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: PLD1

Gene summary for PLD1

Gene summary.

Gene information	Species	Human
	Gene symbol	PLD1
	Gene ID	5337
	Gene name	phospholipase D1
	Gene Alias	CVDD
	Cytomap	3q26.31
	Gene Type	protein-coding
	GO ID	GO:0006412
	UniProtAcc	Q59EA4

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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
5337	PLD1	CA_HPV_2	Human	Cervix	CC	3.15e-03	2.45e-01	0.0391
5337	PLD1	CCI_1	Human	Cervix	CC	3.26e-11	1.37e+00	0.528
5337	PLD1	CCI_2	Human	Cervix	CC	1.19e-19	2.29e+00	0.5249
5337	PLD1	CCI_3	Human	Cervix	CC	4.64e-21	1.15e+00	0.516
5337	PLD1	HTA11_3410_2000001011	Human	Colorectum	AD	9.11e-15	-5.69e-01	0.0155
5337	PLD1	HTA11_347_2000001011	Human	Colorectum	AD	9.40e-15	6.97e-01	-0.1954
5337	PLD1	HTA11_866_3004761011	Human	Colorectum	AD	2.62e-10	-6.05e-01	0.096
5337	PLD1	HTA11_8622_2000001021	Human	Colorectum	SER	5.92e-05	-7.13e-01	0.0528
5337	PLD1	HTA11_10711_2000001011	Human	Colorectum	AD	2.90e-04	-5.40e-01	0.0338
5337	PLD1	HTA11_7696_3000711011	Human	Colorectum	AD	9.62e-12	-4.38e-01	0.0674
5337	PLD1	HTA11_99999970781_79442	Human	Colorectum	MSS	9.35e-42	-8.30e-01	0.294
5337	PLD1	HTA11_99999965104_69814	Human	Colorectum	MSS	1.84e-02	-5.08e-01	0.281
5337	PLD1	HTA11_99999971662_82457	Human	Colorectum	MSS	1.10e-16	-5.14e-01	0.3859
5337	PLD1	HTA11_99999973899_84307	Human	Colorectum	MSS	9.68e-13	-9.21e-01	0.2585
5337	PLD1	HTA11_99999974143_84620	Human	Colorectum	MSS	2.54e-48	-9.17e-01	0.3005
5337	PLD1	A001-C-207	Human	Colorectum	FAP	6.01e-03	-2.47e-01	0.1278
5337	PLD1	A015-C-203	Human	Colorectum	FAP	2.79e-37	-5.91e-01	-0.1294
5337	PLD1	A015-C-204	Human	Colorectum	FAP	2.86e-06	-3.90e-01	-0.0228
5337	PLD1	A014-C-040	Human	Colorectum	FAP	1.85e-05	-4.71e-01	-0.1184
5337	PLD1	A002-C-201	Human	Colorectum	FAP	4.77e-14	-3.21e-01	0.0324

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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
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma

∗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:00072656	Cervix	CC	Ras protein signal transduction	79/2311	337/18723	9.49e-09	7.77e-07	79
GO:003425010	Cervix	CC	positive regulation of cellular amide metabolic process	40/2311	162/18723	1.11e-05	2.41e-04	40
GO:000641710	Cervix	CC	regulation of translation	89/2311	468/18723	1.86e-05	3.46e-04	89
GO:004572710	Cervix	CC	positive regulation of translation	33/2311	136/18723	9.09e-05	1.20e-03	33
GO:01200328	Cervix	CC	regulation of plasma membrane bounded cell projection assembly	38/2311	186/18723	1.14e-03	9.35e-03	38
GO:00604917	Cervix	CC	regulation of cell projection assembly	38/2311	188/18723	1.40e-03	1.10e-02	38
GO:00300337	Cervix	CC	microvillus assembly	7/2311	16/18723	1.79e-03	1.34e-02	7
GO:0006417	Colorectum	AD	regulation of translation	141/3918	468/18723	1.32e-06	4.22e-05	141
GO:0007265	Colorectum	AD	Ras protein signal transduction	104/3918	337/18723	1.01e-05	2.35e-04	104
GO:0032530	Colorectum	AD	regulation of microvillus organization	10/3918	13/18723	2.43e-05	4.69e-04	10
GO:0016042	Colorectum	AD	lipid catabolic process	97/3918	320/18723	4.31e-05	7.56e-04	97
GO:0032528	Colorectum	AD	microvillus organization	14/3918	24/18723	6.90e-05	1.11e-03	14
GO:0034250	Colorectum	AD	positive regulation of cellular amide metabolic process	53/3918	162/18723	2.98e-04	3.60e-03	53
GO:0045727	Colorectum	AD	positive regulation of translation	45/3918	136/18723	6.24e-04	6.48e-03	45
GO:0030033	Colorectum	AD	microvillus assembly	9/3918	16/18723	2.06e-03	1.64e-02	9
GO:0048017	Colorectum	AD	inositol lipid-mediated signaling	53/3918	182/18723	5.35e-03	3.52e-02	53
GO:0006650	Colorectum	AD	glycerophospholipid metabolic process	83/3918	306/18723	5.40e-03	3.55e-02	83
GO:0006644	Colorectum	AD	phospholipid metabolic process	101/3918	383/18723	5.80e-03	3.67e-02	101
GO:0099003	Colorectum	AD	vesicle-mediated transport in synapse	57/3918	200/18723	6.53e-03	4.06e-02	57
GO:0045017	Colorectum	AD	glycerolipid biosynthetic process	69/3918	252/18723	8.33e-03	4.88e-02	69

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0520820	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa0414418	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0466612	Cervix	CC	Fc gamma R-mediated phagocytosis	31/1267	97/8465	1.78e-05	1.42e-04	8.40e-05	31
hsa0407110	Cervix	CC	Sphingolipid signaling pathway	35/1267	121/8465	5.70e-05	3.93e-04	2.32e-04	35
hsa052128	Cervix	CC	Pancreatic cancer	24/1267	76/8465	1.89e-04	1.11e-03	6.55e-04	24
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
hsa040142	Cervix	CC	Ras signaling pathway	51/1267	236/8465	3.55e-03	1.34e-02	7.91e-03	51
hsa05208110	Cervix	CC	Chemical carcinogenesis - reactive oxygen species	92/1267	223/8465	4.71e-22	5.09e-20	3.01e-20	92
hsa0414419	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0466613	Cervix	CC	Fc gamma R-mediated phagocytosis	31/1267	97/8465	1.78e-05	1.42e-04	8.40e-05	31
hsa0407113	Cervix	CC	Sphingolipid signaling pathway	35/1267	121/8465	5.70e-05	3.93e-04	2.32e-04	35
hsa0521213	Cervix	CC	Pancreatic cancer	24/1267	76/8465	1.89e-04	1.11e-03	6.55e-04	24
hsa0491213	Cervix	CC	GnRH signaling pathway	26/1267	93/8465	8.72e-04	3.87e-03	2.29e-03	26
hsa0492813	Cervix	CC	Parathyroid hormone synthesis, secretion and action	27/1267	106/8465	3.12e-03	1.19e-02	7.03e-03	27
hsa0401411	Cervix	CC	Ras signaling pathway	51/1267	236/8465	3.55e-03	1.34e-02	7.91e-03	51
hsa05208	Colorectum	AD	Chemical carcinogenesis - reactive oxygen species	126/2092	223/8465	1.01e-24	1.68e-22	1.07e-22	126
hsa04144	Colorectum	AD	Endocytosis	111/2092	251/8465	5.95e-12	1.42e-10	9.08e-11	111
hsa04666	Colorectum	AD	Fc gamma R-mediated phagocytosis	46/2092	97/8465	9.10e-07	1.22e-05	7.77e-06	46
hsa04912	Colorectum	AD	GnRH signaling pathway	35/2092	93/8465	3.69e-03	1.90e-02	1.21e-02	35

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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

PLD1

SNV

Missense_Mutation

rs774453063

c.1376N>G

p.Tyr459Cys

p.Y459C

Q13393

protein_coding

deleterious(0)

probably_damaging(0.981)

TCGA-A2-A25D-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

PLD1

SNV

Missense_Mutation

c.1448N>T

p.Ala483Val

p.A483V

Q13393

protein_coding

deleterious(0.01)

probably_damaging(0.995)

TCGA-A8-A08P-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

PLD1

SNV

Missense_Mutation

c.1583N>C

p.Lys528Thr

p.K528T

Q13393

protein_coding

tolerated(0.46)

benign(0.013)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PLD1

SNV

Missense_Mutation

c.734G>A

p.Arg245Lys

p.R245K

Q13393

protein_coding

tolerated(0.52)

benign(0.021)

TCGA-AR-A0TX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PLD1

SNV

Missense_Mutation

c.1183G>C

p.Glu395Gln

p.E395Q

Q13393

protein_coding

tolerated(0.05)

possibly_damaging(0.84)

TCGA-C8-A1HK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PLD1

SNV

Missense_Mutation

c.3218N>C

p.Trp1073Ser

p.W1073S

Q13393

protein_coding

deleterious(0)

probably_damaging(0.99)

TCGA-C8-A27B-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

PLD1

SNV

Missense_Mutation

c.247G>A

p.Ala83Thr

p.A83T

Q13393

protein_coding

deleterious(0.04)

benign(0.287)

TCGA-D8-A27N-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

taxol+adriamycin+cyclophosphamide+herceptin

PLD1

SNV

Missense_Mutation

novel

c.179C>A

p.Ala60Asp

p.A60D

Q13393

protein_coding

tolerated(0.06)

benign(0.282)

TCGA-MS-A51U-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

PLD1

deletion

Frame_Shift_Del

novel

c.2769_2770delNN

p.Asp924GlnfsTer2

p.D924Qfs*2

Q13393

protein_coding

TCGA-A2-A3XY-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

PLD1

insertion

Frame_Shift_Ins

novel

c.75_76insCGTCTCACCCCTGCCAATTGCCTGGTGCACGGCTTATATTTGTG

p.Glu26ArgfsTer30

p.E26Rfs*30

Q13393

protein_coding

TCGA-AO-A0J9-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

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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
5337	PLD1	ENZYME, DRUGGABLE GENOME	inhibitor	252827439
5337	PLD1	ENZYME, DRUGGABLE GENOME		US9127005, P0L
5337	PLD1	ENZYME, DRUGGABLE GENOME		US9127005, P2B
5337	PLD1	ENZYME, DRUGGABLE GENOME		TAMOXIFEN	TAMOXIFEN	12237338
5337	PLD1	ENZYME, DRUGGABLE GENOME		ML272
5337	PLD1	ENZYME, DRUGGABLE GENOME		TAMOXIFEN	TAMOXIFEN	19136975
5337	PLD1	ENZYME, DRUGGABLE GENOME		US9453017, 2
5337	PLD1	ENZYME, DRUGGABLE GENOME		AFIMOXIFENE	AFIMOXIFENE	19136975
5337	PLD1	ENZYME, DRUGGABLE GENOME		PHORBOL MYRISTATE ACETATE		9989263
5337	PLD1	ENZYME, DRUGGABLE GENOME		US9127005, P2C

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