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: HLA-C

Gene summary for HLA-C

Gene summary.

Gene information	Species	Human
	Gene symbol	HLA-C
	Gene ID	3107
	Gene name	major histocompatibility complex, class I, C
	Gene Alias	D6S204
	Cytomap	6p21.33
	Gene Type	protein-coding
	GO ID	GO:0002250
	UniProtAcc	O19617

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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
3107	HLA-C	GSM4909281	Human	Breast	IDC	2.08e-13	4.05e-01	0.21
3107	HLA-C	GSM4909285	Human	Breast	IDC	3.23e-14	-4.98e-01	0.21
3107	HLA-C	GSM4909286	Human	Breast	IDC	2.27e-75	-1.22e+00	0.1081
3107	HLA-C	GSM4909288	Human	Breast	IDC	8.80e-10	3.37e-01	0.0988
3107	HLA-C	GSM4909291	Human	Breast	IDC	2.03e-09	-5.13e-01	0.1753
3107	HLA-C	GSM4909294	Human	Breast	IDC	4.71e-10	-4.82e-01	0.2022
3107	HLA-C	GSM4909297	Human	Breast	IDC	3.67e-13	-4.29e-01	0.1517
3107	HLA-C	GSM4909298	Human	Breast	IDC	2.01e-07	-3.57e-01	0.1551
3107	HLA-C	GSM4909301	Human	Breast	IDC	9.67e-16	-5.82e-01	0.1577
3107	HLA-C	GSM4909304	Human	Breast	IDC	2.81e-20	-5.40e-01	0.1636
3107	HLA-C	GSM4909305	Human	Breast	IDC	1.01e-04	3.42e-01	0.0436
3107	HLA-C	GSM4909306	Human	Breast	IDC	4.27e-08	3.25e-01	0.1564
3107	HLA-C	GSM4909307	Human	Breast	IDC	2.19e-11	3.58e-01	0.1569
3107	HLA-C	GSM4909308	Human	Breast	IDC	3.94e-51	6.79e-01	0.158
3107	HLA-C	GSM4909311	Human	Breast	IDC	7.59e-40	-6.01e-01	0.1534
3107	HLA-C	GSM4909312	Human	Breast	IDC	2.34e-03	-2.30e-01	0.1552
3107	HLA-C	GSM4909315	Human	Breast	IDC	1.66e-21	-6.97e-01	0.21
3107	HLA-C	GSM4909316	Human	Breast	IDC	3.10e-09	-6.34e-01	0.21
3107	HLA-C	GSM4909319	Human	Breast	IDC	5.05e-42	1.28e-01	0.1563
3107	HLA-C	GSM4909320	Human	Breast	IDC	1.54e-16	-8.17e-01	0.1575

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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
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
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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:001988324	Oral cavity	EOLP	antigen processing and presentation of endogenous antigen	11/2218	26/18723	8.86e-05	1.04e-03	11
GO:001988232	Oral cavity	NEOLP	antigen processing and presentation	23/2005	106/18723	7.22e-04	5.93e-03	23
GO:001988332	Oral cavity	NEOLP	antigen processing and presentation of endogenous antigen	9/2005	26/18723	1.04e-03	7.95e-03	9
GO:001988532	Oral cavity	NEOLP	antigen processing and presentation of endogenous peptide antigen via MHC class I	7/2005	17/18723	1.18e-03	8.72e-03	7
GO:000248332	Oral cavity	NEOLP	antigen processing and presentation of endogenous peptide antigen	7/2005	19/18723	2.51e-03	1.59e-02	7
GO:000247431	Oral cavity	NEOLP	antigen processing and presentation of peptide antigen via MHC class I	8/2005	28/18723	7.44e-03	3.73e-02	8
GO:000248318	Prostate	BPH	antigen processing and presentation of endogenous peptide antigen	11/3107	19/18723	5.28e-05	5.42e-04	11
GO:001988218	Prostate	BPH	antigen processing and presentation	33/3107	106/18723	1.55e-04	1.36e-03	33
GO:000247414	Prostate	BPH	antigen processing and presentation of peptide antigen via MHC class I	13/3107	28/18723	2.22e-04	1.78e-03	13
GO:004800217	Prostate	BPH	antigen processing and presentation of peptide antigen	22/3107	62/18723	2.45e-04	1.94e-03	22
GO:001988317	Prostate	BPH	antigen processing and presentation of endogenous antigen	12/3107	26/18723	4.14e-04	3.01e-03	12
GO:001988515	Prostate	BPH	antigen processing and presentation of endogenous peptide antigen via MHC class I	9/3107	17/18723	6.38e-04	4.33e-03	9
GO:000248319	Prostate	Tumor	antigen processing and presentation of endogenous peptide antigen	12/3246	19/18723	1.09e-05	1.56e-04	12
GO:001988219	Prostate	Tumor	antigen processing and presentation	35/3246	106/18723	6.46e-05	6.99e-04	35
GO:000247415	Prostate	Tumor	antigen processing and presentation of peptide antigen via MHC class I	14/3246	28/18723	7.53e-05	7.86e-04	14
GO:001988318	Prostate	Tumor	antigen processing and presentation of endogenous antigen	13/3246	26/18723	1.36e-04	1.26e-03	13
GO:001988516	Prostate	Tumor	antigen processing and presentation of endogenous peptide antigen via MHC class I	10/3246	17/18723	1.43e-04	1.31e-03	10
GO:004800218	Prostate	Tumor	antigen processing and presentation of peptide antigen	23/3246	62/18723	1.62e-04	1.46e-03	23
GO:001988226	Skin	AK	antigen processing and presentation	22/1910	106/18723	9.13e-04	7.49e-03	22
GO:004800225	Skin	AK	antigen processing and presentation of peptide antigen	14/1910	62/18723	3.32e-03	2.03e-02	14

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0516718	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0461218	Breast	Precancer	Antigen processing and presentation	19/684	78/8465	9.61e-06	1.12e-04	8.62e-05	19
hsa0516918	Breast	Precancer	Epstein-Barr virus infection	35/684	202/8465	1.15e-05	1.26e-04	9.64e-05	35
hsa042189	Breast	Precancer	Cellular senescence	29/684	156/8465	1.66e-05	1.69e-04	1.30e-04	29
hsa0414518	Breast	Precancer	Phagosome	27/684	152/8465	7.37e-05	6.85e-04	5.25e-04	27
hsa0541618	Breast	Precancer	Viral myocarditis	14/684	60/8465	2.32e-04	1.98e-03	1.52e-03	14
hsa0516618	Breast	Precancer	Human T-cell leukemia virus 1 infection	33/684	222/8465	4.29e-04	3.31e-03	2.53e-03	33
hsa0516316	Breast	Precancer	Human cytomegalovirus infection	32/684	225/8465	1.13e-03	7.57e-03	5.80e-03	32
hsa052036	Breast	Precancer	Viral carcinogenesis	27/684	204/8465	7.19e-03	4.06e-02	3.11e-02	27
hsa0516719	Breast	Precancer	Kaposi sarcoma-associated herpesvirus infection	36/684	194/8465	1.68e-06	2.53e-05	1.94e-05	36
hsa0461219	Breast	Precancer	Antigen processing and presentation	19/684	78/8465	9.61e-06	1.12e-04	8.62e-05	19
hsa0516919	Breast	Precancer	Epstein-Barr virus infection	35/684	202/8465	1.15e-05	1.26e-04	9.64e-05	35
hsa0421814	Breast	Precancer	Cellular senescence	29/684	156/8465	1.66e-05	1.69e-04	1.30e-04	29
hsa0414519	Breast	Precancer	Phagosome	27/684	152/8465	7.37e-05	6.85e-04	5.25e-04	27
hsa0541619	Breast	Precancer	Viral myocarditis	14/684	60/8465	2.32e-04	1.98e-03	1.52e-03	14
hsa0516619	Breast	Precancer	Human T-cell leukemia virus 1 infection	33/684	222/8465	4.29e-04	3.31e-03	2.53e-03	33
hsa0516317	Breast	Precancer	Human cytomegalovirus infection	32/684	225/8465	1.13e-03	7.57e-03	5.80e-03	32
hsa0520312	Breast	Precancer	Viral carcinogenesis	27/684	204/8465	7.19e-03	4.06e-02	3.11e-02	27
hsa0516922	Breast	IDC	Epstein-Barr virus infection	45/867	202/8465	3.16e-07	6.05e-06	4.52e-06	45
hsa0461223	Breast	IDC	Antigen processing and presentation	24/867	78/8465	4.61e-07	8.33e-06	6.23e-06	24

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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
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Breast	DCIS
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Breast	DCIS
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Breast	Healthy
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Breast	Healthy
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Breast	IDC
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Breast	IDC
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Breast	Precancer
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Breast	Precancer
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Cervix	ADJ
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Cervix	ADJ
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Cervix	CC
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Cervix	CC
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Cervix	Healthy
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Cervix	Healthy
HLA-C	CD8A	HLA-C_CD8A	MHC-I	Cervix	Precancer
HLA-C	CD8B	HLA-C_CD8B	MHC-I	Cervix	Precancer
HLA-C	CD8A	HLA-C_CD8A	MHC-I	CRC	AD
HLA-C	CD8B	HLA-C_CD8B	MHC-I	CRC	AD
HLA-C	CD8A	HLA-C_CD8A	MHC-I	CRC	ADJ
HLA-C	CD8B	HLA-C_CD8B	MHC-I	CRC	ADJ

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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

HLA-C

SNV

Missense_Mutation

c.575N>G

p.Leu192Arg

p.L192R

P10321

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.994)

TCGA-AR-A24S-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

anastrozole

HLA-C

SNV

Missense_Mutation

novel

c.1008N>C

p.Lys336Asn

p.K336N

P10321

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.992)

TCGA-BH-A0B6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HLA-C

SNV

Missense_Mutation

c.376N>C

p.Asp126His

p.D126H

P10321

protein_coding

deleterious_low_confidence(0.01)

benign(0.028)

TCGA-MY-A5BD-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-C

SNV

Missense_Mutation

novel

c.493C>G

p.Gln165Glu

p.Q165E

P10321

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.984)

TCGA-UC-A7PF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HLA-C

SNV

Missense_Mutation

rs11547351

c.296G>C

p.Arg99Pro

p.R99P

P10321

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(0.98)

TCGA-VS-A9UR-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-C

SNV

Missense_Mutation

novel

c.349N>G

p.His117Asp

p.H117D

P10321

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.999)

TCGA-ZJ-AAXT-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unknown

HLA-C

SNV

Missense_Mutation

c.425A>C

p.Tyr142Ser

p.Y142S

P10321

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-A6-5665-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HLA-C

SNV

Missense_Mutation

c.773N>T

p.Arg258Met

p.R258M

P10321

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-AA-3672-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

HLA-C

SNV

Missense_Mutation

rs281860353

c.170N>C

p.Phe57Ser

p.F57S

P10321

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.999)

TCGA-AA-3947-01

Colorectum

colon adenocarcinoma

Female

<65

I/II

Unknown

HLA-C

SNV

Missense_Mutation

rs281860449

c.367N>C

p.Ser123Pro

p.S123P

P10321

protein_coding

deleterious_low_confidence(0.01)

benign(0.174)

TCGA-AD-5900-01

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
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		flucloxacillin	FLOXACILLIN	30664875
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		peginterferon alfa-2b
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		THERAPEUTIC TUMOR INFILTRATING LYMPHOCYTES		27959684
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		clavulanate	CLAVULANIC ACID	30664875
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		amoxicillin	AMOXICILLIN	30664875
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		Drugs For Treatment Of Tuberculosis		23153709
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		methotrexate	METHOTREXATE	28444425
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		ribavirin	RIBAVIRIN
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		ustekinumab	USTEKINUMAB	23521149
3107	HLA-C	CELL SURFACE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME, DRUG RESISTANCE		clozapine	CLOZAPINE	11266078

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