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: ATF6

Gene summary for ATF6

Gene summary.

Gene information	Species	Human
	Gene symbol	ATF6
	Gene ID	22926
	Gene name	activating transcription factor 6
	Gene Alias	ACHM7
	Cytomap	1q23.3
	Gene Type	protein-coding
	GO ID	GO:0001654
	UniProtAcc	A8K383

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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
22926	ATF6	CCI_1	Human	Cervix	CC	8.94e-06	1.04e+00	0.528
22926	ATF6	CCI_2	Human	Cervix	CC	4.57e-03	5.70e-01	0.5249
22926	ATF6	CCI_3	Human	Cervix	CC	6.31e-03	5.43e-01	0.516
22926	ATF6	HTA11_3410_2000001011	Human	Colorectum	AD	3.44e-12	-4.75e-01	0.0155
22926	ATF6	HTA11_866_2000001011	Human	Colorectum	AD	4.03e-03	-2.72e-01	-0.1001
22926	ATF6	HTA11_866_3004761011	Human	Colorectum	AD	2.78e-08	-3.72e-01	0.096
22926	ATF6	HTA11_7696_3000711011	Human	Colorectum	AD	1.05e-05	-3.50e-01	0.0674
22926	ATF6	HTA11_99999970781_79442	Human	Colorectum	MSS	1.31e-06	-3.53e-01	0.294
22926	ATF6	HTA11_99999974143_84620	Human	Colorectum	MSS	1.72e-08	-3.91e-01	0.3005
22926	ATF6	A015-C-203	Human	Colorectum	FAP	6.91e-24	-3.72e-01	-0.1294
22926	ATF6	A015-C-204	Human	Colorectum	FAP	6.24e-07	-3.24e-01	-0.0228
22926	ATF6	A014-C-040	Human	Colorectum	FAP	3.67e-04	-4.54e-01	-0.1184
22926	ATF6	A002-C-201	Human	Colorectum	FAP	5.50e-13	-3.66e-01	0.0324
22926	ATF6	A002-C-203	Human	Colorectum	FAP	9.70e-06	-2.27e-01	0.2786
22926	ATF6	A001-C-119	Human	Colorectum	FAP	1.44e-07	-4.08e-01	-0.1557
22926	ATF6	A001-C-108	Human	Colorectum	FAP	8.53e-12	-2.26e-01	-0.0272
22926	ATF6	A002-C-205	Human	Colorectum	FAP	1.24e-19	-4.36e-01	-0.1236
22926	ATF6	A001-C-104	Human	Colorectum	FAP	9.32e-03	-1.14e-01	0.0184
22926	ATF6	A015-C-005	Human	Colorectum	FAP	4.57e-06	-3.29e-01	-0.0336
22926	ATF6	A015-C-006	Human	Colorectum	FAP	4.81e-14	-4.14e-01	-0.0994

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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
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:000989610	Cervix	CC	positive regulation of catabolic process	109/2311	492/18723	5.26e-10	6.99e-08	109
GO:004361810	Cervix	CC	regulation of transcription from RNA polymerase II promoter in response to stress	21/2311	47/18723	3.85e-08	2.53e-06	21
GO:004362010	Cervix	CC	regulation of DNA-templated transcription in response to stress	22/2311	53/18723	9.29e-08	5.19e-06	22
GO:003133110	Cervix	CC	positive regulation of cellular catabolic process	91/2311	427/18723	9.64e-08	5.25e-06	91
GO:190589710	Cervix	CC	regulation of response to endoplasmic reticulum stress	27/2311	82/18723	9.24e-07	3.25e-05	27
GO:003497610	Cervix	CC	response to endoplasmic reticulum stress	57/2311	256/18723	5.81e-06	1.42e-04	57
GO:000698610	Cervix	CC	response to unfolded protein	36/2311	137/18723	6.83e-06	1.63e-04	36
GO:003596610	Cervix	CC	response to topologically incorrect protein	39/2311	159/18723	1.68e-05	3.22e-04	39
GO:003462010	Cervix	CC	cellular response to unfolded protein	27/2311	96/18723	2.53e-05	4.29e-04	27
GO:00069846	Cervix	CC	ER-nucleus signaling pathway	16/2311	46/18723	7.12e-05	9.90e-04	16
GO:003596710	Cervix	CC	cellular response to topologically incorrect protein	29/2311	116/18723	1.35e-04	1.66e-03	29
GO:00105067	Cervix	CC	regulation of autophagy	61/2311	317/18723	2.61e-04	2.87e-03	61
GO:00360038	Cervix	CC	positive regulation of transcription from RNA polymerase II promoter in response to stress	10/2311	24/18723	3.05e-04	3.26e-03	10
GO:00064579	Cervix	CC	protein folding	44/2311	212/18723	3.43e-04	3.59e-03	44
GO:19001017	Cervix	CC	regulation of endoplasmic reticulum unfolded protein response	11/2311	30/18723	5.71e-04	5.45e-03	11
GO:19058982	Cervix	CC	positive regulation of response to endoplasmic reticulum stress	11/2311	35/18723	2.43e-03	1.71e-02	11
GO:19001033	Cervix	CC	positive regulation of endoplasmic reticulum unfolded protein response	6/2311	13/18723	2.78e-03	1.87e-02	6
GO:00309688	Cervix	CC	endoplasmic reticulum unfolded protein response	18/2311	74/18723	3.28e-03	2.13e-02	18
GO:0150063	Cervix	CC	visual system development	63/2311	375/18723	6.58e-03	3.65e-02	63
GO:0001654	Cervix	CC	eye development	62/2311	371/18723	7.83e-03	4.13e-02	62

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501220	Cervix	CC	Parkinson disease	102/1267	266/8465	1.81e-21	1.47e-19	8.66e-20	102
hsa0501018	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0502218	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa0501418	Cervix	CC	Amyotrophic lateral sclerosis	103/1267	364/8465	1.79e-11	4.47e-10	2.64e-10	103
hsa0541720	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa0414120	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa05012110	Cervix	CC	Parkinson disease	102/1267	266/8465	1.81e-21	1.47e-19	8.66e-20	102
hsa0501019	Cervix	CC	Alzheimer disease	113/1267	384/8465	9.67e-14	3.92e-12	2.32e-12	113
hsa0502219	Cervix	CC	Pathways of neurodegeneration - multiple diseases	128/1267	476/8465	2.87e-12	9.29e-11	5.50e-11	128
hsa0501419	Cervix	CC	Amyotrophic lateral sclerosis	103/1267	364/8465	1.79e-11	4.47e-10	2.64e-10	103
hsa05417110	Cervix	CC	Lipid and atherosclerosis	65/1267	215/8465	6.47e-09	1.10e-07	6.52e-08	65
hsa04141110	Cervix	CC	Protein processing in endoplasmic reticulum	55/1267	174/8465	1.74e-08	2.68e-07	1.58e-07	55
hsa05010	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa05014	Colorectum	AD	Amyotrophic lateral sclerosis	164/2092	364/8465	4.28e-18	1.27e-16	8.09e-17	164
hsa05022	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa050101	Colorectum	AD	Alzheimer disease	174/2092	384/8465	1.82e-19	9.26e-18	5.91e-18	174
hsa050141	Colorectum	AD	Amyotrophic lateral sclerosis	164/2092	364/8465	4.28e-18	1.27e-16	8.09e-17	164
hsa050221	Colorectum	AD	Pathways of neurodegeneration - multiple diseases	201/2092	476/8465	4.54e-18	1.27e-16	8.09e-17	201
hsa050124	Colorectum	MSS	Parkinson disease	140/1875	266/8465	2.32e-28	7.79e-26	4.77e-26	140
hsa050104	Colorectum	MSS	Alzheimer disease	169/1875	384/8465	1.21e-22	1.01e-20	6.21e-21	169

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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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
ATF6	SMC	Cervix	Healthy	CNKSR3,TXN,AC016831.1, etc.	8.37e-01
ATF6	KER	Esophagus	Healthy	SPRR3,TP63,CSTB, etc.	2.18e-01
ATF6	TRANS	Esophagus	Healthy	SPRR3,TP63,CSTB, etc.	2.09e-01

∗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

ATF6

SNV

Missense_Mutation

c.1093G>C

p.Glu365Gln

p.E365Q

P18850

protein_coding

tolerated(0.06)

possibly_damaging(0.888)

TCGA-A8-A08L-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

ATF6

SNV

Missense_Mutation

c.160N>A

p.Glu54Lys

p.E54K

P18850

protein_coding

tolerated(0.16)

possibly_damaging(0.76)

TCGA-A8-A0A7-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATF6

SNV

Missense_Mutation

c.926G>A

p.Arg309Lys

p.R309K

P18850

protein_coding

tolerated(0.09)

benign(0.24)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATF6

SNV

Missense_Mutation

rs771212825

c.1892C>T

p.Ser631Leu

p.S631L

P18850

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATF6

SNV

Missense_Mutation

c.1745N>T

p.Thr582Ile

p.T582I

P18850

protein_coding

deleterious(0.01)

possibly_damaging(0.521)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

ATF6

SNV

Missense_Mutation

c.1429N>T

p.Leu477Phe

p.L477F

P18850

protein_coding

deleterious(0.01)

probably_damaging(0.965)

TCGA-AR-A2LE-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

ATF6

SNV

Missense_Mutation

novel

c.1342N>A

p.Asp448Asn

p.D448N

P18850

protein_coding

tolerated(0.45)

benign(0.105)

TCGA-E9-A3QA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

ATF6

SNV

Missense_Mutation

rs752288775

c.1451N>A

p.Arg484Gln

p.R484Q

P18850

protein_coding

deleterious(0.03)

possibly_damaging(0.703)

TCGA-GM-A2D9-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

ATF6

insertion

Frame_Shift_Ins

novel

c.1347dupA

p.Ala450SerfsTer7

p.A450Sfs*7

P18850

protein_coding

TCGA-C8-A26X-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

5-fluorouracil

ATF6

deletion

Frame_Shift_Del

novel

c.1588delA

p.Thr530ProfsTer69

p.T530Pfs*69

P18850

protein_coding

TCGA-D8-A27V-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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