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: RIPK1

Gene summary for RIPK1

Gene summary.

Gene information	Species	Human
	Gene symbol	RIPK1
	Gene ID	8737
	Gene name	receptor interacting serine/threonine kinase 1
	Gene Alias	AIEFL
	Cytomap	6p25.2
	Gene Type	protein-coding
	GO ID	GO:0000165
	UniProtAcc	A0A024QZU0

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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
8737	RIPK1	AEH-subject1	Human	Endometrium	AEH	2.98e-26	7.30e-01	-0.3059
8737	RIPK1	AEH-subject2	Human	Endometrium	AEH	1.11e-14	5.70e-01	-0.2525
8737	RIPK1	AEH-subject3	Human	Endometrium	AEH	1.10e-19	6.30e-01	-0.2576
8737	RIPK1	EEC-subject1	Human	Endometrium	EEC	2.16e-04	3.11e-01	-0.2682
8737	RIPK1	EEC-subject2	Human	Endometrium	EEC	1.24e-04	3.34e-01	-0.2607
8737	RIPK1	EEC-subject4	Human	Endometrium	EEC	1.59e-02	1.86e-01	-0.2571
8737	RIPK1	LZE4T	Human	Esophagus	ESCC	1.45e-05	8.73e-02	0.0811
8737	RIPK1	LZE7T	Human	Esophagus	ESCC	3.35e-02	1.61e-01	0.0667
8737	RIPK1	LZE20T	Human	Esophagus	ESCC	4.60e-03	5.91e-02	0.0662
8737	RIPK1	LZE24T	Human	Esophagus	ESCC	5.27e-10	1.27e-01	0.0596
8737	RIPK1	P1T-E	Human	Esophagus	ESCC	2.87e-11	3.10e-01	0.0875
8737	RIPK1	P2T-E	Human	Esophagus	ESCC	5.07e-19	3.07e-01	0.1177
8737	RIPK1	P4T-E	Human	Esophagus	ESCC	2.77e-12	1.43e-01	0.1323
8737	RIPK1	P5T-E	Human	Esophagus	ESCC	1.12e-12	1.48e-02	0.1327
8737	RIPK1	P8T-E	Human	Esophagus	ESCC	2.98e-13	1.74e-01	0.0889
8737	RIPK1	P9T-E	Human	Esophagus	ESCC	1.14e-06	2.03e-01	0.1131
8737	RIPK1	P10T-E	Human	Esophagus	ESCC	3.54e-03	2.44e-02	0.116
8737	RIPK1	P11T-E	Human	Esophagus	ESCC	3.79e-12	4.09e-01	0.1426
8737	RIPK1	P12T-E	Human	Esophagus	ESCC	5.43e-08	1.56e-01	0.1122
8737	RIPK1	P15T-E	Human	Esophagus	ESCC	2.10e-08	1.42e-01	0.1149

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
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
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:00328724	Stomach	GC	regulation of stress-activated MAPK cascade	26/1159	192/18723	1.40e-04	2.59e-03	26
GO:19032016	Stomach	GC	regulation of oxidative stress-induced cell death	14/1159	74/18723	1.55e-04	2.81e-03	14
GO:00703024	Stomach	GC	regulation of stress-activated protein kinase signaling cascade	26/1159	195/18723	1.81e-04	3.13e-03	26
GO:00346146	Stomach	GC	cellular response to reactive oxygen species	22/1159	155/18723	2.27e-04	3.83e-03	22
GO:20012376	Stomach	GC	negative regulation of extrinsic apoptotic signaling pathway	16/1159	97/18723	2.87e-04	4.66e-03	16
GO:00310985	Stomach	GC	stress-activated protein kinase signaling cascade	30/1159	247/18723	3.20e-04	5.10e-03	30
GO:19004076	Stomach	GC	regulation of cellular response to oxidative stress	15/1159	89/18723	3.46e-04	5.47e-03	15
GO:00431224	Stomach	GC	regulation of I-kappaB kinase/NF-kappaB signaling	30/1159	249/18723	3.67e-04	5.70e-03	30
GO:00514035	Stomach	GC	stress-activated MAPK cascade	29/1159	239/18723	4.06e-04	6.18e-03	29
GO:00364736	Stomach	GC	cell death in response to oxidative stress	15/1159	95/18723	7.08e-04	9.39e-03	15
GO:19028826	Stomach	GC	regulation of response to oxidative stress	15/1159	98/18723	9.86e-04	1.18e-02	15
GO:1902105	Stomach	GC	regulation of leukocyte differentiation	31/1159	279/18723	1.17e-03	1.34e-02	31
GO:00072493	Stomach	GC	I-kappaB kinase/NF-kappaB signaling	31/1159	281/18723	1.31e-03	1.46e-02	31
GO:00300996	Stomach	GC	myeloid cell differentiation	39/1159	381/18723	1.42e-03	1.55e-02	39
GO:0045639	Stomach	GC	positive regulation of myeloid cell differentiation	15/1159	103/18723	1.65e-03	1.75e-02	15
GO:0032640	Stomach	GC	tumor necrosis factor production	22/1159	181/18723	1.88e-03	1.94e-02	22
GO:0032680	Stomach	GC	regulation of tumor necrosis factor production	22/1159	181/18723	1.88e-03	1.94e-02	22
GO:0001819	Stomach	GC	positive regulation of cytokine production	45/1159	467/18723	2.17e-03	2.16e-02	45
GO:2001238	Stomach	GC	positive regulation of extrinsic apoptotic signaling pathway	9/1159	48/18723	2.43e-03	2.30e-02	9
GO:00431233	Stomach	GC	positive regulation of I-kappaB kinase/NF-kappaB signaling	22/1159	186/18723	2.66e-03	2.46e-02	22

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0513126	Endometrium	AEH	Shigellosis	78/1197	247/8465	9.23e-13	2.00e-11	1.46e-11	78
hsa0513226	Endometrium	AEH	Salmonella infection	71/1197	249/8465	1.69e-09	3.44e-08	2.52e-08	71
hsa0513026	Endometrium	AEH	Pathogenic Escherichia coli infection	50/1197	197/8465	1.72e-05	1.86e-04	1.36e-04	50
hsa0516924	Endometrium	AEH	Epstein-Barr virus infection	42/1197	202/8465	5.72e-03	3.05e-02	2.23e-02	42
hsa0421010	Endometrium	AEH	Apoptosis	30/1197	136/8465	7.72e-03	4.05e-02	2.96e-02	30
hsa0517018	Endometrium	AEH	Human immunodeficiency virus 1 infection	43/1197	212/8465	8.19e-03	4.22e-02	3.09e-02	43
hsa0516320	Endometrium	AEH	Human cytomegalovirus infection	45/1197	225/8465	8.98e-03	4.56e-02	3.34e-02	45
hsa05131111	Endometrium	AEH	Shigellosis	78/1197	247/8465	9.23e-13	2.00e-11	1.46e-11	78
hsa05132112	Endometrium	AEH	Salmonella infection	71/1197	249/8465	1.69e-09	3.44e-08	2.52e-08	71
hsa05130112	Endometrium	AEH	Pathogenic Escherichia coli infection	50/1197	197/8465	1.72e-05	1.86e-04	1.36e-04	50
hsa05169111	Endometrium	AEH	Epstein-Barr virus infection	42/1197	202/8465	5.72e-03	3.05e-02	2.23e-02	42
hsa0421015	Endometrium	AEH	Apoptosis	30/1197	136/8465	7.72e-03	4.05e-02	2.96e-02	30
hsa0517019	Endometrium	AEH	Human immunodeficiency virus 1 infection	43/1197	212/8465	8.19e-03	4.22e-02	3.09e-02	43
hsa05163110	Endometrium	AEH	Human cytomegalovirus infection	45/1197	225/8465	8.98e-03	4.56e-02	3.34e-02	45
hsa0513127	Endometrium	EEC	Shigellosis	79/1237	247/8465	1.80e-12	3.95e-11	2.95e-11	79
hsa0513227	Endometrium	EEC	Salmonella infection	71/1237	249/8465	7.11e-09	1.30e-07	9.69e-08	71
hsa0513027	Endometrium	EEC	Pathogenic Escherichia coli infection	51/1237	197/8465	1.98e-05	2.28e-04	1.70e-04	51
hsa0516925	Endometrium	EEC	Epstein-Barr virus infection	47/1237	202/8465	6.17e-04	4.41e-03	3.29e-03	47
hsa0516325	Endometrium	EEC	Human cytomegalovirus infection	47/1237	225/8465	6.17e-03	3.12e-02	2.33e-02	47
hsa046687	Endometrium	EEC	TNF signaling pathway	27/1237	114/8465	6.47e-03	3.22e-02	2.40e-02	27

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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

RIPK1

SNV

Missense_Mutation

c.1237N>T

p.Arg413Cys

p.R413C

Q13546

protein_coding

deleterious(0)

probably_damaging(0.925)

TCGA-A8-A09Z-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

RIPK1

SNV

Missense_Mutation

c.919G>C

p.Glu307Gln

p.E307Q

Q13546

protein_coding

tolerated(0.52)

benign(0.003)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

RIPK1

SNV

Missense_Mutation

c.808N>T

p.Ala270Ser

p.A270S

Q13546

protein_coding

tolerated(0.38)

benign(0.173)

TCGA-BH-A0HP-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

doxorubicin

RIPK1

SNV

Missense_Mutation

novel

c.1281N>C

p.Glu427Asp

p.E427D

Q13546

protein_coding

tolerated(0.41)

benign(0)

TCGA-C8-A132-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

RIPK1

SNV

Missense_Mutation

c.439N>A

p.Asp147Asn

p.D147N

Q13546

protein_coding

deleterious(0.03)

probably_damaging(0.987)

TCGA-E2-A152-01

Breast

breast invasive carcinoma

Female

<65

I/II

Targeted Molecular therapy

trastuzumab

RIPK1

insertion

Frame_Shift_Ins

novel

c.1407_1408insGGTCCTGTGGAGGAGTCCTGGTTTGCTCCTTCCCTGG

p.Ser470GlyfsTer42

p.S470Gfs*42

Q13546

protein_coding

TCGA-A8-A092-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

paclitaxel

RIPK1

SNV

Missense_Mutation

c.324N>C

p.Met108Ile

p.M108I

Q13546

protein_coding

tolerated(0.62)

benign(0)

TCGA-JW-A5VL-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

RIPK1

SNV

Missense_Mutation

c.1297G>A

p.Glu433Lys

p.E433K

Q13546

protein_coding

tolerated(0.79)

benign(0.021)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

RIPK1

SNV

Missense_Mutation

rs748885856

c.1571N>T

p.Pro524Leu

p.P524L

Q13546

protein_coding

tolerated(0.12)

benign(0)

TCGA-VS-A953-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

RIPK1

deletion

Frame_Shift_Del

novel

c.1302delN

p.Gly436AlafsTer76

p.G436Afs*76

Q13546

protein_coding

TCGA-MA-AA42-01

Cervix

cervical & endocervical cancer

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
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	340590273
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	249565867
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	178102513	PONATINIB
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	384403680
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		RESVERATROL	RESVERATROL	16116226
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	336446940
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	354702223	NECROSTATIN
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME		GSK2982772
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	354702224
8737	RIPK1	KINASE, SERINE THREONINE KINASE, DRUGGABLE GENOME, ENZYME	inhibitor	354702222

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