

c.6469N>C

p.Gly2157Arg

p.G2157R

Q13936

protein_coding

tolerated_low_confidence(0.24)

benign(0.012)

TCGA-AR-A2LR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

CACNA1C

SNV

Missense_Mutation

rs368700869

c.5209N>A

p.Ala1737Thr

p.A1737T

Q13936

protein_coding

tolerated(0.09)

possibly_damaging(0.675)

TCGA-B6-A0RL-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

CACNA1C

SNV

Missense_Mutation

novel

c.2773N>G

p.His925Asp

p.H925D

Q13936

protein_coding

tolerated(0.39)

benign(0.205)

TCGA-B6-A400-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

CACNA1C

SNV

Missense_Mutation

rs377345545

c.989N>T

p.Thr330Met

p.T330M

Q13936

protein_coding

tolerated(0.07)

probably_damaging(0.999)

TCGA-BH-A0DD-01

Breast

breast invasive carcinoma

Male

<65

I/II

Chemotherapy

docetaxel

CACNA1C

SNV

Missense_Mutation

c.4277N>A

p.Gly1426Glu

p.G1426E

Q13936

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-BH-A0HF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

CACNA1C

SNV

Missense_Mutation

novel

c.4711N>T

p.Arg1571Trp

p.R1571W

Q13936

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-BH-A18G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CACNA1C

SNV

Missense_Mutation

c.4754N>A

p.Arg1585His

p.R1585H

Q13936

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-BH-A1FC-01

Breast

breast invasive carcinoma

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
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	blocker	CHEMBL1200402	AMLODIPINE BESYLATE
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	blocker	135650185	DILTIAZEM
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	blocker	53801058	MIBEFRADIL
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL		VERAPAMIL	VERAPAMIL
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	blocker	CHEMBL29919	ELPETRIGINE
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	inhibitor	135650722	NISOLDIPINE
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	modulator	CHEMBL2103836	IMAGABALIN
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	blocker	CHEMBL1648	ISRADIPINE
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL	blocker	CHEMBL193	NIFEDIPINE
775	CACNA1C	DRUGGABLE GENOME, ION CHANNEL		ARC029

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