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: ANKLE2

Gene summary for ANKLE2

Gene summary.

Gene information	Species	Human
	Gene symbol	ANKLE2
	Gene ID	23141
	Gene name	ankyrin repeat and LEM domain containing 2
	Gene Alias	KIAA0692
	Cytomap	12q24.33
	Gene Type	protein-coding
	GO ID	GO:0000278
	UniProtAcc	Q86XL3

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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
23141	ANKLE2	CCI_1	Human	Cervix	CC	5.86e-05	9.03e-01	0.528
23141	ANKLE2	CCI_3	Human	Cervix	CC	6.47e-05	6.82e-01	0.516
23141	ANKLE2	sample1	Human	Cervix	CC	3.09e-02	4.28e-01	0.0959
23141	ANKLE2	sample3	Human	Cervix	CC	3.54e-09	3.05e-01	0.1387
23141	ANKLE2	T1	Human	Cervix	CC	1.48e-14	6.03e-01	0.0918
23141	ANKLE2	T3	Human	Cervix	CC	8.47e-08	3.16e-01	0.1389
23141	ANKLE2	LZE4T	Human	Esophagus	ESCC	3.06e-04	5.99e-02	0.0811
23141	ANKLE2	LZE5T	Human	Esophagus	ESCC	1.90e-02	1.18e-01	0.0514
23141	ANKLE2	LZE7T	Human	Esophagus	ESCC	6.63e-06	2.53e-01	0.0667
23141	ANKLE2	LZE20T	Human	Esophagus	ESCC	1.26e-05	3.46e-01	0.0662
23141	ANKLE2	LZE24T	Human	Esophagus	ESCC	6.28e-13	5.02e-01	0.0596
23141	ANKLE2	P1T-E	Human	Esophagus	ESCC	3.73e-17	1.14e+00	0.0875
23141	ANKLE2	P2T-E	Human	Esophagus	ESCC	1.39e-72	1.44e+00	0.1177
23141	ANKLE2	P4T-E	Human	Esophagus	ESCC	5.20e-23	7.76e-01	0.1323
23141	ANKLE2	P5T-E	Human	Esophagus	ESCC	5.62e-47	9.28e-01	0.1327
23141	ANKLE2	P8T-E	Human	Esophagus	ESCC	8.98e-27	6.27e-01	0.0889
23141	ANKLE2	P9T-E	Human	Esophagus	ESCC	5.73e-09	2.95e-01	0.1131
23141	ANKLE2	P10T-E	Human	Esophagus	ESCC	1.93e-18	3.79e-01	0.116
23141	ANKLE2	P11T-E	Human	Esophagus	ESCC	4.74e-15	1.12e+00	0.1426
23141	ANKLE2	P12T-E	Human	Esophagus	ESCC	8.35e-24	4.51e-01	0.1122

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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
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:004593610	Cervix	CC	negative regulation of phosphate metabolic process	88/2311	441/18723	2.92e-06	8.27e-05	88
GO:001056310	Cervix	CC	negative regulation of phosphorus metabolic process	88/2311	442/18723	3.21e-06	8.77e-05	88
GO:004232610	Cervix	CC	negative regulation of phosphorylation	77/2311	385/18723	1.09e-05	2.38e-04	77
GO:00064708	Cervix	CC	protein dephosphorylation	60/2311	281/18723	1.33e-05	2.68e-04	60
GO:003530310	Cervix	CC	regulation of dephosphorylation	31/2311	128/18723	1.52e-04	1.83e-03	31
GO:003530410	Cervix	CC	regulation of protein dephosphorylation	24/2311	90/18723	1.73e-04	2.04e-03	24
GO:00163117	Cervix	CC	dephosphorylation	73/2311	417/18723	1.23e-03	9.87e-03	73
GO:01400143	Cervix	CC	mitotic nuclear division	50/2311	287/18723	7.27e-03	3.91e-02	50
GO:00482851	Cervix	CC	organelle fission	78/2311	488/18723	9.70e-03	4.79e-02	78
GO:014001414	Esophagus	ESCC	mitotic nuclear division	218/8552	287/18723	6.17e-26	1.78e-23	218
GO:00482853	Esophagus	ESCC	organelle fission	301/8552	488/18723	4.64e-13	2.12e-11	301
GO:0010563111	Esophagus	ESCC	negative regulation of phosphorus metabolic process	274/8552	442/18723	2.32e-12	9.41e-11	274
GO:0045936111	Esophagus	ESCC	negative regulation of phosphate metabolic process	273/8552	441/18723	3.18e-12	1.25e-10	273
GO:00002802	Esophagus	ESCC	nuclear division	270/8552	439/18723	1.17e-11	4.24e-10	270
GO:0042326111	Esophagus	ESCC	negative regulation of phosphorylation	237/8552	385/18723	1.86e-10	5.33e-09	237
GO:000699713	Esophagus	ESCC	nucleus organization	96/8552	133/18723	4.66e-10	1.21e-08	96
GO:001631110	Esophagus	ESCC	dephosphorylation	251/8552	417/18723	1.26e-09	2.99e-08	251
GO:000647018	Esophagus	ESCC	protein dephosphorylation	177/8552	281/18723	3.13e-09	6.72e-08	177
GO:0035304111	Esophagus	ESCC	regulation of protein dephosphorylation	66/8552	90/18723	8.82e-08	1.48e-06	66
GO:0035303111	Esophagus	ESCC	regulation of dephosphorylation	88/8552	128/18723	1.04e-07	1.71e-06	88

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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

ANKLE2

SNV

Missense_Mutation

rs201586661

c.1547N>T

p.Pro516Leu

p.P516L

Q86XL3

protein_coding

deleterious(0.02)

probably_damaging(1)

TCGA-A1-A0SQ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

ANKLE2

SNV

Missense_Mutation

rs376936921

c.2257G>C

p.Asp753His

p.D753H

Q86XL3

protein_coding

deleterious(0.03)

benign(0.264)

TCGA-A7-A26H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

anastrozole

ANKLE2

SNV

Missense_Mutation

novel

c.1600N>A

p.Asp534Asn

p.D534N

Q86XL3

protein_coding

deleterious(0.03)

possibly_damaging(0.848)

TCGA-A7-A56D-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ANKLE2

SNV

Missense_Mutation

c.1610A>G

p.Lys537Arg

p.K537R

Q86XL3

protein_coding

tolerated(1)

benign(0.003)

TCGA-AR-A1AV-01

Breast

breast invasive carcinoma

Male

>=65

I/II

Chemotherapy

cytoxan

ANKLE2

SNV

Missense_Mutation

c.2209N>C

p.Asp737His

p.D737H

Q86XL3

protein_coding

deleterious(0.03)

possibly_damaging(0.907)

TCGA-BH-A0HP-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

doxorubicin

ANKLE2

SNV

Missense_Mutation

c.511N>T

p.Val171Leu

p.V171L

Q86XL3

protein_coding

tolerated(0.35)

benign(0.003)

TCGA-D8-A1JP-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

ANKLE2

SNV

Missense_Mutation

c.1189N>T

p.Arg397Cys

p.R397C

Q86XL3

protein_coding

tolerated(0.26)

benign(0.01)

TCGA-D8-A1Y1-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

tamoxiphen

ANKLE2

insertion

In_Frame_Ins

novel

c.1513_1514insTAAAAATACAAAAAATTAGCCGGGCGTGGTGGT

p.His505delinsLeuLysIleGlnLysIleSerArgAlaTrpTrpTyr

p.H505delinsLKIQKISRAWWY

Q86XL3

protein_coding

TCGA-A8-A06P-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unspecific

ANKLE2

insertion

Frame_Shift_Ins

novel

c.255_256insCCAAC

p.Lys86ProfsTer6

p.K86Pfs*6

Q86XL3

protein_coding

TCGA-A8-A0A4-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

ANKLE2

insertion

In_Frame_Ins

novel

c.253_254insATCTCCTGACCTTGCGATCTGCATGCCTTGGCC

p.Val85delinsAspLeuLeuThrLeuArgSerAlaCysLeuGlyLeu

p.V85delinsDLLTLRSACLGL

Q86XL3

protein_coding

TCGA-A8-A0A4-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

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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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