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: INPP5D

Gene summary for INPP5D

Gene summary.

Gene information	Species	Human
	Gene symbol	INPP5D
	Gene ID	3635
	Gene name	inositol polyphosphate-5-phosphatase D
	Gene Alias	SHIP
	Cytomap	2q37.1
	Gene Type	protein-coding
	GO ID	GO:0001775
	UniProtAcc	Q92835

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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
3635	INPP5D	HTA11_3410_2000001011	Human	Colorectum	AD	2.77e-23	3.86e-01	0.0155
3635	INPP5D	HTA11_2487_2000001011	Human	Colorectum	SER	1.03e-06	2.53e-01	-0.1808
3635	INPP5D	HTA11_2951_2000001011	Human	Colorectum	AD	4.03e-07	5.92e-01	0.0216
3635	INPP5D	HTA11_1938_2000001011	Human	Colorectum	AD	1.24e-26	6.62e-01	-0.0811
3635	INPP5D	HTA11_78_2000001011	Human	Colorectum	AD	7.84e-13	3.98e-01	-0.1088
3635	INPP5D	HTA11_3361_2000001011	Human	Colorectum	AD	3.75e-08	1.97e-01	-0.1207
3635	INPP5D	HTA11_83_2000001011	Human	Colorectum	SER	4.77e-05	3.69e-01	-0.1526
3635	INPP5D	HTA11_696_2000001011	Human	Colorectum	AD	2.81e-02	1.05e-01	-0.1464
3635	INPP5D	HTA11_866_2000001011	Human	Colorectum	AD	1.70e-12	3.77e-01	-0.1001
3635	INPP5D	HTA11_1391_2000001011	Human	Colorectum	AD	2.72e-21	6.10e-01	-0.059
3635	INPP5D	HTA11_866_3004761011	Human	Colorectum	AD	1.69e-20	4.99e-01	0.096
3635	INPP5D	HTA11_9408_2000001011	Human	Colorectum	AD	6.81e-06	3.67e-01	0.0451
3635	INPP5D	HTA11_10711_2000001011	Human	Colorectum	AD	4.40e-20	5.58e-01	0.0338
3635	INPP5D	HTA11_7696_3000711011	Human	Colorectum	AD	1.08e-27	7.17e-01	0.0674
3635	INPP5D	HTA11_6818_2000001011	Human	Colorectum	AD	5.93e-06	3.72e-01	0.0112
3635	INPP5D	HTA11_6818_2000001021	Human	Colorectum	AD	5.74e-17	3.70e-01	0.0588
3635	INPP5D	HTA11_99999970781_79442	Human	Colorectum	MSS	6.68e-24	4.92e-01	0.294
3635	INPP5D	HTA11_99999965062_69753	Human	Colorectum	MSI-H	8.64e-08	1.10e+00	0.3487
3635	INPP5D	HTA11_99999965104_69814	Human	Colorectum	MSS	2.78e-12	3.99e-01	0.281
3635	INPP5D	HTA11_99999971662_82457	Human	Colorectum	MSS	8.98e-27	7.16e-01	0.3859

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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:00302583	Colorectum	FAP	lipid modification	52/2622	212/18723	2.84e-05	6.49e-04	52
GO:00302184	Colorectum	FAP	erythrocyte differentiation	34/2622	120/18723	3.13e-05	7.11e-04	34
GO:00300994	Colorectum	FAP	myeloid cell differentiation	81/2622	381/18723	6.33e-05	1.22e-03	81
GO:00018944	Colorectum	FAP	tissue homeostasis	61/2622	268/18723	6.71e-05	1.28e-03	61
GO:00602494	Colorectum	FAP	anatomical structure homeostasis	69/2622	314/18723	7.51e-05	1.37e-03	69
GO:00488724	Colorectum	FAP	homeostasis of number of cells	60/2622	272/18723	1.91e-04	2.79e-03	60
GO:00022624	Colorectum	FAP	myeloid cell homeostasis	39/2622	157/18723	2.03e-04	2.92e-03	39
GO:00075682	Colorectum	FAP	aging	69/2622	339/18723	7.66e-04	8.12e-03	69
GO:0008654	Colorectum	FAP	phospholipid biosynthetic process	54/2622	253/18723	8.88e-04	9.08e-03	54
GO:00066502	Colorectum	FAP	glycerophospholipid metabolic process	62/2622	306/18723	1.54e-03	1.38e-02	62
GO:00066442	Colorectum	FAP	phospholipid metabolic process	74/2622	383/18723	2.24e-03	1.83e-02	74
GO:00456463	Colorectum	FAP	regulation of erythrocyte differentiation	14/2622	47/18723	3.95e-03	2.75e-02	14
GO:0046474	Colorectum	FAP	glycerophospholipid biosynthetic process	44/2622	211/18723	3.98e-03	2.76e-02	44
GO:1903131	Colorectum	FAP	mononuclear cell differentiation	79/2622	426/18723	5.00e-03	3.33e-02	79
GO:19037063	Colorectum	FAP	regulation of hemopoiesis	69/2622	367/18723	6.01e-03	3.78e-02	69
GO:00450172	Colorectum	FAP	glycerolipid biosynthetic process	50/2622	252/18723	6.32e-03	3.95e-02	50
GO:00302244	Colorectum	FAP	monocyte differentiation	11/2622	36/18723	8.23e-03	4.82e-02	11
GO:00163114	Colorectum	CRC	dephosphorylation	79/2078	417/18723	1.27e-06	7.21e-05	79
GO:00341015	Colorectum	CRC	erythrocyte homeostasis	30/2078	129/18723	6.14e-05	1.35e-03	30
GO:00086541	Colorectum	CRC	phospholipid biosynthetic process	49/2078	253/18723	7.07e-05	1.51e-03	49

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa04666	Colorectum	AD	Fc gamma R-mediated phagocytosis	46/2092	97/8465	9.10e-07	1.22e-05	7.77e-06	46
hsa046661	Colorectum	AD	Fc gamma R-mediated phagocytosis	46/2092	97/8465	9.10e-07	1.22e-05	7.77e-06	46
hsa046662	Colorectum	SER	Fc gamma R-mediated phagocytosis	39/1580	97/8465	5.84e-07	9.70e-06	7.04e-06	39
hsa046663	Colorectum	SER	Fc gamma R-mediated phagocytosis	39/1580	97/8465	5.84e-07	9.70e-06	7.04e-06	39
hsa046664	Colorectum	MSS	Fc gamma R-mediated phagocytosis	45/1875	97/8465	9.30e-08	1.56e-06	9.55e-07	45
hsa046665	Colorectum	MSS	Fc gamma R-mediated phagocytosis	45/1875	97/8465	9.30e-08	1.56e-06	9.55e-07	45
hsa046666	Colorectum	FAP	Fc gamma R-mediated phagocytosis	35/1404	97/8465	2.46e-06	4.28e-05	2.60e-05	35
hsa046667	Colorectum	FAP	Fc gamma R-mediated phagocytosis	35/1404	97/8465	2.46e-06	4.28e-05	2.60e-05	35
hsa046668	Colorectum	CRC	Fc gamma R-mediated phagocytosis	27/1091	97/8465	6.24e-05	1.12e-03	7.57e-04	27
hsa046669	Colorectum	CRC	Fc gamma R-mediated phagocytosis	27/1091	97/8465	6.24e-05	1.12e-03	7.57e-04	27

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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

INPP5D

SNV

Missense_Mutation

novel

c.345N>A

p.Asp115Glu

p.D115E

Q92835

protein_coding

tolerated(0.58)

benign(0.001)

TCGA-AO-A03V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

fluorouracil

INPP5D

SNV

Missense_Mutation

rs758989076

c.3170N>T

p.Ser1057Leu

p.S1057L

Q92835

protein_coding

deleterious_low_confidence(0.05)

benign(0.003)

TCGA-AQ-A7U7-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Targeted Molecular therapy

rituximab

INPP5D

SNV

Missense_Mutation

c.1606N>A

p.Gly536Arg

p.G536R

Q92835

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-B6-A0RS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

INPP5D

SNV

Missense_Mutation

c.2344N>A

p.Glu782Lys

p.E782K

Q92835

protein_coding

tolerated(0.79)

benign(0.109)

TCGA-BH-A18F-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

INPP5D

SNV

Missense_Mutation

rs781285468

c.1934N>A

p.Arg645His

p.R645H

Q92835

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-D8-A1JK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

INPP5D

SNV

Missense_Mutation

novel

c.1730A>G

p.His577Arg

p.H577R

Q92835

protein_coding

tolerated(0.84)

benign(0.286)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

INPP5D

SNV

Missense_Mutation

c.1982C>T

p.Ala661Val

p.A661V

Q92835

protein_coding

deleterious(0.01)

probably_damaging(0.989)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

INPP5D

SNV

Missense_Mutation

rs769891270

c.3130C>T

p.Arg1044Trp

p.R1044W

Q92835

protein_coding

deleterious(0)

possibly_damaging(0.865)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

INPP5D

SNV

Missense_Mutation

c.3233N>C

p.Val1078Ala

p.V1078A

Q92835

protein_coding

tolerated_low_confidence(0.45)

benign(0)

TCGA-C5-A7UH-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Chemotherapy

cisplatin

INPP5D

SNV

Missense_Mutation

rs201032928

c.3131G>A

p.Arg1044Gln

p.R1044Q

Q92835

protein_coding

deleterious(0.03)

benign(0.267)

TCGA-C5-A7X3-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

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
3635	INPP5D	DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE	activator	315661324	ROSIPTOR
3635	INPP5D	DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		TURNAGAINOLIDE B	TURNAGAINOLIDE B	21539394
3635	INPP5D	DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE	inhibitor	336446950
3635	INPP5D	DRUGGABLE GENOME, KINASE, ENZYME, CLINICALLY ACTIONABLE		AQX-1125	ROSIPTOR

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