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: PHLPP1

Gene summary for PHLPP1

Gene summary.

Gene information	Species	Human
	Gene symbol	PHLPP1
	Gene ID	23239
	Gene name	PH domain and leucine rich repeat protein phosphatase 1
	Gene Alias	PHLPP
	Cytomap	18q21.33
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	O60346

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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
23239	PHLPP1	CCI_1	Human	Cervix	CC	6.83e-18	9.88e-01	0.528
23239	PHLPP1	CCI_2	Human	Cervix	CC	4.87e-12	1.38e+00	0.5249
23239	PHLPP1	CCI_3	Human	Cervix	CC	2.54e-25	1.01e+00	0.516
23239	PHLPP1	HTA11_3410_2000001011	Human	Colorectum	AD	1.27e-24	-6.06e-01	0.0155
23239	PHLPP1	HTA11_2487_2000001011	Human	Colorectum	SER	1.79e-02	-4.40e-01	-0.1808
23239	PHLPP1	HTA11_2951_2000001011	Human	Colorectum	AD	2.14e-03	-6.92e-01	0.0216
23239	PHLPP1	HTA11_3361_2000001011	Human	Colorectum	AD	4.70e-04	-4.59e-01	-0.1207
23239	PHLPP1	HTA11_696_2000001011	Human	Colorectum	AD	3.82e-05	-3.33e-01	-0.1464
23239	PHLPP1	HTA11_5212_2000001011	Human	Colorectum	AD	6.89e-05	-5.39e-01	-0.2061
23239	PHLPP1	HTA11_866_3004761011	Human	Colorectum	AD	6.77e-05	-4.71e-01	0.096
23239	PHLPP1	HTA11_8622_2000001021	Human	Colorectum	SER	1.48e-03	-6.14e-01	0.0528
23239	PHLPP1	HTA11_7696_3000711011	Human	Colorectum	AD	1.27e-06	-4.11e-01	0.0674
23239	PHLPP1	HTA11_6818_2000001021	Human	Colorectum	AD	2.56e-02	-4.50e-01	0.0588
23239	PHLPP1	HTA11_99999970781_79442	Human	Colorectum	MSS	4.78e-05	-3.61e-01	0.294
23239	PHLPP1	HTA11_99999965104_69814	Human	Colorectum	MSS	7.45e-05	-3.20e-01	0.281
23239	PHLPP1	HTA11_99999971662_82457	Human	Colorectum	MSS	3.53e-22	-6.25e-01	0.3859
23239	PHLPP1	HTA11_99999973899_84307	Human	Colorectum	MSS	5.44e-13	-8.94e-01	0.2585
23239	PHLPP1	HTA11_99999974143_84620	Human	Colorectum	MSS	6.78e-35	-7.78e-01	0.3005
23239	PHLPP1	F007	Human	Colorectum	FAP	6.76e-03	-2.75e-01	0.1176
23239	PHLPP1	A001-C-207	Human	Colorectum	FAP	4.57e-05	-3.03e-01	0.1278

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
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
Prostate		BPH: Benign Prostatic Hyperplasia
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ

∗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:00310988	Cervix	CC	stress-activated protein kinase signaling cascade	58/2311	247/18723	8.02e-07	2.89e-05	58
GO:00485118	Cervix	CC	rhythmic process	65/2311	298/18723	2.79e-06	8.04e-05	65
GO:00514038	Cervix	CC	stress-activated MAPK cascade	55/2311	239/18723	2.96e-06	8.31e-05	55
GO:00703027	Cervix	CC	regulation of stress-activated protein kinase signaling cascade	46/2311	195/18723	9.35e-06	2.11e-04	46
GO:00064708	Cervix	CC	protein dephosphorylation	60/2311	281/18723	1.33e-05	2.68e-04	60
GO:00328727	Cervix	CC	regulation of stress-activated MAPK cascade	44/2311	192/18723	3.09e-05	5.10e-04	44
GO:00076238	Cervix	CC	circadian rhythm	46/2311	210/18723	6.76e-05	9.60e-04	46
GO:00380664	Cervix	CC	p38MAPK cascade	17/2311	55/18723	2.25e-04	2.54e-03	17
GO:00518964	Cervix	CC	regulation of protein kinase B signaling	39/2311	185/18723	5.25e-04	5.10e-03	39
GO:00434913	Cervix	CC	protein kinase B signaling	43/2311	211/18723	5.95e-04	5.60e-03	43
GO:00072545	Cervix	CC	JNK cascade	35/2311	167/18723	1.10e-03	9.09e-03	35
GO:19007442	Cervix	CC	regulation of p38MAPK cascade	14/2311	47/18723	1.18e-03	9.56e-03	14
GO:00163117	Cervix	CC	dephosphorylation	73/2311	417/18723	1.23e-03	9.87e-03	73
GO:00463285	Cervix	CC	regulation of JNK cascade	28/2311	133/18723	3.06e-03	2.01e-02	28
GO:0002507	Cervix	CC	tolerance induction	9/2311	28/18723	5.02e-03	2.98e-02	9
GO:0007623	Colorectum	AD	circadian rhythm	72/3918	210/18723	4.50e-06	1.21e-04	72
GO:0048511	Colorectum	AD	rhythmic process	94/3918	298/18723	1.00e-05	2.34e-04	94
GO:0016311	Colorectum	AD	dephosphorylation	123/3918	417/18723	1.84e-05	3.82e-04	123
GO:0006470	Colorectum	AD	protein dephosphorylation	88/3918	281/18723	2.56e-05	4.89e-04	88
GO:0051403	Colorectum	AD	stress-activated MAPK cascade	72/3918	239/18723	4.77e-04	5.25e-03	72

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04151	Colorectum	FAP	PI3K-Akt signaling pathway	75/1404	354/8465	1.23e-02	4.19e-02	2.55e-02	75
hsa041511	Colorectum	FAP	PI3K-Akt signaling pathway	75/1404	354/8465	1.23e-02	4.19e-02	2.55e-02	75
hsa041512	Colorectum	CRC	PI3K-Akt signaling pathway	64/1091	354/8465	2.70e-03	1.77e-02	1.20e-02	64
hsa041513	Colorectum	CRC	PI3K-Akt signaling pathway	64/1091	354/8465	2.70e-03	1.77e-02	1.20e-02	64
hsa041514	Lung	IAC	PI3K-Akt signaling pathway	60/1053	354/8465	7.03e-03	2.86e-02	1.90e-02	60
hsa0415111	Lung	IAC	PI3K-Akt signaling pathway	60/1053	354/8465	7.03e-03	2.86e-02	1.90e-02	60
hsa0415121	Lung	AIS	PI3K-Akt signaling pathway	57/961	354/8465	3.72e-03	2.00e-02	1.28e-02	57
hsa0415131	Lung	AIS	PI3K-Akt signaling pathway	57/961	354/8465	3.72e-03	2.00e-02	1.28e-02	57
hsa041515	Prostate	BPH	PI3K-Akt signaling pathway	104/1718	354/8465	2.07e-05	1.55e-04	9.61e-05	104
hsa0415112	Prostate	BPH	PI3K-Akt signaling pathway	104/1718	354/8465	2.07e-05	1.55e-04	9.61e-05	104
hsa0415122	Prostate	Tumor	PI3K-Akt signaling pathway	105/1791	354/8465	7.42e-05	5.30e-04	3.28e-04	105
hsa0415132	Prostate	Tumor	PI3K-Akt signaling pathway	105/1791	354/8465	7.42e-05	5.30e-04	3.28e-04	105

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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

PHLPP1

SNV

Missense_Mutation

rs775009348

c.3298N>A

p.Glu1100Lys

p.E1100K

O60346

protein_coding

deleterious(0.03)

probably_damaging(0.986)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PHLPP1

SNV

Missense_Mutation

c.3817N>A

p.Asp1273Asn

p.D1273N

O60346

protein_coding

deleterious(0.01)

probably_damaging(0.999)

TCGA-BH-A0EE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

docetaxel

PHLPP1

SNV

Missense_Mutation

c.3976N>G

p.Ile1326Val

p.I1326V

O60346

protein_coding

tolerated(0.17)

benign(0.114)

TCGA-D8-A147-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

PHLPP1

SNV

Missense_Mutation

c.4765N>A

p.Glu1589Lys

p.E1589K

O60346

protein_coding

tolerated(0.2)

benign(0.366)

TCGA-D8-A1JJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

PHLPP1

SNV

Missense_Mutation

c.1569C>G

p.Phe523Leu

p.F523L

O60346

protein_coding

deleterious(0.02)

benign(0.01)

TCGA-D8-A27G-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PHLPP1

SNV

Missense_Mutation

c.2242T>G

p.Phe748Val

p.F748V

O60346

protein_coding

tolerated(0.28)

benign(0.119)

TCGA-E9-A1R7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

fareston

PHLPP1

deletion

Frame_Shift_Del

novel

c.2924delN

p.Glu976SerfsTer7

p.E976Sfs*7

O60346

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PHLPP1

deletion

Frame_Shift_Del

novel

c.3562delN

p.Leu1188CysfsTer8

p.L1188Cfs*8

O60346

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PHLPP1

deletion

Frame_Shift_Del

novel

c.1455delN

p.Glu486ArgfsTer69

p.E486Rfs*69

O60346

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

PHLPP1

SNV

Missense_Mutation

c.3902N>T

p.Pro1301Leu

p.P1301L

O60346

protein_coding

deleterious(0.01)

probably_damaging(0.931)

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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