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: ADCY1

Gene summary for ADCY1

Gene summary.

Gene information	Species	Human
	Gene symbol	ADCY1
	Gene ID	107
	Gene name	adenylate cyclase 1
	Gene Alias	AC1
	Cytomap	7p12.3
	Gene Type	protein-coding
	GO ID	GO:0000902
	UniProtAcc	C9J1J0

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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
107	ADCY1	S43	Human	Liver	Cirrhotic	4.33e-03	-1.11e-01	-0.0187
107	ADCY1	HCC1_Meng	Human	Liver	HCC	1.84e-04	-1.01e-01	0.0246
107	ADCY1	HCC2_Meng	Human	Liver	HCC	4.06e-02	-1.10e-01	0.0107
107	ADCY1	HCC1	Human	Liver	HCC	4.51e-08	1.16e+00	0.5336
107	ADCY1	HCC2	Human	Liver	HCC	2.79e-13	1.92e+00	0.5341
107	ADCY1	HCC5	Human	Liver	HCC	1.66e-20	1.32e+00	0.4932
107	ADCY1	ATC12	Human	Thyroid	ATC	6.74e-12	3.36e-01	0.34
107	ADCY1	ATC13	Human	Thyroid	ATC	4.54e-29	5.70e-01	0.34
107	ADCY1	ATC4	Human	Thyroid	ATC	4.81e-12	3.86e-01	0.34
107	ADCY1	ATC5	Human	Thyroid	ATC	4.96e-29	5.89e-01	0.34

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
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:000675312	Liver	Cirrhotic	nucleoside phosphate metabolic process	190/4634	497/18723	1.10e-11	6.96e-10	190
GO:000911712	Liver	Cirrhotic	nucleotide metabolic process	187/4634	489/18723	1.55e-11	9.63e-10	187
GO:001003812	Liver	Cirrhotic	response to metal ion	150/4634	373/18723	2.27e-11	1.37e-09	150
GO:001969312	Liver	Cirrhotic	ribose phosphate metabolic process	156/4634	396/18723	5.83e-11	3.23e-09	156
GO:000925912	Liver	Cirrhotic	ribonucleotide metabolic process	151/4634	385/18723	1.72e-10	8.70e-09	151
GO:190165412	Liver	Cirrhotic	response to ketone	86/4634	194/18723	1.82e-09	7.73e-08	86
GO:007252112	Liver	Cirrhotic	purine-containing compound metabolic process	156/4634	416/18723	3.74e-09	1.52e-07	156
GO:000915012	Liver	Cirrhotic	purine ribonucleotide metabolic process	141/4634	368/18723	4.22e-09	1.70e-07	141
GO:000616312	Liver	Cirrhotic	purine nucleotide metabolic process	146/4634	396/18723	4.12e-08	1.34e-06	146
GO:000941012	Liver	Cirrhotic	response to xenobiotic stimulus	165/4634	462/18723	6.82e-08	2.09e-06	165
GO:000762312	Liver	Cirrhotic	circadian rhythm	84/4634	210/18723	7.04e-07	1.50e-05	84
GO:009730512	Liver	Cirrhotic	response to alcohol	96/4634	253/18723	1.97e-06	3.65e-05	96
GO:005159211	Liver	Cirrhotic	response to calcium ion	61/4634	149/18723	9.47e-06	1.38e-04	61
GO:19016551	Liver	Cirrhotic	cellular response to ketone	42/4634	96/18723	3.55e-05	4.32e-04	42
GO:00463905	Liver	Cirrhotic	ribose phosphate biosynthetic process	71/4634	190/18723	7.09e-05	7.98e-04	71
GO:00712487	Liver	Cirrhotic	cellular response to metal ion	73/4634	197/18723	7.73e-05	8.54e-04	73
GO:004851111	Liver	Cirrhotic	rhythmic process	103/4634	298/18723	8.47e-05	9.19e-04	103
GO:00092605	Liver	Cirrhotic	ribonucleotide biosynthetic process	68/4634	182/18723	1.00e-04	1.05e-03	68
GO:00712417	Liver	Cirrhotic	cellular response to inorganic substance	81/4634	226/18723	1.21e-04	1.20e-03	81
GO:00091654	Liver	Cirrhotic	nucleotide biosynthetic process	89/4634	254/18723	1.45e-04	1.40e-03	89

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0471414	Liver	Cirrhotic	Thermogenesis	121/2530	232/8465	5.70e-13	1.36e-11	8.36e-12	121
hsa0516614	Liver	Cirrhotic	Human T-cell leukemia virus 1 infection	87/2530	222/8465	1.69e-03	8.01e-03	4.94e-03	87
hsa0516312	Liver	Cirrhotic	Human cytomegalovirus infection	87/2530	225/8465	2.67e-03	1.10e-02	6.76e-03	87
hsa042118	Liver	Cirrhotic	Longevity regulating pathway	37/2530	89/8465	1.22e-02	3.89e-02	2.40e-02	37
hsa0472314	Liver	Cirrhotic	Retrograde endocannabinoid signaling	57/2530	148/8465	1.45e-02	4.39e-02	2.71e-02	57
hsa0471415	Liver	Cirrhotic	Thermogenesis	121/2530	232/8465	5.70e-13	1.36e-11	8.36e-12	121
hsa0516615	Liver	Cirrhotic	Human T-cell leukemia virus 1 infection	87/2530	222/8465	1.69e-03	8.01e-03	4.94e-03	87
hsa0516313	Liver	Cirrhotic	Human cytomegalovirus infection	87/2530	225/8465	2.67e-03	1.10e-02	6.76e-03	87
hsa0421111	Liver	Cirrhotic	Longevity regulating pathway	37/2530	89/8465	1.22e-02	3.89e-02	2.40e-02	37
hsa0472315	Liver	Cirrhotic	Retrograde endocannabinoid signaling	57/2530	148/8465	1.45e-02	4.39e-02	2.71e-02	57
hsa0471422	Liver	HCC	Thermogenesis	170/4020	232/8465	5.36e-16	2.25e-14	1.25e-14	170
hsa0516622	Liver	HCC	Human T-cell leukemia virus 1 infection	139/4020	222/8465	3.17e-06	2.79e-05	1.55e-05	139
hsa0421121	Liver	HCC	Longevity regulating pathway	61/4020	89/8465	4.46e-05	2.37e-04	1.32e-04	61
hsa0516322	Liver	HCC	Human cytomegalovirus infection	131/4020	225/8465	6.86e-04	2.77e-03	1.54e-03	131
hsa042138	Liver	HCC	Longevity regulating pathway - multiple species	41/4020	62/8465	2.30e-03	7.86e-03	4.37e-03	41
hsa05142	Liver	HCC	Chagas disease	61/4020	102/8465	8.04e-03	2.17e-02	1.21e-02	61
hsa049262	Liver	HCC	Relaxin signaling pathway	75/4020	129/8465	9.33e-03	2.46e-02	1.37e-02	75
hsa01522	Liver	HCC	Endocrine resistance	58/4020	98/8465	1.28e-02	3.19e-02	1.78e-02	58
hsa046112	Liver	HCC	Platelet activation	71/4020	124/8465	1.77e-02	4.15e-02	2.31e-02	71
hsa0471432	Liver	HCC	Thermogenesis	170/4020	232/8465	5.36e-16	2.25e-14	1.25e-14	170

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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

ADCY1

SNV

Missense_Mutation

c.911N>G

p.Ile304Ser

p.I304S

Q08828

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A1-A0SO-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

ADCY1

SNV

Missense_Mutation

rs369079165

c.664G>A

p.Val222Ile

p.V222I

Q08828

protein_coding

tolerated(0.69)

benign(0.007)

TCGA-A8-A07F-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

ADCY1

SNV

Missense_Mutation

c.1561N>A

p.Glu521Lys

p.E521K

Q08828

protein_coding

tolerated(0.08)

benign(0.031)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ADCY1

SNV

Missense_Mutation

c.2927G>A

p.Arg976Gln

p.R976Q

Q08828

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ADCY1

SNV

Missense_Mutation

novel

c.1705N>C

p.Ile569Leu

p.I569L

Q08828

protein_coding

tolerated(0.73)

benign(0.007)

TCGA-AN-A04C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ADCY1

SNV

Missense_Mutation

rs770046299

c.3263N>T

p.Pro1088Leu

p.P1088L

Q08828

protein_coding

deleterious_low_confidence(0.02)

benign(0.001)

TCGA-E2-A15P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

ADCY1

SNV

Missense_Mutation

novel

c.2248T>G

p.Leu750Val

p.L750V

Q08828

protein_coding

tolerated(0.08)

benign(0.024)

TCGA-GI-A2C9-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

ADCY1

insertion

Nonsense_Mutation

novel

c.2454_2454+1insACTGGGTAAGTGTGTGGCTCCTCAAGAAAAAGGCCTAA

p.Ala819ThrfsTer3

p.A819Tfs*3

Q08828

protein_coding

TCGA-A8-A07O-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

ADCY1

insertion

Frame_Shift_Ins

novel

c.2525_2526insATCTGCTCTGCCGTGTCCTCTCCCCATGGTG

p.Ala843SerfsTer47

p.A843Sfs*47

Q08828

protein_coding

TCGA-B6-A0I6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ADCY1

SNV

Missense_Mutation

rs760996289

c.667G>A

p.Gly223Ser

p.G223S

Q08828

protein_coding

tolerated(0.61)

benign(0.005)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

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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
107	ADCY1	DRUGGABLE GENOME, ENZYME		NSC-270718	CHEMBL401844	18630896
107	ADCY1	DRUGGABLE GENOME, ENZYME		Adenosine monophosphate
107	ADCY1	DRUGGABLE GENOME, ENZYME	inhibitor	381118802
107	ADCY1	DRUGGABLE GENOME, ENZYME		lithium	LITHIUM	29121268

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