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: PHLDB2

Gene summary for PHLDB2

Gene summary.

Gene information	Species	Human
	Gene symbol	PHLDB2
	Gene ID	90102
	Gene name	pleckstrin homology like domain family B member 2
	Gene Alias	LL5b
	Cytomap	3q13.2
	Gene Type	protein-coding
	GO ID	GO:0000226
	UniProtAcc	Q86SQ0

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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
90102	PHLDB2	CCI_1	Human	Cervix	CC	1.53e-03	9.03e-01	0.528
90102	PHLDB2	CCI_3	Human	Cervix	CC	7.19e-05	6.17e-01	0.516
90102	PHLDB2	CCII_1	Human	Cervix	CC	7.87e-06	3.42e-01	0.3249
90102	PHLDB2	sample1	Human	Cervix	CC	3.20e-22	8.14e-01	0.0959
90102	PHLDB2	T1	Human	Cervix	CC	6.64e-45	9.32e-01	0.0918
90102	PHLDB2	LZE4T	Human	Esophagus	ESCC	1.39e-33	1.16e+00	0.0811
90102	PHLDB2	LZE7T	Human	Esophagus	ESCC	6.41e-08	1.60e+00	0.0667
90102	PHLDB2	LZE8T	Human	Esophagus	ESCC	3.86e-08	3.59e-01	0.067
90102	PHLDB2	LZE20T	Human	Esophagus	ESCC	4.68e-02	1.11e-01	0.0662
90102	PHLDB2	LZE21T	Human	Esophagus	ESCC	5.44e-07	3.37e-01	0.0655
90102	PHLDB2	P2T-E	Human	Esophagus	ESCC	5.40e-04	-1.07e-01	0.1177
90102	PHLDB2	P4T-E	Human	Esophagus	ESCC	1.44e-16	7.51e-01	0.1323
90102	PHLDB2	P5T-E	Human	Esophagus	ESCC	1.71e-14	5.23e-01	0.1327
90102	PHLDB2	P9T-E	Human	Esophagus	ESCC	2.88e-34	1.29e+00	0.1131
90102	PHLDB2	P10T-E	Human	Esophagus	ESCC	3.36e-07	2.54e-01	0.116
90102	PHLDB2	P11T-E	Human	Esophagus	ESCC	1.31e-24	1.24e+00	0.1426
90102	PHLDB2	P12T-E	Human	Esophagus	ESCC	3.70e-04	2.27e-01	0.1122
90102	PHLDB2	P15T-E	Human	Esophagus	ESCC	2.04e-23	6.81e-01	0.1149
90102	PHLDB2	P16T-E	Human	Esophagus	ESCC	3.44e-09	5.54e-02	0.1153
90102	PHLDB2	P17T-E	Human	Esophagus	ESCC	2.22e-06	4.54e-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
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
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:00717114	Oral cavity	OSCC	basement membrane organization	20/7305	31/18723	3.57e-03	1.49e-02	20
GO:003432916	Oral cavity	OSCC	cell junction assembly	190/7305	420/18723	4.99e-03	1.96e-02	190
GO:19030531	Oral cavity	OSCC	regulation of extracellular matrix organization	28/7305	48/18723	5.17e-03	2.02e-02	28
GO:005149220	Oral cavity	OSCC	regulation of stress fiber assembly	48/7305	91/18723	5.32e-03	2.07e-02	48
GO:190290417	Oral cavity	OSCC	negative regulation of supramolecular fiber organization	81/7305	167/18723	7.70e-03	2.82e-02	81
GO:003103217	Oral cavity	OSCC	actomyosin structure organization	93/7305	196/18723	9.63e-03	3.41e-02	93
GO:011002020	Oral cavity	OSCC	regulation of actomyosin structure organization	51/7305	100/18723	9.74e-03	3.45e-02	51
GO:19012032	Oral cavity	OSCC	positive regulation of extracellular matrix assembly	8/7305	10/18723	1.03e-02	3.53e-02	8
GO:00487627	Oral cavity	OSCC	mesenchymal cell differentiation	109/7305	236/18723	1.43e-02	4.69e-02	109
GO:001063919	Oral cavity	LP	negative regulation of organelle organization	127/4623	348/18723	5.07e-07	1.40e-05	127
GO:1902903110	Oral cavity	LP	regulation of supramolecular fiber organization	131/4623	383/18723	1.58e-05	2.78e-04	131
GO:0032970110	Oral cavity	LP	regulation of actin filament-based process	133/4623	397/18723	4.21e-05	6.09e-04	133
GO:0042060110	Oral cavity	LP	wound healing	139/4623	422/18723	7.10e-05	9.48e-04	139
GO:0032956110	Oral cavity	LP	regulation of actin cytoskeleton organization	120/4623	358/18723	9.47e-05	1.18e-03	120
GO:0007015110	Oral cavity	LP	actin filament organization	143/4623	442/18723	1.44e-04	1.65e-03	143
GO:0110053110	Oral cavity	LP	regulation of actin filament organization	92/4623	278/18723	9.25e-04	7.85e-03	92
GO:007050715	Oral cavity	LP	regulation of microtubule cytoskeleton organization	53/4623	148/18723	1.60e-03	1.23e-02	53
GO:0010810110	Oral cavity	LP	regulation of cell-substrate adhesion	72/4623	221/18723	4.80e-03	3.03e-02	72
GO:003158918	Oral cavity	LP	cell-substrate adhesion	111/4623	363/18723	5.94e-03	3.53e-02	111
GO:190290418	Oral cavity	LP	negative regulation of supramolecular fiber organization	56/4623	167/18723	6.19e-03	3.66e-02	56

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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

PHLDB2

SNV

Missense_Mutation

novel

c.1172N>T

p.Asp391Val

p.D391V

Q86SQ0

protein_coding

deleterious(0)

benign(0.203)

TCGA-A7-A425-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

adriamycin

PHLDB2

SNV

Missense_Mutation

novel

c.3502N>A

p.Asp1168Asn

p.D1168N

Q86SQ0

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PHLDB2

SNV

Missense_Mutation

c.359N>A

p.Gly120Glu

p.G120E

Q86SQ0

protein_coding

tolerated_low_confidence(0.09)

benign(0.018)

TCGA-AR-A250-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

PHLDB2

SNV

Missense_Mutation

c.1708N>G

p.Ile570Val

p.I570V

Q86SQ0

protein_coding

tolerated(0.1)

benign(0.255)

TCGA-B6-A0WV-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PHLDB2

SNV

Missense_Mutation

c.604C>T

p.Pro202Ser

p.P202S

Q86SQ0

protein_coding

deleterious(0)

possibly_damaging(0.549)

TCGA-BH-A1FU-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PHLDB2

SNV

Missense_Mutation

c.1690N>C

p.Glu564Gln

p.E564Q

Q86SQ0

protein_coding

deleterious(0.05)

benign(0.388)

TCGA-BH-A209-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PHLDB2

SNV

Missense_Mutation

c.1608N>T

p.Arg536Ser

p.R536S

Q86SQ0

protein_coding

tolerated(0.07)

benign(0.057)

TCGA-D8-A1XG-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

PHLDB2

SNV

Missense_Mutation

c.3134N>T

p.Ala1045Val

p.A1045V

Q86SQ0

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-D8-A1XK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine+cyclophosphamide

PHLDB2

SNV

Missense_Mutation

novel

c.7N>A

p.Glu3Lys

p.E3K

Q86SQ0

protein_coding

deleterious_low_confidence(0)

benign(0.214)

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

PHLDB2

SNV

Missense_Mutation

novel

c.3132N>T

p.Gln1044His

p.Q1044H

Q86SQ0

protein_coding

deleterious(0)

possibly_damaging(0.885)

TCGA-LQ-A4E4-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

anastrozole

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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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