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-G

Gene summary for HLA-G

Gene summary.

Gene information	Species	Human
	Gene symbol	HLA-G
	Gene ID	3135
	Gene name	major histocompatibility complex, class I, G
	Gene Alias	MHC-G
	Cytomap	6p22.1
	Gene Type	protein-coding
	GO ID	GO:0001525
	UniProtAcc	P17693

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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
3135	HLA-G	sample1	Human	Cervix	CC	8.53e-38	8.96e-01	0.0959
3135	HLA-G	T1	Human	Cervix	CC	3.24e-45	7.60e-01	0.0918
3135	HLA-G	P1T-E	Human	Esophagus	ESCC	1.08e-09	7.81e-01	0.0875
3135	HLA-G	P2T-E	Human	Esophagus	ESCC	5.97e-19	2.99e-01	0.1177
3135	HLA-G	P11T-E	Human	Esophagus	ESCC	1.22e-06	2.58e-01	0.1426
3135	HLA-G	P17T-E	Human	Esophagus	ESCC	1.21e-04	2.92e-01	0.1278
3135	HLA-G	P21T-E	Human	Esophagus	ESCC	4.15e-02	8.81e-02	0.1617
3135	HLA-G	P37T-E	Human	Esophagus	ESCC	9.10e-10	1.62e-01	0.1371
3135	HLA-G	P44T-E	Human	Esophagus	ESCC	6.80e-04	1.91e-01	0.1096
3135	HLA-G	P49T-E	Human	Esophagus	ESCC	2.04e-02	2.09e-01	0.1768
3135	HLA-G	P62T-E	Human	Esophagus	ESCC	1.01e-05	9.33e-02	0.1302
3135	HLA-G	P75T-E	Human	Esophagus	ESCC	6.52e-11	2.38e-01	0.1125
3135	HLA-G	P79T-E	Human	Esophagus	ESCC	4.89e-06	1.18e-01	0.1154
3135	HLA-G	P80T-E	Human	Esophagus	ESCC	5.23e-27	8.89e-01	0.155
3135	HLA-G	P83T-E	Human	Esophagus	ESCC	1.11e-21	5.59e-01	0.1738
3135	HLA-G	P94T-E	Human	Esophagus	ESCC	1.64e-05	8.55e-01	0.0879
3135	HLA-G	P104T-E	Human	Esophagus	ESCC	4.70e-09	1.64e+00	0.0931

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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
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias

∗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:0002507	Cervix	CC	tolerance induction	9/2311	28/18723	5.02e-03	2.98e-02	9
GO:0045589	Cervix	CC	regulation of regulatory T cell differentiation	9/2311	28/18723	5.02e-03	2.98e-02	9
GO:0002699	Cervix	CC	positive regulation of immune effector process	43/2311	235/18723	5.13e-03	3.02e-02	43
GO:0050672	Cervix	CC	negative regulation of lymphocyte proliferation	19/2311	83/18723	5.25e-03	3.08e-02	19
GO:0002819	Cervix	CC	regulation of adaptive immune response	35/2311	183/18723	5.38e-03	3.11e-02	35
GO:0002716	Cervix	CC	negative regulation of natural killer cell mediated immunity	7/2311	19/18723	5.65e-03	3.25e-02	7
GO:0032945	Cervix	CC	negative regulation of mononuclear cell proliferation	19/2311	84/18723	6.02e-03	3.43e-02	19
GO:00019147	Cervix	CC	regulation of T cell mediated cytotoxicity	11/2311	39/18723	6.13e-03	3.48e-02	11
GO:00300981	Cervix	CC	lymphocyte differentiation	63/2311	374/18723	6.21e-03	3.52e-02	63
GO:0001911	Cervix	CC	negative regulation of leukocyte mediated cytotoxicity	8/2311	24/18723	6.29e-03	3.54e-02	8
GO:0042130	Cervix	CC	negative regulation of T cell proliferation	16/2311	67/18723	6.51e-03	3.61e-02	16
GO:00109482	Cervix	CC	negative regulation of cell cycle process	51/2311	294/18723	7.35e-03	3.94e-02	51
GO:0002822	Cervix	CC	regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	32/2311	168/18723	8.00e-03	4.18e-02	32
GO:0045089	Cervix	CC	positive regulation of innate immune response	26/2311	131/18723	9.33e-03	4.66e-02	26
GO:19021073	Cervix	CC	positive regulation of leukocyte differentiation	30/2311	157/18723	9.56e-03	4.73e-02	30
GO:19037083	Cervix	CC	positive regulation of hemopoiesis	30/2311	157/18723	9.56e-03	4.73e-02	30
GO:0045066	Cervix	CC	regulatory T cell differentiation	9/2311	31/18723	1.04e-02	4.97e-02	9
GO:00457865	Esophagus	ESCC	negative regulation of cell cycle	236/8552	385/18723	3.62e-10	9.93e-09	236
GO:004578527	Esophagus	ESCC	positive regulation of cell adhesion	255/8552	437/18723	5.07e-08	9.11e-07	255
GO:000756820	Esophagus	ESCC	aging	201/8552	339/18723	2.64e-07	3.94e-06	201

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0461220	Cervix	CC	Antigen processing and presentation	34/1267	78/8465	1.06e-09	2.14e-08	1.26e-08	34
hsa0516720	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516318	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa0414520	Cervix	CC	Phagosome	47/1267	152/8465	3.95e-07	4.26e-06	2.52e-06	47
hsa0414418	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0517016	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa04612110	Cervix	CC	Antigen processing and presentation	34/1267	78/8465	1.06e-09	2.14e-08	1.26e-08	34
hsa05167110	Cervix	CC	Kaposi sarcoma-associated herpesvirus infection	60/1267	194/8465	9.74e-09	1.58e-07	9.33e-08	60
hsa0516319	Cervix	CC	Human cytomegalovirus infection	65/1267	225/8465	4.59e-08	6.47e-07	3.83e-07	65
hsa04145110	Cervix	CC	Phagosome	47/1267	152/8465	3.95e-07	4.26e-06	2.52e-06	47
hsa0414419	Cervix	CC	Endocytosis	64/1267	251/8465	6.97e-06	6.10e-05	3.61e-05	64
hsa0517017	Cervix	CC	Human immunodeficiency virus 1 infection	55/1267	212/8465	1.80e-05	1.42e-04	8.40e-05	55
hsa04144210	Esophagus	ESCC	Endocytosis	186/4205	251/8465	9.74e-16	4.66e-14	2.39e-14	186
hsa05166211	Esophagus	ESCC	Human T-cell leukemia virus 1 infection	164/4205	222/8465	8.13e-14	2.09e-12	1.07e-12	164
hsa05169210	Esophagus	ESCC	Epstein-Barr virus infection	151/4205	202/8465	1.55e-13	3.45e-12	1.77e-12	151
hsa0421829	Esophagus	ESCC	Cellular senescence	119/4205	156/8465	5.89e-12	9.40e-11	4.81e-11	119
hsa05170210	Esophagus	ESCC	Human immunodeficiency virus 1 infection	147/4205	212/8465	3.37e-09	3.53e-08	1.81e-08	147
hsa05167211	Esophagus	ESCC	Kaposi sarcoma-associated herpesvirus infection	136/4205	194/8465	4.28e-09	4.22e-08	2.16e-08	136
hsa0516510	Esophagus	ESCC	Human papillomavirus infection	215/4205	331/8465	7.86e-09	7.12e-08	3.65e-08	215
hsa05163210	Esophagus	ESCC	Human cytomegalovirus infection	148/4205	225/8465	5.73e-07	4.00e-06	2.05e-06	148

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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

HLA-G

SNV

Missense_Mutation

c.648C>A

p.His216Gln

p.H216Q

P17693

protein_coding

deleterious_low_confidence(0)

benign(0.031)

TCGA-A8-A07L-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

HLA-G

SNV

Missense_Mutation

rs767964419

c.593A>G

p.Asn198Ser

p.N198S

P17693

protein_coding

deleterious_low_confidence(0.04)

probably_damaging(0.982)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HLA-G

SNV

Missense_Mutation

novel

c.733N>A

p.Gly245Arg

p.G245R

P17693

protein_coding

deleterious_low_confidence(0.02)

probably_damaging(1)

TCGA-AN-A0XW-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Unknown

HLA-G

insertion

Nonsense_Mutation

novel

c.68_69insCTTAAGAGCTTTGTGAGTCCTGTT

p.Trp23delinsCysLeuArgAlaLeuTerValLeuLeu

p.W23delinsCLRAL*VLL

P17693

protein_coding

TCGA-A8-A07I-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

HLA-G

SNV

Missense_Mutation

novel

c.532N>A

p.Glu178Lys

p.E178K

P17693

protein_coding

deleterious_low_confidence(0.03)

probably_damaging(0.997)

TCGA-DS-A7WH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HLA-G

SNV

Missense_Mutation

c.256N>C

p.Glu86Gln

p.E86Q

P17693

protein_coding

tolerated_low_confidence(0.32)

benign(0.006)

TCGA-IR-A3LF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HLA-G

SNV

Missense_Mutation

c.258N>T

p.Glu86Asp

p.E86D

P17693

protein_coding

tolerated_low_confidence(0.09)

benign(0.027)

TCGA-AA-3815-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HLA-G

SNV

Missense_Mutation

c.910N>T

p.Pro304Ser

p.P304S

P17693

protein_coding

tolerated_low_confidence(0.66)

possibly_damaging(0.506)

TCGA-AA-3966-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HLA-G

SNV

Missense_Mutation

c.391N>A

p.Gly131Arg

p.G131R

P17693

protein_coding

deleterious_low_confidence(0.04)

probably_damaging(0.997)

TCGA-AD-6889-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Chemotherapy

xeloda

HLA-G

SNV

Missense_Mutation

rs780775783

c.316N>T

p.Arg106Cys

p.R106C

P17693

protein_coding

deleterious_low_confidence(0.01)

probably_damaging(0.925)

TCGA-AY-6197-01

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
3135	HLA-G	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME		hmg coa reductase inhibitors
3135	HLA-G	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME		fluorouracil	FLUOROURACIL
3135	HLA-G	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME		methotrexate	METHOTREXATE	16906016,19088262
3135	HLA-G	EXTERNAL SIDE OF PLASMA MEMBRANE, CLINICALLY ACTIONABLE, DRUGGABLE GENOME		capecitabine	CAPECITABINE

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