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: KRAS

Gene summary for KRAS

Gene summary.

Gene information	Species	Human
	Gene symbol	KRAS
	Gene ID	3845
	Gene name	KRAS proto-oncogene, GTPase
	Gene Alias	'C-K-RAS
	Cytomap	12p12.1
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	A0A024RAV5

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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
3845	KRAS	LZE2T	Human	Esophagus	ESCC	2.69e-07	1.22e+00	0.082
3845	KRAS	LZE4T	Human	Esophagus	ESCC	4.44e-17	4.47e-01	0.0811
3845	KRAS	LZE5T	Human	Esophagus	ESCC	3.77e-03	4.62e-01	0.0514
3845	KRAS	LZE7T	Human	Esophagus	ESCC	1.67e-10	6.29e-01	0.0667
3845	KRAS	LZE8T	Human	Esophagus	ESCC	1.07e-09	4.57e-01	0.067
3845	KRAS	LZE20T	Human	Esophagus	ESCC	1.03e-15	6.41e-01	0.0662
3845	KRAS	LZE22D1	Human	Esophagus	HGIN	2.44e-05	2.48e-01	0.0595
3845	KRAS	LZE22T	Human	Esophagus	ESCC	7.96e-07	4.85e-01	0.068
3845	KRAS	LZE24T	Human	Esophagus	ESCC	4.79e-29	7.53e-01	0.0596
3845	KRAS	LZE21T	Human	Esophagus	ESCC	1.51e-08	8.13e-01	0.0655
3845	KRAS	LZE6T	Human	Esophagus	ESCC	1.79e-04	1.95e-01	0.0845
3845	KRAS	P1T-E	Human	Esophagus	ESCC	2.58e-13	8.44e-01	0.0875
3845	KRAS	P2T-E	Human	Esophagus	ESCC	1.19e-63	1.32e+00	0.1177
3845	KRAS	P4T-E	Human	Esophagus	ESCC	2.00e-68	1.45e+00	0.1323
3845	KRAS	P5T-E	Human	Esophagus	ESCC	4.25e-53	1.04e+00	0.1327
3845	KRAS	P8T-E	Human	Esophagus	ESCC	4.78e-58	1.39e+00	0.0889
3845	KRAS	P9T-E	Human	Esophagus	ESCC	1.35e-32	8.17e-01	0.1131
3845	KRAS	P10T-E	Human	Esophagus	ESCC	4.35e-62	1.33e+00	0.116
3845	KRAS	P11T-E	Human	Esophagus	ESCC	1.49e-15	6.91e-01	0.1426
3845	KRAS	P12T-E	Human	Esophagus	ESCC	7.90e-76	1.51e+00	0.1122

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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
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
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:003164727	Esophagus	HGIN	regulation of protein stability	96/2587	298/18723	2.21e-16	5.76e-14	96
GO:007099727	Esophagus	HGIN	neuron death	81/2587	361/18723	5.01e-06	1.61e-04	81
GO:004854527	Esophagus	HGIN	response to steroid hormone	73/2587	339/18723	6.06e-05	1.40e-03	73
GO:004873225	Esophagus	HGIN	gland development	88/2587	436/18723	1.34e-04	2.71e-03	88
GO:190121424	Esophagus	HGIN	regulation of neuron death	68/2587	319/18723	1.46e-04	2.91e-03	68
GO:006100820	Esophagus	HGIN	hepaticobiliary system development	37/2587	150/18723	2.58e-04	4.53e-03	37
GO:000188920	Esophagus	HGIN	liver development	36/2587	147/18723	3.61e-04	5.68e-03	36
GO:000931418	Esophagus	HGIN	response to radiation	88/2587	456/18723	6.26e-04	8.65e-03	88
GO:005140219	Esophagus	HGIN	neuron apoptotic process	52/2587	246/18723	1.01e-03	1.26e-02	52
GO:004887227	Esophagus	HGIN	homeostasis of number of cells	54/2587	272/18723	3.50e-03	3.23e-02	54
GO:190121510	Esophagus	HGIN	negative regulation of neuron death	43/2587	208/18723	4.04e-03	3.64e-02	43
GO:00094165	Esophagus	HGIN	response to light stimulus	61/2587	320/18723	5.20e-03	4.30e-02	61
GO:0031647111	Esophagus	ESCC	regulation of protein stability	223/8552	298/18723	5.76e-25	1.52e-22	223
GO:0048732111	Esophagus	ESCC	gland development	269/8552	436/18723	7.81e-12	2.95e-10	269
GO:007190016	Esophagus	ESCC	regulation of protein serine/threonine kinase activity	227/8552	359/18723	1.12e-11	4.10e-10	227
GO:000931419	Esophagus	ESCC	response to radiation	277/8552	456/18723	4.42e-11	1.43e-09	277
GO:0070997111	Esophagus	ESCC	neuron death	216/8552	361/18723	3.49e-08	6.45e-07	216
GO:0048545111	Esophagus	ESCC	response to steroid hormone	204/8552	339/18723	4.47e-08	8.11e-07	204
GO:000726510	Esophagus	ESCC	Ras protein signal transduction	201/8552	337/18723	1.44e-07	2.30e-06	201
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
hsa0520839	Esophagus	HGIN	Chemical carcinogenesis - reactive oxygen species	92/1383	223/8465	2.41e-19	9.83e-18	7.80e-18	92
hsa0502230	Esophagus	HGIN	Pathways of neurodegeneration - multiple diseases	153/1383	476/8465	1.22e-18	4.41e-17	3.50e-17	153
hsa0501030	Esophagus	HGIN	Alzheimer disease	130/1383	384/8465	5.26e-18	1.71e-16	1.36e-16	130
hsa0471439	Esophagus	HGIN	Thermogenesis	91/1383	232/8465	1.97e-17	5.36e-16	4.25e-16	91
hsa0516730	Esophagus	HGIN	Kaposi sarcoma-associated herpesvirus infection	51/1383	194/8465	2.46e-04	2.69e-03	2.14e-03	51
hsa052039	Esophagus	HGIN	Viral carcinogenesis	53/1383	204/8465	2.58e-04	2.71e-03	2.15e-03	53
hsa0421828	Esophagus	HGIN	Cellular senescence	42/1383	156/8465	4.94e-04	5.03e-03	4.00e-03	42
hsa0413730	Esophagus	HGIN	Mitophagy - animal	23/1383	72/8465	7.69e-04	7.59e-03	6.03e-03	23
hsa0421020	Esophagus	HGIN	Apoptosis	36/1383	136/8465	1.67e-03	1.52e-02	1.20e-02	36
hsa0517029	Esophagus	HGIN	Human immunodeficiency virus 1 infection	51/1383	212/8465	2.16e-03	1.90e-02	1.51e-02	51
hsa0541739	Esophagus	HGIN	Lipid and atherosclerosis	51/1383	215/8465	2.95e-03	2.41e-02	1.91e-02	51
hsa0521620	Esophagus	HGIN	Thyroid cancer	13/1383	37/8465	4.20e-03	3.04e-02	2.41e-02	13
hsa0516639	Esophagus	HGIN	Human T-cell leukemia virus 1 infection	51/1383	222/8465	5.84e-03	4.05e-02	3.22e-02	51
hsa0516330	Esophagus	HGIN	Human cytomegalovirus infection	51/1383	225/8465	7.67e-03	4.63e-02	3.68e-02	51
hsa0520528	Esophagus	HGIN	Proteoglycans in cancer	47/1383	205/8465	8.23e-03	4.71e-02	3.74e-02	47
hsa05208115	Esophagus	HGIN	Chemical carcinogenesis - reactive oxygen species	92/1383	223/8465	2.41e-19	9.83e-18	7.80e-18	92
hsa05022113	Esophagus	HGIN	Pathways of neurodegeneration - multiple diseases	153/1383	476/8465	1.22e-18	4.41e-17	3.50e-17	153
hsa05010113	Esophagus	HGIN	Alzheimer disease	130/1383	384/8465	5.26e-18	1.71e-16	1.36e-16	130
hsa04714114	Esophagus	HGIN	Thermogenesis	91/1383	232/8465	1.97e-17	5.36e-16	4.25e-16	91
hsa05167114	Esophagus	HGIN	Kaposi sarcoma-associated herpesvirus infection	51/1383	194/8465	2.46e-04	2.69e-03	2.14e-03	51

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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

KRAS

SNV

Missense_Mutation

c.274N>T

p.Asp92Tyr

p.D92Y

P01116

protein_coding

deleterious(0)

probably_damaging(0.963)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

KRAS

SNV

Missense_Mutation

rs121913530

c.34N>T

p.Gly12Cys

p.G12C

P01116

protein_coding

deleterious(0.04)

probably_damaging(0.991)

TCGA-AR-A1AL-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

anastrozole

KRAS

SNV

Missense_Mutation

rs121913529

c.35N>T

p.Gly12Val

p.G12V

P01116

protein_coding

deleterious(0)

probably_damaging(0.972)

TCGA-AR-A1AS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

KRAS

SNV

Missense_Mutation

rs121913529

c.35N>T

p.Gly12Val

p.G12V

P01116

protein_coding

deleterious(0)

probably_damaging(0.972)

TCGA-C8-A131-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Chemotherapy

5-fluorouracil

KRAS

SNV

Missense_Mutation

rs121913529

c.35N>A

p.Gly12Asp

p.G12D

P01116

protein_coding

deleterious(0)

benign(0.303)

TCGA-E2-A1IF-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

arimidex

KRAS

SNV

Missense_Mutation

rs121913529

c.35N>T

p.Gly12Val

p.G12V

P01116

protein_coding

deleterious(0)

probably_damaging(0.972)

TCGA-E9-A1NG-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

letrozole

KRAS

SNV

Missense_Mutation

rs121913529

c.35N>A

p.Gly12Asp

p.G12D

P01116

protein_coding

deleterious(0)

benign(0.303)

TCGA-C5-A1ME-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

KRAS

SNV

Missense_Mutation

rs121913527

c.436N>A

p.Ala146Thr

p.A146T

P01116

protein_coding

deleterious(0.03)

possibly_damaging(0.844)

TCGA-C5-A2M1-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

KRAS

SNV

Missense_Mutation

rs112445441

c.38N>A

p.Gly13Asp

p.G13D

P01116

protein_coding

deleterious(0.04)

benign(0.44)

TCGA-C5-A3HF-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

KRAS

SNV

Missense_Mutation

rs104894365

c.40N>A

p.Val14Ile

p.V14I

P01116

protein_coding

deleterious(0)

probably_damaging(0.959)

TCGA-C5-A905-01

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
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		lenalidomide	LENALIDOMIDE	27458141
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		GA201	IMGATUZUMAB	23209031
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		3144		28235199
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		Cobimetinib	COBIMETINIB
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		BKM120	BUPARLISIB	26715098,22159814,26098748,24576621
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		AZD4785	AZD-4785
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		Gefitinib	GEFITINIB	15696205,27338794,25870145
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		CGM097	CGM-097	27659046
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		IRX4204
3845	KRAS	CLINICALLY ACTIONABLE, DRUG RESISTANCE, ENZYME		MK2206	MK-2206	26676756,25931518,26725216,22025163,27480147

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