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: ADRA1A

Gene summary for ADRA1A

Gene summary.

Gene information	Species	Human
	Gene symbol	ADRA1A
	Gene ID	148
	Gene name	adrenoceptor alpha 1A
	Gene Alias	ADRA1C
	Cytomap	8p21.2
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	P35348

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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
148	ADRA1A	NAFLD1	Human	Liver	NAFLD	7.47e-16	1.53e+00	-0.04
148	ADRA1A	S41	Human	Liver	Cirrhotic	1.68e-02	7.18e-01	-0.0343
148	ADRA1A	S43	Human	Liver	Cirrhotic	1.72e-02	-3.00e-01	-0.0187
148	ADRA1A	HCC1_Meng	Human	Liver	HCC	3.62e-20	-4.41e-01	0.0246
148	ADRA1A	HCC2_Meng	Human	Liver	HCC	4.58e-11	-4.44e-01	0.0107
148	ADRA1A	cirrhotic1	Human	Liver	Cirrhotic	4.58e-11	-4.43e-01	0.0202
148	ADRA1A	cirrhotic2	Human	Liver	Cirrhotic	4.58e-11	-4.44e-01	0.0201
148	ADRA1A	cirrhotic3	Human	Liver	Cirrhotic	4.84e-04	-4.40e-01	0.0215
148	ADRA1A	Pt13.a	Human	Liver	HCC	1.08e-09	-4.40e-01	0.021
148	ADRA1A	Pt13.b	Human	Liver	HCC	7.12e-04	-4.44e-01	0.0251
148	ADRA1A	Pt14.d	Human	Liver	HCC	7.79e-10	-4.38e-01	0.0143
148	ADRA1A	S014	Human	Liver	HCC	1.21e-02	-4.44e-01	0.2254
148	ADRA1A	S016	Human	Liver	HCC	5.80e-04	-4.44e-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:00094107	Liver	NAFLD	response to xenobiotic stimulus	88/1882	462/18723	2.53e-09	4.11e-07	88
GO:00098957	Liver	NAFLD	negative regulation of catabolic process	65/1882	320/18723	2.50e-08	2.71e-06	65
GO:00072654	Liver	NAFLD	Ras protein signal transduction	66/1882	337/18723	8.43e-08	7.09e-06	66
GO:00313307	Liver	NAFLD	negative regulation of cellular catabolic process	55/1882	262/18723	9.35e-08	7.59e-06	55
GO:00160495	Liver	NAFLD	cell growth	85/1882	482/18723	1.75e-07	1.25e-05	85
GO:00510564	Liver	NAFLD	regulation of small GTPase mediated signal transduction	56/1882	302/18723	4.62e-06	1.75e-04	56
GO:00105065	Liver	NAFLD	regulation of autophagy	57/1882	317/18723	1.00e-05	3.18e-04	57
GO:00072664	Liver	NAFLD	Rho protein signal transduction	31/1882	137/18723	1.19e-05	3.67e-04	31
GO:00485884	Liver	NAFLD	developmental cell growth	45/1882	234/18723	1.50e-05	4.38e-04	45
GO:0035024	Liver	NAFLD	negative regulation of Rho protein signal transduction	10/1882	22/18723	2.13e-05	5.97e-04	10
GO:00458606	Liver	NAFLD	positive regulation of protein kinase activity	65/1882	386/18723	2.22e-05	6.13e-04	65
GO:00465783	Liver	NAFLD	regulation of Ras protein signal transduction	38/1882	189/18723	2.42e-05	6.61e-04	38
GO:00336747	Liver	NAFLD	positive regulation of kinase activity	74/1882	467/18723	5.16e-05	1.19e-03	74
GO:00510583	Liver	NAFLD	negative regulation of small GTPase mediated signal transduction	16/1882	56/18723	8.53e-05	1.72e-03	16
GO:00030182	Liver	NAFLD	vascular process in circulatory system	46/1882	263/18723	1.36e-04	2.58e-03	46
GO:00075687	Liver	NAFLD	aging	53/1882	339/18723	7.78e-04	9.77e-03	53
GO:00465802	Liver	NAFLD	negative regulation of Ras protein signal transduction	13/1882	49/18723	8.43e-04	1.03e-02	13
GO:00033001	Liver	NAFLD	cardiac muscle hypertrophy	20/1882	99/18723	1.80e-03	1.85e-02	20
GO:00350233	Liver	NAFLD	regulation of Rho protein signal transduction	18/1882	86/18723	1.98e-03	1.98e-02	18
GO:0014897	Liver	NAFLD	striated muscle hypertrophy	20/1882	102/18723	2.61e-03	2.41e-02	20

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa041528	Liver	NAFLD	AMPK signaling pathway	28/1043	121/8465	6.26e-04	9.78e-03	7.88e-03	28
hsa0415211	Liver	NAFLD	AMPK signaling pathway	28/1043	121/8465	6.26e-04	9.78e-03	7.88e-03	28
hsa0415241	Liver	HCC	AMPK signaling pathway	77/4020	121/8465	2.32e-04	1.11e-03	6.18e-04	77
hsa0415251	Liver	HCC	AMPK signaling pathway	77/4020	121/8465	2.32e-04	1.11e-03	6.18e-04	77

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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

ADRA1A

SNV

Missense_Mutation

novel

c.495N>C

p.Trp165Cys

p.W165C

P35348

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

ADRA1A

SNV

Missense_Mutation

rs558845106

c.1180N>A

p.Val394Ile

p.V394I

P35348

protein_coding

tolerated_low_confidence(0.14)

benign(0.003)

TCGA-A2-A0EO-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ADRA1A

SNV

Missense_Mutation

c.617N>A

p.Arg206His

p.R206H

P35348

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AR-A1AH-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

ADRA1A

SNV

Missense_Mutation

rs772047975

c.310N>T

p.Ala104Ser

p.A104S

P35348

protein_coding

tolerated(0.17)

probably_damaging(0.953)

TCGA-GI-A2C9-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

ADRA1A

SNV

Missense_Mutation

novel

c.592N>A

p.Ala198Thr

p.A198T

P35348

protein_coding

tolerated(0.51)

benign(0.02)

TCGA-PE-A5DE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

ADRA1A

insertion

Nonsense_Mutation

novel

c.1249_1250insATTTCTGTCCGTTTATATAGCACTTTATGTTTGTCAAAGTAATTG

p.Ser417delinsTyrPheCysProPheIleTerHisPheMetPheValLysValIleAla

p.S417delinsYFCPFI*HFMFVKVIA

P35348

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

ADRA1A

SNV

Missense_Mutation

rs757286802

c.694G>T

p.Val232Leu

p.V232L

P35348

protein_coding

tolerated(0.46)

benign(0.267)

TCGA-C5-A1BN-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ADRA1A

SNV

Missense_Mutation

novel

c.1034N>A

p.Cys345Tyr

p.C345Y

P35348

protein_coding

deleterious(0.02)

benign(0.248)

TCGA-C5-A902-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ADRA1A

SNV

Missense_Mutation

c.391N>T

p.Pro131Ser

p.P131S

P35348

protein_coding

tolerated(0.32)

possibly_damaging(0.773)

TCGA-JW-A5VJ-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ADRA1A

SNV

Missense_Mutation

novel

c.903N>G

p.Phe301Leu

p.F301L

P35348

protein_coding

tolerated(1)

benign(0.001)

TCGA-MA-AA3Y-01

Cervix

cervical & endocervical cancer

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
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		ASENAPINE	ASENAPINE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		LISDEXAMFETAMINE	LISDEXAMFETAMINE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR	agonist	CHEMBL2062264	PHENYLEPHRINE BITARTRATE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		PHENYLPROPANOLAMINE	PHENYLPROPANOLAMINE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR	agonist	135651527
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		OXYMETAZOLINE	OXYMETAZOLINE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		PHENYLPROPANOLAMINE	PHENYLPROPANOLAMINE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		PROPERICIAZINE	PERICIAZINE
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		TERAZOSIN	TERAZOSIN
148	ADRA1A	DRUGGABLE GENOME, G PROTEIN COUPLED RECEPTOR		AMIODARONE	AMIODARONE

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