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: CACNA1H

Gene summary for CACNA1H

Gene summary.

Gene information	Species	Human
	Gene symbol	CACNA1H
	Gene ID	8912
	Gene name	calcium voltage-gated channel subunit alpha1 H
	Gene Alias	CACNA1HB
	Cytomap	16p13.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	B3KQH9

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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
8912	CACNA1H	HCC1_Meng	Human	Liver	HCC	2.43e-11	7.63e-03	0.0246
8912	CACNA1H	HCC1	Human	Liver	HCC	1.97e-05	3.89e-01	0.5336
8912	CACNA1H	S014	Human	Liver	HCC	3.81e-14	8.40e-01	0.2254
8912	CACNA1H	S015	Human	Liver	HCC	4.20e-15	9.15e-01	0.2375
8912	CACNA1H	S016	Human	Liver	HCC	5.73e-27	9.10e-01	0.2243

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		NAFLD: Non-alcoholic fatty liver disease

∗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:000606621	Liver	HCC	alcohol metabolic process	208/7958	353/18723	2.80e-10	9.50e-09	208
GO:00082022	Liver	HCC	steroid metabolic process	188/7958	319/18723	1.96e-09	5.63e-08	188
GO:001003822	Liver	HCC	response to metal ion	208/7958	373/18723	1.35e-07	2.56e-06	208
GO:00066942	Liver	HCC	steroid biosynthetic process	104/7958	173/18723	2.13e-06	2.91e-05	104
GO:004218021	Liver	HCC	cellular ketone metabolic process	123/7958	211/18723	2.52e-06	3.37e-05	123
GO:19016172	Liver	HCC	organic hydroxy compound biosynthetic process	129/7958	237/18723	1.32e-04	1.08e-03	129
GO:00461651	Liver	HCC	alcohol biosynthetic process	81/7958	140/18723	1.73e-04	1.36e-03	81
GO:000608112	Liver	HCC	cellular aldehyde metabolic process	39/7958	60/18723	3.61e-04	2.50e-03	39
GO:007124112	Liver	HCC	cellular response to inorganic substance	119/7958	226/18723	1.26e-03	6.92e-03	119
GO:007124812	Liver	HCC	cellular response to metal ion	101/7958	197/18723	7.82e-03	3.10e-02	101
GO:003430812	Liver	HCC	primary alcohol metabolic process	55/7958	102/18723	1.30e-02	4.67e-02	55

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

CACNA1H

SNV

Missense_Mutation

rs534632699

c.3758G>A

p.Arg1253His

p.R1253H

O95180

protein_coding

deleterious(0)

probably_damaging(0.948)

TCGA-A2-A0SU-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

CACNA1H

SNV

Missense_Mutation

c.1691N>A

p.Arg564His

p.R564H

O95180

protein_coding

tolerated(0.14)

benign(0)

TCGA-A2-A3XS-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cytoxan

CACNA1H

SNV

Missense_Mutation

rs369630836

c.718N>A

p.Val240Ile

p.V240I

O95180

protein_coding

deleterious(0.01)

probably_damaging(0.995)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

CACNA1H

SNV

Missense_Mutation

c.1459N>T

p.Arg487Cys

p.R487C

O95180

protein_coding

tolerated(0.08)

benign(0.003)

TCGA-B6-A0WX-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

CACNA1H

SNV

Missense_Mutation

novel

c.1227C>A

p.Phe409Leu

p.F409L

O95180

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-B6-A409-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

CACNA1H

SNV

Missense_Mutation

rs369630836

c.718G>A

p.Val240Ile

p.V240I

O95180

protein_coding

deleterious(0.01)

probably_damaging(0.995)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

CACNA1H

SNV

Missense_Mutation

c.2738N>G

p.Asp913Gly

p.D913G

O95180

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-E2-A1IN-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

CACNA1H

SNV

Missense_Mutation

c.667C>G

p.Leu223Val

p.L223V

O95180

protein_coding

deleterious(0.01)

probably_damaging(0.997)

TCGA-EW-A1IZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxotere

CACNA1H

SNV

Missense_Mutation

c.1084N>A

p.Asp362Asn

p.D362N

O95180

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-EW-A3U0-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cisplatin

CACNA1H

SNV

Missense_Mutation

rs747598216

c.4789N>T

p.Arg1597Trp

p.R1597W

O95180

protein_coding

deleterious(0.02)

probably_damaging(0.919)

TCGA-GI-A2C8-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

Adriamycin

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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
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME		FLUNARIZINE DIHYDROCHLORIDE	FLUNARIZINE DIHYDROCHLORIDE
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME		ELLIPTECINE	ELLIPTECINE
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME		SJ000019194	CHEMBL592106
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME	blocker	53801058	MIBEFRADIL
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME		Mibefradil	MIBEFRADIL
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME	blocker	223366057
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME		NAFTOPIDIL	NAFTOPIDIL
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME	blocker	CHEMBL1100	PARAMETHADIONE
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME		CID 94381	CHEMBL374632
8912	CACNA1H	ION CHANNEL, DRUGGABLE GENOME	blocker	CHEMBL797	PHENSUXIMIDE

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