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: PAM

Gene summary for PAM

Gene summary.

Gene information	Species	Human
	Gene symbol	PAM
	Gene ID	5066
	Gene name	peptidylglycine alpha-amidating monooxygenase
	Gene Alias	PAL
	Cytomap	5q21.1
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P19021

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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
5066	PAM	GSM4909281	Human	Breast	IDC	4.72e-26	7.25e-01	0.21
5066	PAM	GSM4909285	Human	Breast	IDC	1.30e-20	6.12e-01	0.21
5066	PAM	GSM4909286	Human	Breast	IDC	3.52e-11	-1.61e-01	0.1081
5066	PAM	GSM4909287	Human	Breast	IDC	9.18e-03	3.09e-01	0.2057
5066	PAM	GSM4909290	Human	Breast	IDC	3.17e-04	-1.62e-01	0.2096
5066	PAM	GSM4909294	Human	Breast	IDC	6.42e-09	-1.43e-01	0.2022
5066	PAM	GSM4909296	Human	Breast	IDC	5.78e-03	-2.23e-03	0.1524
5066	PAM	GSM4909297	Human	Breast	IDC	2.74e-03	-1.19e-01	0.1517
5066	PAM	GSM4909301	Human	Breast	IDC	2.79e-03	-1.08e-01	0.1577
5066	PAM	GSM4909304	Human	Breast	IDC	2.24e-02	-1.18e-01	0.1636
5066	PAM	GSM4909308	Human	Breast	IDC	3.04e-09	4.15e-01	0.158
5066	PAM	GSM4909311	Human	Breast	IDC	4.84e-12	-6.92e-03	0.1534
5066	PAM	GSM4909312	Human	Breast	IDC	1.09e-03	-5.47e-02	0.1552
5066	PAM	GSM4909315	Human	Breast	IDC	2.51e-08	-1.51e-01	0.21
5066	PAM	GSM4909319	Human	Breast	IDC	8.04e-10	-1.59e-01	0.1563
5066	PAM	GSM4909321	Human	Breast	IDC	5.17e-05	4.83e-02	0.1559
5066	PAM	NCCBC14	Human	Breast	DCIS	4.04e-02	-1.36e-01	0.2021
5066	PAM	NCCBC5	Human	Breast	DCIS	2.12e-03	-1.45e-01	0.2046
5066	PAM	P1	Human	Breast	IDC	4.05e-03	-1.49e-01	0.1527
5066	PAM	DCIS2	Human	Breast	DCIS	9.75e-50	3.99e-01	0.0085

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
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
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:004854514	Breast	IDC	response to steroid hormone	70/1434	339/18723	1.34e-14	4.23e-12	70
GO:007048214	Breast	IDC	response to oxygen levels	64/1434	347/18723	3.45e-11	5.57e-09	64
GO:003629314	Breast	IDC	response to decreased oxygen levels	60/1434	322/18723	9.26e-11	1.25e-08	60
GO:000166614	Breast	IDC	response to hypoxia	58/1434	307/18723	1.09e-10	1.38e-08	58
GO:001003814	Breast	IDC	response to metal ion	65/1434	373/18723	2.95e-10	3.42e-08	65
GO:003196013	Breast	IDC	response to corticosteroid	37/1434	167/18723	3.10e-09	2.63e-07	37
GO:000756511	Breast	IDC	female pregnancy	39/1434	193/18723	1.81e-08	1.27e-06	39
GO:005138413	Breast	IDC	response to glucocorticoid	32/1434	148/18723	6.52e-08	4.07e-06	32
GO:00447061	Breast	IDC	multi-multicellular organism process	41/1434	220/18723	8.58e-08	5.19e-06	41
GO:004873214	Breast	IDC	gland development	64/1434	436/18723	3.47e-07	1.74e-05	64
GO:003297014	Breast	IDC	regulation of actin filament-based process	56/1434	397/18723	6.37e-06	1.99e-04	56
GO:003235512	Breast	IDC	response to estradiol	27/1434	141/18723	7.87e-06	2.35e-04	27
GO:000941013	Breast	IDC	response to xenobiotic stimulus	62/1434	462/18723	1.05e-05	2.88e-04	62
GO:00601352	Breast	IDC	maternal process involved in female pregnancy	16/1434	62/18723	1.20e-05	3.17e-04	16
GO:003295614	Breast	IDC	regulation of actin cytoskeleton organization	48/1434	358/18723	1.03e-04	1.96e-03	48
GO:005087813	Breast	IDC	regulation of body fluid levels	50/1434	379/18723	1.12e-04	2.10e-03	50
GO:003087911	Breast	IDC	mammary gland development	23/1434	137/18723	2.87e-04	4.37e-03	23
GO:001004311	Breast	IDC	response to zinc ion	13/1434	58/18723	3.59e-04	5.18e-03	13
GO:005070812	Breast	IDC	regulation of protein secretion	36/1434	268/18723	6.93e-04	8.50e-03	36
GO:00466887	Breast	IDC	response to copper ion	10/1434	42/18723	1.03e-03	1.14e-02	10

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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

PAM

SNV

Missense_Mutation

novel

c.371N>T

p.Gly124Val

p.G124V

P19021

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

PAM

SNV

Missense_Mutation

rs752414913

c.2119C>T

p.Arg707Trp

p.R707W

P19021

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A8-A09C-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PAM

SNV

Missense_Mutation

rs771873156

c.2710N>A

p.Glu904Lys

p.E904K

P19021

protein_coding

tolerated(0.06)

benign(0.308)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

PAM

SNV

Missense_Mutation

c.239N>C

p.Arg80Pro

p.R80P

P19021

protein_coding

tolerated(0.95)

benign(0.007)

TCGA-BH-A0AW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

carboplatin

PAM

SNV

Missense_Mutation

c.2333A>G

p.His778Arg

p.H778R

P19021

protein_coding

tolerated(0.34)

benign(0)

TCGA-C8-A1HK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

PAM

SNV

Missense_Mutation

novel

c.2433N>C

p.Lys811Asn

p.K811N

P19021

protein_coding

tolerated(0.05)

benign(0.018)

TCGA-EW-A1PC-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

PAM

deletion

Frame_Shift_Del

novel

c.673delN

p.Asn226IlefsTer16

p.N226Ifs*16

P19021

protein_coding

TCGA-EW-A2FV-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

docetaxel

PAM

SNV

Missense_Mutation

novel

c.304C>T

p.His102Tyr

p.H102Y

P19021

protein_coding

deleterious(0)

possibly_damaging(0.899)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PAM

SNV

Missense_Mutation

c.1175N>T

p.Ser392Leu

p.S392L

P19021

protein_coding

tolerated(0.07)

probably_damaging(0.992)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

PAM

SNV

Missense_Mutation

c.2038N>T

p.Pro680Ser

p.P680S

P19021

protein_coding

deleterious(0.05)

possibly_damaging(0.632)

TCGA-AA-3510-01

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

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