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: ATR

Gene summary for ATR

Gene summary.

Gene information	Species	Human
	Gene symbol	ATR
	Gene ID	545
	Gene name	ATR serine/threonine kinase
	Gene Alias	FCTCS
	Cytomap	3q23
	Gene Type	protein-coding
	GO ID	GO:0000075
	UniProtAcc	Q13535

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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
545	ATR	CCI_1	Human	Cervix	CC	9.22e-06	7.52e-01	0.528
545	ATR	CCI_2	Human	Cervix	CC	2.66e-20	1.82e+00	0.5249
545	ATR	CCI_3	Human	Cervix	CC	1.85e-31	1.65e+00	0.516
545	ATR	HTA11_3410_2000001011	Human	Colorectum	AD	9.81e-04	-1.55e-01	0.0155
545	ATR	HTA11_866_3004761011	Human	Colorectum	AD	2.32e-07	-4.71e-01	0.096
545	ATR	HTA11_8622_2000001021	Human	Colorectum	SER	8.98e-03	-6.25e-01	0.0528
545	ATR	HTA11_10711_2000001011	Human	Colorectum	AD	1.20e-04	-4.59e-01	0.0338
545	ATR	HTA11_7696_3000711011	Human	Colorectum	AD	4.16e-05	-4.36e-01	0.0674
545	ATR	HTA11_6818_2000001021	Human	Colorectum	AD	9.23e-05	-5.17e-01	0.0588
545	ATR	HTA11_99999970781_79442	Human	Colorectum	MSS	9.86e-04	-2.88e-01	0.294
545	ATR	HTA11_99999973899_84307	Human	Colorectum	MSS	3.21e-04	-4.73e-01	0.2585
545	ATR	HTA11_99999974143_84620	Human	Colorectum	MSS	5.32e-11	-4.93e-01	0.3005
545	ATR	A001-C-207	Human	Colorectum	FAP	9.23e-04	-8.77e-02	0.1278
545	ATR	A015-C-203	Human	Colorectum	FAP	3.21e-25	-2.57e-01	-0.1294
545	ATR	A015-C-204	Human	Colorectum	FAP	5.94e-04	-2.35e-01	-0.0228
545	ATR	A014-C-040	Human	Colorectum	FAP	1.55e-03	-2.39e-01	-0.1184
545	ATR	A002-C-201	Human	Colorectum	FAP	1.92e-11	-2.64e-01	0.0324
545	ATR	A002-C-203	Human	Colorectum	FAP	1.76e-02	-1.11e-01	0.2786
545	ATR	A001-C-119	Human	Colorectum	FAP	2.57e-03	-2.22e-01	-0.1557
545	ATR	A001-C-108	Human	Colorectum	FAP	3.43e-15	-2.05e-03	-0.0272

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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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma

∗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:001657114	Skin	cSCC	histone methylation	52/4864	141/18723	2.74e-03	1.54e-02	52
GO:004508812	Skin	cSCC	regulation of innate immune response	75/4864	218/18723	3.40e-03	1.84e-02	75
GO:00711031	Skin	cSCC	DNA conformation change	96/4864	290/18723	3.87e-03	2.07e-02	96
GO:000979122	Skin	cSCC	post-embryonic development	32/4864	80/18723	4.18e-03	2.21e-02	32
GO:00085845	Skin	cSCC	male gonad development	51/4864	141/18723	4.70e-03	2.40e-02	51
GO:00465465	Skin	cSCC	development of primary male sexual characteristics	51/4864	142/18723	5.52e-03	2.73e-02	51
GO:004574011	Skin	cSCC	positive regulation of DNA replication	18/4864	40/18723	7.10e-03	3.40e-02	18
GO:2000232	Skin	cSCC	regulation of rRNA processing	9/4864	16/18723	9.73e-03	4.31e-02	9
GO:003106014	Skin	cSCC	regulation of histone methylation	27/4864	69/18723	1.13e-02	4.92e-02	27
GO:004217630	Thyroid	HT	regulation of protein catabolic process	70/1272	391/18723	5.96e-14	1.66e-11	70
GO:190336230	Thyroid	HT	regulation of cellular protein catabolic process	50/1272	255/18723	7.98e-12	1.48e-09	50
GO:000989528	Thyroid	HT	negative regulation of catabolic process	50/1272	320/18723	2.72e-08	2.02e-06	50
GO:003133029	Thyroid	HT	negative regulation of cellular catabolic process	42/1272	262/18723	1.70e-07	9.25e-06	42
GO:00321039	Thyroid	HT	positive regulation of response to external stimulus	55/1272	427/18723	3.50e-06	1.16e-04	55
GO:00313497	Thyroid	HT	positive regulation of defense response	40/1272	278/18723	5.40e-06	1.66e-04	40
GO:000150320	Thyroid	HT	ossification	51/1272	408/18723	1.81e-05	4.29e-04	51
GO:004217726	Thyroid	HT	negative regulation of protein catabolic process	22/1272	121/18723	1.97e-05	4.60e-04	22
GO:00022536	Thyroid	HT	activation of immune response	47/1272	375/18723	3.55e-05	7.40e-04	47
GO:000164920	Thyroid	HT	osteoblast differentiation	32/1272	229/18723	8.06e-05	1.40e-03	32
GO:190336326	Thyroid	HT	negative regulation of cellular protein catabolic process	15/1272	75/18723	1.33e-04	2.10e-03	15

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0421810	Cervix	CC	Cellular senescence	49/1267	156/8465	1.30e-07	1.63e-06	9.61e-07	49
hsa0516620	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0517016	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa051657	Cervix	CC	Human papillomavirus infection	74/1267	331/8465	1.70e-04	1.02e-03	6.03e-04	74
hsa041106	Cervix	CC	Cell cycle	36/1267	157/8465	4.94e-03	1.67e-02	9.86e-03	36
hsa0421815	Cervix	CC	Cellular senescence	49/1267	156/8465	1.30e-07	1.63e-06	9.61e-07	49
hsa05166110	Cervix	CC	Human T-cell leukemia virus 1 infection	61/1267	222/8465	8.13e-07	7.98e-06	4.72e-06	61
hsa0517017	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa0516512	Cervix	CC	Human papillomavirus infection	74/1267	331/8465	1.70e-04	1.02e-03	6.03e-04	74
hsa0411013	Cervix	CC	Cell cycle	36/1267	157/8465	4.94e-03	1.67e-02	9.86e-03	36
hsa05170	Colorectum	AD	Human immunodeficiency virus 1 infection	72/2092	212/8465	1.40e-03	8.46e-03	5.39e-03	72
hsa05166	Colorectum	AD	Human T-cell leukemia virus 1 infection	72/2092	222/8465	5.24e-03	2.44e-02	1.55e-02	72
hsa051701	Colorectum	AD	Human immunodeficiency virus 1 infection	72/2092	212/8465	1.40e-03	8.46e-03	5.39e-03	72
hsa051661	Colorectum	AD	Human T-cell leukemia virus 1 infection	72/2092	222/8465	5.24e-03	2.44e-02	1.55e-02	72
hsa051702	Colorectum	SER	Human immunodeficiency virus 1 infection	58/1580	212/8465	1.08e-03	8.56e-03	6.21e-03	58
hsa051703	Colorectum	SER	Human immunodeficiency virus 1 infection	58/1580	212/8465	1.08e-03	8.56e-03	6.21e-03	58
hsa051704	Colorectum	MSS	Human immunodeficiency virus 1 infection	69/1875	212/8465	2.66e-04	1.98e-03	1.21e-03	69
hsa042182	Colorectum	MSS	Cellular senescence	52/1875	156/8465	7.87e-04	5.07e-03	3.11e-03	52
hsa051662	Colorectum	MSS	Human T-cell leukemia virus 1 infection	68/1875	222/8465	1.84e-03	9.61e-03	5.89e-03	68
hsa051705	Colorectum	MSS	Human immunodeficiency virus 1 infection	69/1875	212/8465	2.66e-04	1.98e-03	1.21e-03	69

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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

ATR

SNV

Missense_Mutation

novel

c.6307G>A

p.Glu2103Lys

p.E2103K

Q13535

protein_coding

deleterious(0.01)

benign(0.075)

TCGA-5L-AAT0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ATR

SNV

Missense_Mutation

novel

c.5518G>C

p.Glu1840Gln

p.E1840Q

Q13535

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-5L-AAT0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

ATR

SNV

Missense_Mutation

rs762196224

c.7724N>T

p.Ala2575Val

p.A2575V

Q13535

protein_coding

tolerated(0.07)

benign(0.304)

TCGA-A2-A04W-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

ATR

SNV

Missense_Mutation

c.6400G>T

p.Ala2134Ser

p.A2134S

Q13535

protein_coding

tolerated(0.12)

benign(0.021)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATR

SNV

Missense_Mutation

c.2246N>G

p.Ser749Cys

p.S749C

Q13535

protein_coding

tolerated(0.11)

benign(0.001)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATR

SNV

Missense_Mutation

rs746049210

c.7219N>T

p.Arg2407Cys

p.R2407C

Q13535

protein_coding

deleterious(0)

probably_damaging(0.943)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATR

SNV

Missense_Mutation

rs780802796

c.3548N>A

p.Arg1183Gln

p.R1183Q

Q13535

protein_coding

tolerated(0.11)

possibly_damaging(0.688)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATR

SNV

Missense_Mutation

rs369309229

c.6196N>T

p.Arg2066Trp

p.R2066W

Q13535

protein_coding

tolerated(0.08)

probably_damaging(0.939)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ATR

SNV

Missense_Mutation

c.226N>C

p.Met76Leu

p.M76L

Q13535

protein_coding

tolerated_low_confidence(0.05)

benign(0.01)

TCGA-C8-A1HJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATR

SNV

Missense_Mutation

novel

c.4627N>C

p.Glu1543Gln

p.E1543Q

Q13535

protein_coding

tolerated(0.11)

possibly_damaging(0.743)

TCGA-C8-A8HP-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

5-fluorouracil

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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
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE		M4344
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE		E7449	2X-121
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE	inhibitor	384403635
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE	inhibitor	CHEMBL3545178	CERALASERTIB
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE	inhibitor	328083492	CERALASERTIB
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE	inhibitor	249565722
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE		CISPLATIN	CISPLATIN	12894503
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE	inhibitor	249565633	DACTOLISIB
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE		BMN673
545	ATR	SERINE THREONINE KINASE, DNA REPAIR, CLINICALLY ACTIONABLE, ENZYME, KINASE, DRUGGABLE GENOME, PHOSPHATIDYLINOSITOL 3 KINASE	inhibitor	252166686

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