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: NRG1

Gene summary for NRG1

Gene summary.

Gene information	Species	Human
	Gene symbol	NRG1
	Gene ID	3084
	Gene name	neuregulin 1
	Gene Alias	ARIA
	Cytomap	8p12
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	A6MW56

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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
3084	NRG1	LZE4T	Human	Esophagus	ESCC	4.08e-07	1.75e-01	0.0811
3084	NRG1	P2T-E	Human	Esophagus	ESCC	1.06e-07	-8.89e-02	0.1177
3084	NRG1	P4T-E	Human	Esophagus	ESCC	1.84e-05	4.37e-01	0.1323
3084	NRG1	P5T-E	Human	Esophagus	ESCC	5.68e-07	2.48e-01	0.1327
3084	NRG1	P8T-E	Human	Esophagus	ESCC	8.44e-03	5.55e-02	0.0889
3084	NRG1	P9T-E	Human	Esophagus	ESCC	5.44e-03	2.87e-01	0.1131
3084	NRG1	P12T-E	Human	Esophagus	ESCC	9.55e-10	4.93e-01	0.1122
3084	NRG1	P15T-E	Human	Esophagus	ESCC	8.54e-20	8.56e-01	0.1149
3084	NRG1	P16T-E	Human	Esophagus	ESCC	1.52e-08	-1.54e-03	0.1153
3084	NRG1	P21T-E	Human	Esophagus	ESCC	3.99e-31	1.44e+00	0.1617
3084	NRG1	P22T-E	Human	Esophagus	ESCC	5.24e-04	1.32e-02	0.1236
3084	NRG1	P26T-E	Human	Esophagus	ESCC	1.88e-29	9.50e-01	0.1276
3084	NRG1	P27T-E	Human	Esophagus	ESCC	6.09e-07	-1.32e-01	0.1055
3084	NRG1	P28T-E	Human	Esophagus	ESCC	2.93e-04	3.28e-01	0.1149
3084	NRG1	P30T-E	Human	Esophagus	ESCC	2.80e-27	1.75e+00	0.137
3084	NRG1	P31T-E	Human	Esophagus	ESCC	1.73e-03	-3.49e-02	0.1251
3084	NRG1	P32T-E	Human	Esophagus	ESCC	1.22e-05	4.75e-01	0.1666
3084	NRG1	P37T-E	Human	Esophagus	ESCC	9.22e-09	4.34e-01	0.1371
3084	NRG1	P39T-E	Human	Esophagus	ESCC	4.66e-02	-1.51e-01	0.0894
3084	NRG1	P40T-E	Human	Esophagus	ESCC	2.83e-02	4.05e-01	0.109

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
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

∗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:00605378	Oral cavity	OSCC	muscle tissue development	185/7305	403/18723	2.60e-03	1.14e-02	185
GO:00454469	Oral cavity	OSCC	endothelial cell differentiation	61/7305	118/18723	3.40e-03	1.44e-02	61
GO:00331733	Oral cavity	OSCC	calcineurin-NFAT signaling cascade	26/7305	43/18723	3.55e-03	1.49e-02	26
GO:003087910	Oral cavity	OSCC	mammary gland development	69/7305	137/18723	4.43e-03	1.79e-02	69
GO:00426927	Oral cavity	OSCC	muscle cell differentiation	175/7305	384/18723	4.79e-03	1.92e-02	175
GO:003432916	Oral cavity	OSCC	cell junction assembly	190/7305	420/18723	4.99e-03	1.96e-02	190
GO:00518976	Oral cavity	OSCC	positive regulation of protein kinase B signaling	61/7305	120/18723	5.52e-03	2.14e-02	61
GO:00147067	Oral cavity	OSCC	striated muscle tissue development	174/7305	384/18723	6.45e-03	2.40e-02	174
GO:0061097	Oral cavity	OSCC	regulation of protein tyrosine kinase activity	47/7305	90/18723	7.37e-03	2.73e-02	47
GO:00434107	Oral cavity	OSCC	positive regulation of MAPK cascade	213/7305	480/18723	8.71e-03	3.16e-02	213
GO:00703716	Oral cavity	OSCC	ERK1 and ERK2 cascade	150/7305	330/18723	9.47e-03	3.38e-02	150
GO:00465788	Oral cavity	OSCC	regulation of Ras protein signal transduction	90/7305	189/18723	9.58e-03	3.40e-02	90
GO:00518967	Oral cavity	OSCC	regulation of protein kinase B signaling	88/7305	185/18723	1.07e-02	3.64e-02	88
GO:00703724	Oral cavity	OSCC	regulation of ERK1 and ERK2 cascade	140/7305	309/18723	1.34e-02	4.46e-02	140
GO:00480164	Oral cavity	OSCC	inositol phosphate-mediated signaling	30/7305	55/18723	1.39e-02	4.59e-02	30
GO:00487627	Oral cavity	OSCC	mesenchymal cell differentiation	109/7305	236/18723	1.43e-02	4.69e-02	109
GO:00708843	Oral cavity	OSCC	regulation of calcineurin-NFAT signaling cascade	20/7305	34/18723	1.51e-02	4.91e-02	20
GO:00488637	Oral cavity	OSCC	stem cell differentiation	96/7305	206/18723	1.55e-02	4.99e-02	96
GO:0050850	Oral cavity	OSCC	positive regulation of calcium-mediated signaling	19/7305	32/18723	1.56e-02	5.00e-02	19
GO:004217618	Prostate	BPH	regulation of protein catabolic process	139/3107	391/18723	3.71e-20	3.28e-17	139

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa05014210	Esophagus	ESCC	Amyotrophic lateral sclerosis	266/4205	364/8465	1.31e-20	2.20e-18	1.13e-18	266
hsa0152110	Esophagus	ESCC	EGFR tyrosine kinase inhibitor resistance	55/4205	79/8465	2.44e-04	8.78e-04	4.50e-04	55
hsa0401218	Esophagus	ESCC	ErbB signaling pathway	56/4205	85/8465	1.78e-03	5.24e-03	2.68e-03	56
hsa0501438	Esophagus	ESCC	Amyotrophic lateral sclerosis	266/4205	364/8465	1.31e-20	2.20e-18	1.13e-18	266
hsa0152115	Esophagus	ESCC	EGFR tyrosine kinase inhibitor resistance	55/4205	79/8465	2.44e-04	8.78e-04	4.50e-04	55
hsa0401219	Esophagus	ESCC	ErbB signaling pathway	56/4205	85/8465	1.78e-03	5.24e-03	2.68e-03	56
hsa0501428	Oral cavity	OSCC	Amyotrophic lateral sclerosis	246/3704	364/8465	6.65e-21	1.11e-18	5.67e-19	246
hsa015219	Oral cavity	OSCC	EGFR tyrosine kinase inhibitor resistance	54/3704	79/8465	8.11e-06	3.72e-05	1.89e-05	54
hsa0401216	Oral cavity	OSCC	ErbB signaling pathway	55/3704	85/8465	7.46e-05	2.81e-04	1.43e-04	55
hsa05014112	Oral cavity	OSCC	Amyotrophic lateral sclerosis	246/3704	364/8465	6.65e-21	1.11e-18	5.67e-19	246
hsa0152114	Oral cavity	OSCC	EGFR tyrosine kinase inhibitor resistance	54/3704	79/8465	8.11e-06	3.72e-05	1.89e-05	54
hsa0401217	Oral cavity	OSCC	ErbB signaling pathway	55/3704	85/8465	7.46e-05	2.81e-04	1.43e-04	55
hsa0501426	Prostate	BPH	Amyotrophic lateral sclerosis	151/1718	364/8465	3.37e-21	1.01e-19	6.25e-20	151
hsa015218	Prostate	BPH	EGFR tyrosine kinase inhibitor resistance	30/1718	79/8465	2.10e-04	1.13e-03	6.98e-04	30
hsa0401214	Prostate	BPH	ErbB signaling pathway	28/1718	85/8465	4.12e-03	1.45e-02	8.95e-03	28
hsa05014111	Prostate	BPH	Amyotrophic lateral sclerosis	151/1718	364/8465	3.37e-21	1.01e-19	6.25e-20	151
hsa0152113	Prostate	BPH	EGFR tyrosine kinase inhibitor resistance	30/1718	79/8465	2.10e-04	1.13e-03	6.98e-04	30
hsa0401215	Prostate	BPH	ErbB signaling pathway	28/1718	85/8465	4.12e-03	1.45e-02	8.95e-03	28
hsa0501427	Prostate	Tumor	Amyotrophic lateral sclerosis	155/1791	364/8465	3.41e-21	1.13e-19	6.99e-20	155
hsa0152123	Prostate	Tumor	EGFR tyrosine kinase inhibitor resistance	31/1791	79/8465	1.82e-04	1.08e-03	6.68e-04	31

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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
NRG1	ERBB3	NRG1_ERBB3	NRG	Breast	DCIS
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	Breast	DCIS
NRG1	ERBB3	NRG1_ERBB3	NRG	Cervix	CC
NRG1	ERBB4	NRG1_ERBB4	NRG	Cervix	CC
NRG1	ERBB2_ERBB4	NRG1_ERBB2_ERBB4	NRG	Cervix	CC
NRG1	ERBB3	NRG1_ERBB3	NRG	Cervix	Precancer
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	Cervix	Precancer
NRG1	ERBB3	NRG1_ERBB3	NRG	CRC	AD
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	CRC	AD
NRG1	ERBB3	NRG1_ERBB3	NRG	CRC	ADJ
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	CRC	ADJ
NRG1	ERBB4	NRG1_ERBB4	NRG	CRC	ADJ
NRG1	ERBB3	NRG1_ERBB3	NRG	CRC	FAP
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	CRC	FAP
NRG1	ERBB3	NRG1_ERBB3	NRG	CRC	MSS
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	CRC	MSS
NRG1	ERBB3	NRG1_ERBB3	NRG	Esophagus	ESCC
NRG1	ERBB2_ERBB3	NRG1_ERBB2_ERBB3	NRG	Esophagus	ESCC
NRG1	ERBB3	NRG1_ERBB3	NRG	GC	ADJ
NRG1	ERBB3	NRG1_ERBB3	NRG	GC	GC

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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

NRG1

SNV

Missense_Mutation

novel

c.514N>T

p.Ala172Ser

p.A172S

Q02297

protein_coding

tolerated(0.7)

benign(0.031)

TCGA-AC-A8OR-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NRG1

SNV

Missense_Mutation

novel

c.464N>T

p.Arg155Ile

p.R155I

Q02297

protein_coding

tolerated(0.16)

possibly_damaging(0.642)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

NRG1

SNV

Missense_Mutation

c.1639N>A

p.Ala547Thr

p.A547T

Q02297

protein_coding

tolerated(0.29)

benign(0.001)

TCGA-LL-A73Z-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

adriamycin

NRG1

SNV

Missense_Mutation

novel

c.53N>A

p.Arg18Gln

p.R18Q

Q02297

protein_coding

tolerated(0.45)

benign(0.091)

TCGA-PE-A5DE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

taxotere

NRG1

insertion

Nonsense_Mutation

novel

c.1795_1796insTCTACTTCTCGTGACACCACCAAGGCTGCGGGAGAAGAAGTTTGA

p.Pro599delinsLeuTyrPheSerTerHisHisGlnGlyCysGlyArgArgSerLeuThr

p.P599delinsLYFS*HHQGCGRRSLT

Q02297

protein_coding

TCGA-A7-A0CE-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

NRG1

insertion

Frame_Shift_Ins

novel

c.1743_1744insCCATCACCCTCAGCAGTTCAGCTCCTTCCACC

p.Thr582ProfsTer17

p.T582Pfs*17

Q02297

protein_coding

TCGA-A8-A07Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unspecific

Exemestane

NRG1

SNV

Missense_Mutation

novel

c.1813N>C

p.Glu605Gln

p.E605Q

Q02297

protein_coding

deleterious(0.04)

probably_damaging(0.966)

TCGA-C5-A2LZ-01

Cervix

cervical & endocervical cancer

Female

>=65

III/IV

Unknown

NRG1

SNV

Missense_Mutation

rs146885321

c.292C>T

p.Arg98Cys

p.R98C

Q02297

protein_coding

deleterious(0)

possibly_damaging(0.899)

TCGA-VS-A8EK-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

cisplatin

NRG1

SNV

Missense_Mutation

c.289C>A

p.Leu97Ile

p.L97I

Q02297

protein_coding

tolerated(0.09)

probably_damaging(0.998)

TCGA-A6-5657-01

Colorectum

colon adenocarcinoma

Male

>=65

III/IV

Ancillary

leucovorin

NRG1

SNV

Missense_Mutation

c.5G>T

p.Arg2Ile

p.R2I

Q02297

protein_coding

deleterious_low_confidence(0)

benign(0.053)

TCGA-A6-5661-01

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
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		NERVE GROWTH FACTOR		11069896
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		PERTUZUMAB	PERTUZUMAB	29802158
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		ANTI-HER3 MONOCLONAL ANTIBODY GSK2849330		29610121
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		PROGESTERONE	PROGESTERONE	12529413
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		ISOPROTERENOL	ISOPROTERENOL	14732742
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		ASPIRIN	ASPIRIN	10921413
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		DEXAMETHASONE	DEXAMETHASONE	7599067
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		CISPLATIN	CISPLATIN	23390248
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		WORTMANNIN	WORTMANNIN	10559227
3084	NRG1	GROWTH FACTOR, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE, KINASE		GENISTEIN	GENISTEIN	17539658

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