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: ADCY3

Gene summary for ADCY3

Gene summary.

Gene information	Species	Human
	Gene symbol	ADCY3
	Gene ID	109
	Gene name	adenylate cyclase 3
	Gene Alias	AC-III
	Cytomap	2p23.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A0A0MSC1

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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
109	ADCY3	CCI_1	Human	Cervix	CC	5.47e-05	5.80e-01	0.528
109	ADCY3	CCI_2	Human	Cervix	CC	1.00e-10	6.74e-01	0.5249
109	ADCY3	HTA11_3410_2000001011	Human	Colorectum	AD	1.02e-04	2.46e-01	0.0155
109	ADCY3	HTA11_1938_2000001011	Human	Colorectum	AD	2.47e-04	4.23e-01	-0.0811
109	ADCY3	HTA11_1391_2000001011	Human	Colorectum	AD	2.55e-08	6.24e-01	-0.059
109	ADCY3	HTA11_866_3004761011	Human	Colorectum	AD	7.80e-12	4.72e-01	0.096
109	ADCY3	HTA11_10623_2000001011	Human	Colorectum	AD	3.59e-05	5.20e-01	-0.0177
109	ADCY3	HTA11_10711_2000001011	Human	Colorectum	AD	1.09e-11	5.82e-01	0.0338
109	ADCY3	HTA11_7696_3000711011	Human	Colorectum	AD	3.38e-21	7.27e-01	0.0674
109	ADCY3	HTA11_6818_2000001021	Human	Colorectum	AD	1.28e-02	2.88e-01	0.0588
109	ADCY3	HTA11_99999970781_79442	Human	Colorectum	MSS	6.96e-05	4.09e-01	0.294
109	ADCY3	HTA11_99999971662_82457	Human	Colorectum	MSS	2.26e-27	9.74e-01	0.3859
109	ADCY3	HTA11_99999973899_84307	Human	Colorectum	MSS	2.33e-12	7.68e-01	0.2585
109	ADCY3	HTA11_99999974143_84620	Human	Colorectum	MSS	3.33e-11	5.13e-01	0.3005

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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

∗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:190165410	Cervix	CC	response to ketone	45/2311	194/18723	1.83e-05	3.44e-04	45
GO:00196939	Cervix	CC	ribose phosphate metabolic process	72/2311	396/18723	4.49e-04	4.48e-03	72
GO:00092599	Cervix	CC	ribonucleotide metabolic process	70/2311	385/18723	5.35e-04	5.18e-03	70
GO:00463908	Cervix	CC	ribose phosphate biosynthetic process	39/2311	190/18723	9.02e-04	7.77e-03	39
GO:000915010	Cervix	CC	purine ribonucleotide metabolic process	66/2311	368/18723	1.09e-03	9.07e-03	66
GO:00092608	Cervix	CC	ribonucleotide biosynthetic process	37/2311	182/18723	1.44e-03	1.13e-02	37
GO:00091529	Cervix	CC	purine ribonucleotide biosynthetic process	34/2311	169/18723	2.62e-03	1.81e-02	34
GO:00973059	Cervix	CC	response to alcohol	46/2311	253/18723	4.40e-03	2.69e-02	46
GO:000616310	Cervix	CC	purine nucleotide metabolic process	67/2311	396/18723	4.41e-03	2.69e-02	67
GO:007252110	Cervix	CC	purine-containing compound metabolic process	69/2311	416/18723	6.27e-03	3.54e-02	69
GO:000911710	Cervix	CC	nucleotide metabolic process	79/2311	489/18723	7.16e-03	3.85e-02	79
GO:0009150	Colorectum	AD	purine ribonucleotide metabolic process	142/3918	368/18723	4.29e-15	1.17e-12	142
GO:0006163	Colorectum	AD	purine nucleotide metabolic process	149/3918	396/18723	1.08e-14	2.80e-12	149
GO:0072521	Colorectum	AD	purine-containing compound metabolic process	153/3918	416/18723	4.34e-14	1.01e-11	153
GO:0009259	Colorectum	AD	ribonucleotide metabolic process	144/3918	385/18723	5.25e-14	1.13e-11	144
GO:0019693	Colorectum	AD	ribose phosphate metabolic process	145/3918	396/18723	3.01e-13	5.71e-11	145
GO:0009117	Colorectum	AD	nucleotide metabolic process	168/3918	489/18723	2.20e-12	3.36e-10	168
GO:0006753	Colorectum	AD	nucleoside phosphate metabolic process	169/3918	497/18723	4.99e-12	6.98e-10	169
GO:0009152	Colorectum	AD	purine ribonucleotide biosynthetic process	64/3918	169/18723	3.09e-07	1.22e-05	64
GO:0009260	Colorectum	AD	ribonucleotide biosynthetic process	66/3918	182/18723	1.25e-06	4.02e-05	66

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0471420	Cervix	CC	Thermogenesis	76/1267	232/8465	4.29e-12	1.16e-10	6.85e-11	76
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0491520	Cervix	CC	Estrogen signaling pathway	44/1267	138/8465	3.55e-07	3.97e-06	2.35e-06	44
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0401512	Cervix	CC	Rap1 signaling pathway	56/1267	210/8465	6.23e-06	5.61e-05	3.32e-05	56
hsa0472318	Cervix	CC	Retrograde endocannabinoid signaling	42/1267	148/8465	1.79e-05	1.42e-04	8.40e-05	42
hsa0511016	Cervix	CC	Vibrio cholerae infection	18/1267	50/8465	1.91e-04	1.11e-03	6.55e-04	18
hsa015223	Cervix	CC	Endocrine resistance	28/1267	98/8465	3.82e-04	1.87e-03	1.11e-03	28
hsa0491212	Cervix	CC	GnRH signaling pathway	26/1267	93/8465	8.72e-04	3.87e-03	2.29e-03	26
hsa0492812	Cervix	CC	Parathyroid hormone synthesis, secretion and action	27/1267	106/8465	3.12e-03	1.19e-02	7.03e-03	27
hsa04062	Cervix	CC	Chemokine signaling pathway	43/1267	192/8465	3.60e-03	1.34e-02	7.91e-03	43
hsa0497116	Cervix	CC	Gastric acid secretion	20/1267	76/8465	6.93e-03	2.27e-02	1.34e-02	20
hsa049265	Cervix	CC	Relaxin signaling pathway	30/1267	129/8465	7.92e-03	2.56e-02	1.51e-02	30
hsa04540	Cervix	CC	Gap junction	22/1267	88/8465	9.07e-03	2.85e-02	1.69e-02	22
hsa049218	Cervix	CC	Oxytocin signaling pathway	34/1267	154/8465	1.12e-02	3.42e-02	2.02e-02	34
hsa046115	Cervix	CC	Platelet activation	28/1267	124/8465	1.50e-02	4.45e-02	2.63e-02	28
hsa04714110	Cervix	CC	Thermogenesis	76/1267	232/8465	4.29e-12	1.16e-10	6.85e-11	76
hsa0516319	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa04915110	Cervix	CC	Estrogen signaling pathway	44/1267	138/8465	3.55e-07	3.97e-06	2.35e-06	44
hsa05166110	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61

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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

ADCY3

SNV

Missense_Mutation

c.2768N>C

p.Ile923Thr

p.I923T

protein_coding

deleterious(0.03)

possibly_damaging(0.808)

TCGA-A2-A0YC-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

ADCY3

SNV

Missense_Mutation

novel

c.1163N>A

p.Ile388Asn

p.I388N

protein_coding

deleterious(0)

probably_damaging(0.976)

TCGA-A8-A07R-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Ancillary

zoledronic

ADCY3

SNV

Missense_Mutation

novel

c.581N>G

p.Ser194Cys

p.S194C

protein_coding

deleterious(0.02)

possibly_damaging(0.83)

TCGA-AO-A03O-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

doxorubicin

ADCY3

SNV

Missense_Mutation

c.2657N>A

p.Arg886Gln

p.R886Q

protein_coding

deleterious(0)

benign(0.082)

TCGA-AR-A1AI-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ADCY3

SNV

Missense_Mutation

novel

c.3032N>C

p.Trp1011Ser

p.W1011S

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ADCY3

SNV

Missense_Mutation

novel

c.331G>A

p.Ala111Thr

p.A111T

protein_coding

tolerated(0.38)

benign(0.264)

TCGA-LL-A6FP-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ADCY3

insertion

Frame_Shift_Ins

novel

c.1776_1777insAAGAGAAACACCTTCCTCTTGTCCATGCGGTTCATGGACCCCGA

p.Ala593LysfsTer25

p.A593Kfs*25

protein_coding

TCGA-A2-A0CM-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

ADCY3

insertion

In_Frame_Ins

novel

c.697_698insCAGATG

p.Tyr233delinsSerAspAsp

p.Y233delinsSDD

protein_coding

TCGA-AN-A0FX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ADCY3

insertion

Frame_Shift_Ins

novel

c.695_696insTT

p.Tyr233SerfsTer33

p.Y233Sfs*33

protein_coding

TCGA-AN-A0FX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ADCY3

SNV

Missense_Mutation

c.2657G>A

p.Arg886Gln

p.R886Q

protein_coding

deleterious(0)

benign(0.082)

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

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