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: EML4

Gene summary for EML4

Gene summary.

Gene information	Species	Human
	Gene symbol	EML4
	Gene ID	27436
	Gene name	EMAP like 4
	Gene Alias	C2orf2
	Cytomap	2p21
	Gene Type	protein-coding
	GO ID	GO:0000070
	UniProtAcc	Q9HC35

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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
27436	EML4	CA_HPV_1	Human	Cervix	CC	1.82e-03	1.22e-01	0.0264
27436	EML4	CCI_2	Human	Cervix	CC	2.40e-04	1.07e+00	0.5249
27436	EML4	CCI_3	Human	Cervix	CC	7.21e-08	8.27e-01	0.516
27436	EML4	HTA11_3410_2000001011	Human	Colorectum	AD	5.03e-19	-6.43e-01	0.0155
27436	EML4	HTA11_347_2000001011	Human	Colorectum	AD	8.07e-03	3.59e-01	-0.1954
27436	EML4	HTA11_3361_2000001011	Human	Colorectum	AD	5.79e-10	-7.60e-01	-0.1207
27436	EML4	HTA11_696_2000001011	Human	Colorectum	AD	3.59e-04	-3.80e-01	-0.1464
27436	EML4	HTA11_5216_2000001011	Human	Colorectum	SER	1.41e-02	-4.27e-01	-0.1462
27436	EML4	HTA11_866_3004761011	Human	Colorectum	AD	3.87e-06	-5.07e-01	0.096
27436	EML4	HTA11_8622_2000001021	Human	Colorectum	SER	2.00e-02	-4.70e-01	0.0528
27436	EML4	HTA11_10711_2000001011	Human	Colorectum	AD	1.71e-05	-4.20e-01	0.0338
27436	EML4	HTA11_7696_3000711011	Human	Colorectum	AD	1.30e-11	-5.16e-01	0.0674
27436	EML4	HTA11_6818_2000001021	Human	Colorectum	AD	1.27e-04	-5.32e-01	0.0588
27436	EML4	HTA11_99999970781_79442	Human	Colorectum	MSS	3.22e-02	-3.05e-01	0.294
27436	EML4	HTA11_99999965062_69753	Human	Colorectum	MSI-H	1.24e-04	7.69e-01	0.3487
27436	EML4	HTA11_99999974143_84620	Human	Colorectum	MSS	4.23e-04	-3.79e-01	0.3005
27436	EML4	F007	Human	Colorectum	FAP	2.08e-02	-3.21e-01	0.1176
27436	EML4	A001-C-207	Human	Colorectum	FAP	5.12e-04	-2.37e-01	0.1278
27436	EML4	A015-C-203	Human	Colorectum	FAP	6.17e-35	-4.50e-01	-0.1294
27436	EML4	A015-C-204	Human	Colorectum	FAP	7.51e-06	-2.38e-01	-0.0228

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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
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid 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
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:00516567	Cervix	CC	establishment of organelle localization	76/2311	390/18723	3.17e-05	5.21e-04	76
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:0051656	Colorectum	AD	establishment of organelle localization	131/3918	390/18723	3.00e-09	2.06e-07	131
GO:0140014	Colorectum	AD	mitotic nuclear division	78/3918	287/18723	6.48e-03	4.05e-02	78
GO:00516561	Colorectum	SER	establishment of organelle localization	100/2897	390/18723	1.11e-07	6.79e-06	100
GO:00516562	Colorectum	MSS	establishment of organelle localization	115/3467	390/18723	7.30e-08	3.67e-06	115
GO:01400141	Colorectum	MSS	mitotic nuclear division	70/3467	287/18723	7.48e-03	4.72e-02	70
GO:00516563	Colorectum	FAP	establishment of organelle localization	97/2622	390/18723	5.91e-09	9.48e-07	97
GO:00516564	Colorectum	CRC	establishment of organelle localization	76/2078	390/18723	6.53e-07	4.50e-05	76
GO:00516568	Endometrium	AEH	establishment of organelle localization	77/2100	390/18723	4.89e-07	1.94e-05	77
GO:005165613	Endometrium	EEC	establishment of organelle localization	75/2168	390/18723	6.23e-06	1.49e-04	75
GO:005165616	Esophagus	HGIN	establishment of organelle localization	90/2587	390/18723	4.27e-07	1.94e-05	90
GO:00500003	Esophagus	HGIN	chromosome localization	24/2587	82/18723	2.07e-04	3.82e-03	24
GO:01400146	Esophagus	HGIN	mitotic nuclear division	61/2587	287/18723	3.38e-04	5.55e-03	61
GO:00070593	Esophagus	HGIN	chromosome segregation	71/2587	346/18723	3.47e-04	5.62e-03	71
GO:00513033	Esophagus	HGIN	establishment of chromosome localization	23/2587	80/18723	3.71e-04	5.77e-03	23
GO:00070803	Esophagus	HGIN	mitotic metaphase plate congression	15/2587	50/18723	2.35e-03	2.39e-02	15
GO:00513103	Esophagus	HGIN	metaphase plate congression	18/2587	65/18723	2.46e-03	2.45e-02	18
GO:00000703	Esophagus	HGIN	mitotic sister chromatid segregation	36/2587	168/18723	4.42e-03	3.87e-02	36

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa052234	Cervix	CC	Non-small cell lung cancer	21/1267	72/8465	1.48e-03	6.32e-03	3.74e-03	21
hsa0522313	Cervix	CC	Non-small cell lung cancer	21/1267	72/8465	1.48e-03	6.32e-03	3.74e-03	21
hsa05223	Colorectum	FAP	Non-small cell lung cancer	20/1404	72/8465	1.14e-02	3.92e-02	2.38e-02	20
hsa052231	Colorectum	FAP	Non-small cell lung cancer	20/1404	72/8465	1.14e-02	3.92e-02	2.38e-02	20
hsa052356	Esophagus	ESCC	PD-L1 expression and PD-1 checkpoint pathway in cancer	58/4205	89/8465	2.19e-03	6.16e-03	3.16e-03	58
hsa052237	Esophagus	ESCC	Non-small cell lung cancer	48/4205	72/8465	2.57e-03	7.05e-03	3.61e-03	48
hsa0523511	Esophagus	ESCC	PD-L1 expression and PD-1 checkpoint pathway in cancer	58/4205	89/8465	2.19e-03	6.16e-03	3.16e-03	58
hsa0522316	Esophagus	ESCC	Non-small cell lung cancer	48/4205	72/8465	2.57e-03	7.05e-03	3.61e-03	48
hsa052232	Liver	HCC	Non-small cell lung cancer	46/4020	72/8465	3.61e-03	1.12e-02	6.22e-03	46
hsa0522311	Liver	HCC	Non-small cell lung cancer	46/4020	72/8465	3.61e-03	1.12e-02	6.22e-03	46
hsa052233	Lung	IAC	Non-small cell lung cancer	17/1053	72/8465	6.15e-03	2.60e-02	1.72e-02	17
hsa0522312	Lung	IAC	Non-small cell lung cancer	17/1053	72/8465	6.15e-03	2.60e-02	1.72e-02	17
hsa05235	Oral cavity	OSCC	PD-L1 expression and PD-1 checkpoint pathway in cancer	56/3704	89/8465	1.97e-04	6.55e-04	3.33e-04	56
hsa052236	Oral cavity	OSCC	Non-small cell lung cancer	46/3704	72/8465	4.37e-04	1.32e-03	6.72e-04	46
hsa052351	Oral cavity	OSCC	PD-L1 expression and PD-1 checkpoint pathway in cancer	56/3704	89/8465	1.97e-04	6.55e-04	3.33e-04	56
hsa0522315	Oral cavity	OSCC	Non-small cell lung cancer	46/3704	72/8465	4.37e-04	1.32e-03	6.72e-04	46
hsa052352	Oral cavity	EOLP	PD-L1 expression and PD-1 checkpoint pathway in cancer	32/1218	89/8465	2.96e-07	3.18e-06	1.88e-06	32
hsa0522322	Oral cavity	EOLP	Non-small cell lung cancer	19/1218	72/8465	5.29e-03	1.63e-02	9.60e-03	19
hsa052353	Oral cavity	EOLP	PD-L1 expression and PD-1 checkpoint pathway in cancer	32/1218	89/8465	2.96e-07	3.18e-06	1.88e-06	32
hsa0522332	Oral cavity	EOLP	Non-small cell lung cancer	19/1218	72/8465	5.29e-03	1.63e-02	9.60e-03	19

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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

EML4

SNV

Missense_Mutation

c.2867A>T

p.Glu956Val

p.E956V

Q9HC35

protein_coding

tolerated_low_confidence(0.05)

benign(0.003)

TCGA-A8-A085-01

Breast

breast invasive carcinoma

Male

<65

I/II

Hormone Therapy

tamoxiphen

EML4

SNV

Missense_Mutation

c.1778N>G

p.Asp593Gly

p.D593G

Q9HC35

protein_coding

deleterious(0)

possibly_damaging(0.73)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

EML4

SNV

Missense_Mutation

c.2908N>A

p.Leu970Ile

p.L970I

Q9HC35

protein_coding

tolerated_low_confidence(0.63)

benign(0)

TCGA-B6-A0IJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

EML4

insertion

In_Frame_Ins

novel

c.301_302insGAGTCAAATGCTTCT

p.Ile101delinsArgValLysCysPhePhe

p.I101delinsRVKCFF

Q9HC35

protein_coding

TCGA-A2-A04Y-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

EML4

insertion

Nonsense_Mutation

novel

c.2910_2911insTGCCGATGACTTTTGTAAAGTC

p.Leu971CysfsTer3

p.L971Cfs*3

Q9HC35

protein_coding

TCGA-BH-A0B1-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

adriamycin

EML4

insertion

Frame_Shift_Ins

novel

c.122_123insA

p.Ala43GlyfsTer5

p.A43Gfs*5

Q9HC35

protein_coding

TCGA-C8-A135-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

EML4

SNV

Missense_Mutation

novel

c.1658G>A

p.Gly553Asp

p.G553D

Q9HC35

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EML4

SNV

Missense_Mutation

novel

c.1934G>A

p.Gly645Asp

p.G645D

Q9HC35

protein_coding

deleterious(0)

probably_damaging(0.98)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EML4

SNV

Missense_Mutation

novel

c.1919N>T

p.Asp640Val

p.D640V

Q9HC35

protein_coding

tolerated(0.09)

possibly_damaging(0.682)

TCGA-C5-A1M9-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

EML4

SNV

Missense_Mutation

c.1603C>A

p.Leu535Met

p.L535M

Q9HC35

protein_coding

tolerated(0.13)

benign(0.077)

TCGA-AA-3977-01

Colorectum

colon adenocarcinoma

Male

>=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
27436	EML4	CLINICALLY ACTIONABLE, KINASE		TAE226		26090892
27436	EML4	CLINICALLY ACTIONABLE, KINASE		Sirolimus	SIROLIMUS	21613408
27436	EML4	CLINICALLY ACTIONABLE, KINASE		AZD3463		27009859
27436	EML4	CLINICALLY ACTIONABLE, KINASE		Crizotinib	CRIZOTINIB	26775591,27009859,22277784,20979469,22235099,28476735,27354483,27432227,25228534,26698910,21613408,26554404,23344087,21791641,27780853,24675041
27436	EML4	CLINICALLY ACTIONABLE, KINASE		Alectinib	ALECTINIB	27009859,28476735,25393796,26849637,27432227,26682573,25228534,21575866,26698910,23344087
27436	EML4	CLINICALLY ACTIONABLE, KINASE		AUY922		26698910
27436	EML4	CLINICALLY ACTIONABLE, KINASE		PF-06463922	LORLATINIB	27432227,26698910,26144315,26554404
27436	EML4	CLINICALLY ACTIONABLE, KINASE		Afatinib	AFATINIB	26682573
27436	EML4	CLINICALLY ACTIONABLE, KINASE		X-396	ENSARTINIB	21613408
27436	EML4	CLINICALLY ACTIONABLE, KINASE		AP26113	CHEMBL3397300	27009859,27432227,25228534,26698910,27780853

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