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: ATRAID

Gene summary for ATRAID

Gene summary.

Gene information	Species	Human
	Gene symbol	ATRAID
	Gene ID	51374
	Gene name	all-trans retinoic acid induced differentiation factor
	Gene Alias	APR--3
	Cytomap	2p23.3
	Gene Type	protein-coding
	GO ID	GO:0001503
	UniProtAcc	Q6UW56

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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
51374	ATRAID	CA_HPV_1	Human	Cervix	CC	3.06e-07	-2.54e-01	0.0264
51374	ATRAID	CA_HPV_3	Human	Cervix	CC	1.44e-02	2.04e-01	0.0414
51374	ATRAID	CCI_1	Human	Cervix	CC	5.61e-04	-5.22e-01	0.528
51374	ATRAID	CCI_3	Human	Cervix	CC	8.70e-05	-5.00e-01	0.516
51374	ATRAID	CCII_1	Human	Cervix	CC	1.41e-10	-5.40e-01	0.3249
51374	ATRAID	sample3	Human	Cervix	CC	9.96e-03	2.68e-02	0.1387
51374	ATRAID	L1	Human	Cervix	CC	6.61e-04	-2.90e-01	0.0802
51374	ATRAID	HTA11_3410_2000001011	Human	Colorectum	AD	5.57e-08	2.85e-01	0.0155
51374	ATRAID	HTA11_2487_2000001011	Human	Colorectum	SER	1.22e-07	4.16e-01	-0.1808
51374	ATRAID	HTA11_1938_2000001011	Human	Colorectum	AD	3.05e-06	4.88e-01	-0.0811
51374	ATRAID	HTA11_78_2000001011	Human	Colorectum	AD	5.88e-03	2.59e-01	-0.1088
51374	ATRAID	HTA11_347_2000001011	Human	Colorectum	AD	6.41e-19	5.32e-01	-0.1954
51374	ATRAID	HTA11_696_2000001011	Human	Colorectum	AD	1.60e-14	4.15e-01	-0.1464
51374	ATRAID	HTA11_866_2000001011	Human	Colorectum	AD	2.07e-08	2.80e-01	-0.1001
51374	ATRAID	HTA11_1391_2000001011	Human	Colorectum	AD	1.12e-14	4.95e-01	-0.059
51374	ATRAID	HTA11_2992_2000001011	Human	Colorectum	SER	1.58e-06	5.27e-01	-0.1706
51374	ATRAID	HTA11_5212_2000001011	Human	Colorectum	AD	8.31e-05	5.46e-01	-0.2061
51374	ATRAID	HTA11_5216_2000001011	Human	Colorectum	SER	7.70e-03	5.69e-01	-0.1462
51374	ATRAID	HTA11_546_2000001011	Human	Colorectum	AD	3.98e-10	5.04e-01	-0.0842
51374	ATRAID	HTA11_7862_2000001011	Human	Colorectum	AD	8.82e-05	4.13e-01	-0.0179

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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
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:00015032	Colorectum	MSS	ossification	96/3467	408/18723	6.09e-03	4.07e-02	96
GO:00421763	Colorectum	MSI-H	regulation of protein catabolic process	65/1319	391/18723	6.96e-11	1.29e-08	65
GO:19033623	Colorectum	MSI-H	regulation of cellular protein catabolic process	49/1319	255/18723	9.82e-11	1.66e-08	49
GO:19033633	Colorectum	MSI-H	negative regulation of cellular protein catabolic process	20/1319	75/18723	1.50e-07	1.32e-05	20
GO:00313303	Colorectum	MSI-H	negative regulation of cellular catabolic process	43/1319	262/18723	1.68e-07	1.46e-05	43
GO:00098953	Colorectum	MSI-H	negative regulation of catabolic process	46/1319	320/18723	3.00e-06	1.68e-04	46
GO:00421773	Colorectum	MSI-H	negative regulation of protein catabolic process	23/1319	121/18723	1.08e-05	5.00e-04	23
GO:004217616	Endometrium	AEH	regulation of protein catabolic process	100/2100	391/18723	9.58e-16	3.59e-13	100
GO:190336216	Endometrium	AEH	regulation of cellular protein catabolic process	70/2100	255/18723	5.40e-13	1.25e-10	70
GO:004217715	Endometrium	AEH	negative regulation of protein catabolic process	34/2100	121/18723	2.67e-07	1.17e-05	34
GO:00016498	Endometrium	AEH	osteoblast differentiation	52/2100	229/18723	4.74e-07	1.92e-05	52
GO:190336310	Endometrium	AEH	negative regulation of cellular protein catabolic process	24/2100	75/18723	1.18e-06	3.85e-05	24
GO:00015038	Endometrium	AEH	ossification	78/2100	408/18723	1.54e-06	4.85e-05	78
GO:003133016	Endometrium	AEH	negative regulation of cellular catabolic process	53/2100	262/18723	1.40e-05	2.99e-04	53
GO:000989515	Endometrium	AEH	negative regulation of catabolic process	60/2100	320/18723	4.32e-05	7.28e-04	60
GO:00336872	Endometrium	AEH	osteoblast proliferation	11/2100	32/18723	4.71e-04	4.91e-03	11
GO:00456672	Endometrium	AEH	regulation of osteoblast differentiation	27/2100	132/18723	1.40e-03	1.18e-02	27
GO:00336882	Endometrium	AEH	regulation of osteoblast proliferation	9/2100	27/18723	1.96e-03	1.54e-02	9
GO:00456692	Endometrium	AEH	positive regulation of osteoblast differentiation	16/2100	69/18723	3.46e-03	2.39e-02	16
GO:0070167	Endometrium	AEH	regulation of biomineral tissue development	20/2100	97/18723	5.00e-03	3.14e-02	20

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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

ATRAID

SNV

Missense_Mutation

c.371N>G

p.Lys124Arg

p.K124R

Q6UW56

protein_coding

tolerated(0.22)

benign(0.005)

TCGA-AO-A128-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

ATRAID

SNV

Missense_Mutation

c.369N>C

p.Gln123His

p.Q123H

Q6UW56

protein_coding

deleterious(0.02)

possibly_damaging(0.655)

TCGA-B6-A0I2-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATRAID

SNV

Missense_Mutation

novel

c.71G>A

p.Arg24His

p.R24H

Q6UW56

protein_coding

tolerated_low_confidence(0.07)

benign(0.381)

TCGA-E2-A9RU-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Hormone Therapy

arimidex

ATRAID

deletion

In_Frame_Del

novel

c.787_804delNNNNNNNNNNNNNNNNNN

p.Gly263_Ser268del

p.G263_S268del

Q6UW56

protein_coding

TCGA-C8-A12L-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATRAID

SNV

Missense_Mutation

novel

c.328A>G

p.Thr110Ala

p.T110A

Q6UW56

protein_coding

tolerated(0.12)

benign(0.013)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ATRAID

SNV

Missense_Mutation

c.145N>A

p.Gly49Arg

p.G49R

Q6UW56

protein_coding

tolerated_low_confidence(0.59)

benign(0.001)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ATRAID

SNV

Missense_Mutation

c.637N>G

p.Asn213Asp

p.N213D

Q6UW56

protein_coding

tolerated(0.1)

benign(0.046)

TCGA-Q1-A73P-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

ATRAID

SNV

Missense_Mutation

novel

c.6N>T

p.Lys2Asn

p.K2N

Q6UW56

protein_coding

deleterious_low_confidence(0)

benign(0.039)

TCGA-VS-A958-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

ATRAID

SNV

Missense_Mutation

c.584N>G

p.Ile195Ser

p.I195S

Q6UW56

protein_coding

deleterious(0)

possibly_damaging(0.448)

TCGA-CA-6718-01

Colorectum

colon adenocarcinoma

Male

<65

I/II

Unknown

ATRAID

SNV

Missense_Mutation

rs375386400

c.746N>A

p.Arg249His

p.R249H

Q6UW56

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-F4-6570-01

Colorectum

colon adenocarcinoma

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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