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: PNKD

Gene summary for PNKD

Gene summary.

Gene information	Species	Human
	Gene symbol	PNKD
	Gene ID	25953
	Gene name	PNKD metallo-beta-lactamase domain containing
	Gene Alias	BRP17
	Cytomap	2q35
	Gene Type	protein-coding
	GO ID	GO:0001505
	UniProtAcc	Q8N490

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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
25953	PNKD	P23T-E	Human	Esophagus	ESCC	2.21e-37	8.29e-01	0.108
25953	PNKD	P24T-E	Human	Esophagus	ESCC	1.37e-29	7.10e-01	0.1287
25953	PNKD	P26T-E	Human	Esophagus	ESCC	7.26e-26	5.20e-01	0.1276
25953	PNKD	P27T-E	Human	Esophagus	ESCC	5.31e-53	1.02e+00	0.1055
25953	PNKD	P28T-E	Human	Esophagus	ESCC	1.74e-44	9.32e-01	0.1149
25953	PNKD	P30T-E	Human	Esophagus	ESCC	4.19e-49	1.74e+00	0.137
25953	PNKD	P31T-E	Human	Esophagus	ESCC	2.55e-59	1.19e+00	0.1251
25953	PNKD	P32T-E	Human	Esophagus	ESCC	2.13e-61	1.37e+00	0.1666
25953	PNKD	P36T-E	Human	Esophagus	ESCC	1.52e-13	5.97e-01	0.1187
25953	PNKD	P37T-E	Human	Esophagus	ESCC	5.90e-34	7.06e-01	0.1371
25953	PNKD	P38T-E	Human	Esophagus	ESCC	5.11e-07	8.03e-02	0.127
25953	PNKD	P39T-E	Human	Esophagus	ESCC	2.00e-22	1.28e-01	0.0894
25953	PNKD	P40T-E	Human	Esophagus	ESCC	2.74e-19	5.95e-01	0.109
25953	PNKD	P42T-E	Human	Esophagus	ESCC	6.66e-29	5.62e-01	0.1175
25953	PNKD	P44T-E	Human	Esophagus	ESCC	4.76e-13	4.82e-01	0.1096
25953	PNKD	P47T-E	Human	Esophagus	ESCC	5.46e-20	3.67e-01	0.1067
25953	PNKD	P48T-E	Human	Esophagus	ESCC	6.27e-28	5.87e-01	0.0959
25953	PNKD	P49T-E	Human	Esophagus	ESCC	9.05e-14	1.74e+00	0.1768
25953	PNKD	P52T-E	Human	Esophagus	ESCC	1.00e-54	1.07e+00	0.1555
25953	PNKD	P54T-E	Human	Esophagus	ESCC	5.37e-35	8.11e-01	0.0975

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
Skin		AK: Actinic keratosis
		cSCC: Cutaneous squamous cell carcinoma
		SCCIS:squamous cell carcinoma in situ
Thyroid		ATC: Anaplastic thyroid cancer
		HT: Hashimoto's thyroiditis
		PTC: Papillary thyroid 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:0044282	Colorectum	AD	small molecule catabolic process	118/3918	376/18723	1.05e-06	3.55e-05	118
GO:0006081	Colorectum	AD	cellular aldehyde metabolic process	22/3918	60/18723	3.64e-03	2.60e-02	22
GO:00442821	Colorectum	SER	small molecule catabolic process	87/2897	376/18723	5.31e-05	1.27e-03	87
GO:0051051	Colorectum	SER	negative regulation of transport	98/2897	470/18723	1.01e-03	1.19e-02	98
GO:1903531	Colorectum	SER	negative regulation of secretion by cell	35/2897	147/18723	5.21e-03	3.95e-02	35
GO:0051048	Colorectum	SER	negative regulation of secretion	39/2897	171/18723	7.17e-03	4.99e-02	39
GO:00442822	Colorectum	MSS	small molecule catabolic process	94/3467	376/18723	9.85e-04	9.86e-03	94
GO:00060811	Colorectum	MSS	cellular aldehyde metabolic process	21/3467	60/18723	1.81e-03	1.60e-02	21
GO:00510511	Colorectum	MSS	negative regulation of transport	110/3467	470/18723	4.20e-03	3.04e-02	110
GO:0023061	Colorectum	FAP	signal release	94/2622	463/18723	1.06e-04	1.76e-03	94
GO:00442823	Colorectum	FAP	small molecule catabolic process	77/2622	376/18723	3.25e-04	4.16e-03	77
GO:00510512	Colorectum	FAP	negative regulation of transport	91/2622	470/18723	7.09e-04	7.64e-03	91
GO:00421805	Esophagus	ESCC	cellular ketone metabolic process	120/8552	211/18723	6.70e-04	3.55e-03	120
GO:00060818	Esophagus	ESCC	cellular aldehyde metabolic process	40/8552	60/18723	8.30e-04	4.28e-03	40
GO:00442827	Esophagus	ESCC	small molecule catabolic process	201/8552	376/18723	1.35e-03	6.41e-03	201
GO:004428211	Liver	Cirrhotic	small molecule catabolic process	151/4634	376/18723	2.20e-11	1.34e-09	151
GO:004218011	Liver	Cirrhotic	cellular ketone metabolic process	80/4634	211/18723	1.40e-05	1.95e-04	80
GO:00060815	Liver	Cirrhotic	cellular aldehyde metabolic process	28/4634	60/18723	1.83e-04	1.71e-03	28
GO:0044106	Liver	Cirrhotic	cellular amine metabolic process	43/4634	113/18723	1.15e-03	7.83e-03	43
GO:0046185	Liver	Cirrhotic	aldehyde catabolic process	8/4634	12/18723	2.59e-03	1.53e-02	8

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

PNKD

SNV

Missense_Mutation

novel

c.1070N>C

p.Gly357Ala

p.G357A

Q8N490

protein_coding

tolerated(0.61)

benign(0.003)

TCGA-A2-A3Y0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

PNKD

SNV

Missense_Mutation

novel

c.449N>T

p.Asp150Val

p.D150V

Q8N490

protein_coding

tolerated(0.09)

probably_damaging(0.99)

TCGA-AQ-A7U7-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Targeted Molecular therapy

rituximab

PNKD

insertion

Frame_Shift_Ins

novel

c.116_117insTCCT

p.Ala40ProfsTer16

p.A40Pfs*16

Q8N490

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

PNKD

insertion

Frame_Shift_Ins

novel

c.117_118insCCTCAACCTCCCGAGGAGCTGGGACTACAGGC

p.Ala40ProfsTer44

p.A40Pfs*44

Q8N490

protein_coding

TCGA-A8-A07J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

PNKD

insertion

In_Frame_Ins

novel

c.815_816insTGGCCCCCTTCA

p.Leu272_Ser273insGlyProLeuGln

p.L272_S273insGPLQ

Q8N490

protein_coding

TCGA-BH-A0BR-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PNKD

SNV

Missense_Mutation

novel

c.341G>C

p.Arg114Pro

p.R114P

Q8N490

protein_coding

tolerated(0.2)

benign(0.371)

TCGA-C5-A902-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PNKD

SNV

Missense_Mutation

rs148141539

c.1130N>A

p.Arg377Gln

p.R377Q

Q8N490

protein_coding

tolerated(0.24)

benign(0)

TCGA-IR-A3LK-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

cisplatin

PNKD

SNV

Missense_Mutation

c.505N>A

p.Leu169Met

p.L169M

Q8N490

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AZ-4315-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

PNKD

SNV

Missense_Mutation

novel

c.899N>G

p.Phe300Cys

p.F300C

Q8N490

protein_coding

deleterious(0)

probably_damaging(0.991)

TCGA-AJ-A3EK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

PNKD

SNV

Missense_Mutation

c.505N>A

p.Leu169Met

p.L169M

Q8N490

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AP-A056-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

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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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