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: SHMT1

Gene summary for SHMT1

Gene summary.

Gene information	Species	Human
	Gene symbol	SHMT1
	Gene ID	6470
	Gene name	serine hydroxymethyltransferase 1
	Gene Alias	CSHMT
	Cytomap	17p11.2
	Gene Type	protein-coding
	GO ID	GO:0006082
	UniProtAcc	P34896

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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
6470	SHMT1	LZE4T	Human	Esophagus	ESCC	1.54e-05	2.41e-02	0.0811
6470	SHMT1	LZE22D1	Human	Esophagus	HGIN	1.29e-02	5.07e-02	0.0595
6470	SHMT1	LZE24T	Human	Esophagus	ESCC	8.21e-16	2.64e-01	0.0596
6470	SHMT1	LZE6T	Human	Esophagus	ESCC	7.45e-07	1.13e-01	0.0845
6470	SHMT1	P2T-E	Human	Esophagus	ESCC	2.14e-17	4.56e-01	0.1177
6470	SHMT1	P4T-E	Human	Esophagus	ESCC	8.69e-20	5.32e-01	0.1323
6470	SHMT1	P5T-E	Human	Esophagus	ESCC	1.16e-10	3.34e-03	0.1327
6470	SHMT1	P8T-E	Human	Esophagus	ESCC	5.18e-29	6.69e-01	0.0889
6470	SHMT1	P9T-E	Human	Esophagus	ESCC	4.21e-03	6.55e-02	0.1131
6470	SHMT1	P10T-E	Human	Esophagus	ESCC	1.50e-08	2.35e-01	0.116
6470	SHMT1	P11T-E	Human	Esophagus	ESCC	6.64e-04	3.58e-01	0.1426
6470	SHMT1	P12T-E	Human	Esophagus	ESCC	4.97e-25	3.02e-01	0.1122
6470	SHMT1	P15T-E	Human	Esophagus	ESCC	1.80e-04	1.78e-01	0.1149
6470	SHMT1	P16T-E	Human	Esophagus	ESCC	4.66e-32	7.05e-01	0.1153
6470	SHMT1	P19T-E	Human	Esophagus	ESCC	5.76e-03	4.55e-01	0.1662
6470	SHMT1	P20T-E	Human	Esophagus	ESCC	3.44e-11	2.11e-01	0.1124
6470	SHMT1	P21T-E	Human	Esophagus	ESCC	1.11e-28	6.52e-01	0.1617
6470	SHMT1	P22T-E	Human	Esophagus	ESCC	1.86e-11	2.10e-01	0.1236
6470	SHMT1	P23T-E	Human	Esophagus	ESCC	9.66e-03	1.75e-01	0.108
6470	SHMT1	P24T-E	Human	Esophagus	ESCC	1.79e-09	1.46e-01	0.1287

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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:000641727	Esophagus	HGIN	regulation of translation	139/2587	468/18723	1.46e-19	7.98e-17	139
GO:00342496	Esophagus	HGIN	negative regulation of cellular amide metabolic process	66/2587	273/18723	2.74e-06	9.60e-05	66
GO:00171486	Esophagus	HGIN	negative regulation of translation	59/2587	245/18723	1.03e-05	2.96e-04	59
GO:007252216	Esophagus	HGIN	purine-containing compound biosynthetic process	47/2587	200/18723	1.46e-04	2.91e-03	47
GO:007252125	Esophagus	HGIN	purine-containing compound metabolic process	78/2587	416/18723	2.78e-03	2.73e-02	78
GO:19908308	Esophagus	HGIN	cellular response to leukemia inhibitory factor	23/2587	94/18723	3.92e-03	3.54e-02	23
GO:19908238	Esophagus	HGIN	response to leukemia inhibitory factor	23/2587	95/18723	4.51e-03	3.93e-02	23
GO:0006417111	Esophagus	ESCC	regulation of translation	304/8552	468/18723	1.53e-17	1.33e-15	304
GO:0072521111	Esophagus	ESCC	purine-containing compound metabolic process	238/8552	416/18723	1.20e-06	1.49e-05	238
GO:007252217	Esophagus	ESCC	purine-containing compound biosynthetic process	120/8552	200/18723	3.02e-05	2.51e-04	120
GO:00065757	Esophagus	ESCC	cellular modified amino acid metabolic process	112/8552	188/18723	8.31e-05	6.06e-04	112
GO:00086525	Esophagus	ESCC	cellular amino acid biosynthetic process	51/8552	76/18723	1.30e-04	8.88e-04	51
GO:00067671	Esophagus	ESCC	water-soluble vitamin metabolic process	41/8552	59/18723	1.84e-04	1.17e-03	41
GO:00463948	Esophagus	ESCC	carboxylic acid biosynthetic process	175/8552	314/18723	1.98e-04	1.26e-03	175
GO:00067661	Esophagus	ESCC	vitamin metabolic process	67/8552	106/18723	2.03e-04	1.28e-03	67
GO:00160538	Esophagus	ESCC	organic acid biosynthetic process	175/8552	316/18723	3.04e-04	1.82e-03	175
GO:00091133	Esophagus	ESCC	purine nucleobase biosynthetic process	10/8552	10/18723	3.94e-04	2.26e-03	10
GO:00425584	Esophagus	ESCC	pteridine-containing compound metabolic process	25/8552	33/18723	4.30e-04	2.43e-03	25
GO:199082316	Esophagus	ESCC	response to leukemia inhibitory factor	60/8552	95/18723	4.41e-04	2.48e-03	60
GO:19016075	Esophagus	ESCC	alpha-amino acid biosynthetic process	45/8552	68/18723	5.13e-04	2.84e-03	45

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0120016	Esophagus	HGIN	Carbon metabolism	31/1383	115/8465	2.51e-03	2.10e-02	1.67e-02	31
hsa012306	Esophagus	HGIN	Biosynthesis of amino acids	21/1383	75/8465	7.38e-03	4.63e-02	3.68e-02	21
hsa0120017	Esophagus	HGIN	Carbon metabolism	31/1383	115/8465	2.51e-03	2.10e-02	1.67e-02	31
hsa0123013	Esophagus	HGIN	Biosynthesis of amino acids	21/1383	75/8465	7.38e-03	4.63e-02	3.68e-02	21
hsa0120023	Esophagus	ESCC	Carbon metabolism	79/4205	115/8465	2.50e-05	1.21e-04	6.22e-05	79
hsa012405	Esophagus	ESCC	Biosynthesis of cofactors	97/4205	153/8465	3.88e-04	1.35e-03	6.94e-04	97
hsa0123023	Esophagus	ESCC	Biosynthesis of amino acids	49/4205	75/8465	4.35e-03	1.12e-02	5.74e-03	49
hsa015232	Esophagus	ESCC	Antifolate resistance	22/4205	30/8465	7.23e-03	1.76e-02	8.99e-03	22
hsa006306	Esophagus	ESCC	Glyoxylate and dicarboxylate metabolism	21/4205	30/8465	1.95e-02	4.35e-02	2.23e-02	21
hsa0120033	Esophagus	ESCC	Carbon metabolism	79/4205	115/8465	2.50e-05	1.21e-04	6.22e-05	79
hsa0124012	Esophagus	ESCC	Biosynthesis of cofactors	97/4205	153/8465	3.88e-04	1.35e-03	6.94e-04	97
hsa0123033	Esophagus	ESCC	Biosynthesis of amino acids	49/4205	75/8465	4.35e-03	1.12e-02	5.74e-03	49
hsa0152311	Esophagus	ESCC	Antifolate resistance	22/4205	30/8465	7.23e-03	1.76e-02	8.99e-03	22
hsa0063013	Esophagus	ESCC	Glyoxylate and dicarboxylate metabolism	21/4205	30/8465	1.95e-02	4.35e-02	2.23e-02	21
hsa0120010	Liver	NAFLD	Carbon metabolism	26/1043	115/8465	1.39e-03	1.71e-02	1.38e-02	26
hsa0120011	Liver	NAFLD	Carbon metabolism	26/1043	115/8465	1.39e-03	1.71e-02	1.38e-02	26
hsa0120021	Liver	Cirrhotic	Carbon metabolism	64/2530	115/8465	6.37e-09	1.18e-07	7.26e-08	64
hsa006304	Liver	Cirrhotic	Glyoxylate and dicarboxylate metabolism	20/2530	30/8465	3.36e-05	2.54e-04	1.57e-04	20
hsa01240	Liver	Cirrhotic	Biosynthesis of cofactors	66/2530	153/8465	3.11e-04	1.99e-03	1.23e-03	66
hsa00260	Liver	Cirrhotic	Glycine, serine and threonine metabolism	22/2530	40/8465	7.85e-04	4.51e-03	2.78e-03	22

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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

SHMT1

SNV

Missense_Mutation

novel

c.800T>A

p.Ile267Asn

p.I267N

P34896

protein_coding

deleterious(0)

probably_damaging(0.999)

TCGA-A2-A0CT-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Chemotherapy

cytoxan

SHMT1

SNV

Missense_Mutation

novel

c.998N>A

p.Ala333Asp

p.A333D

P34896

protein_coding

tolerated(0.17)

possibly_damaging(0.624)

TCGA-AO-A12A-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

SHMT1

SNV

Missense_Mutation

novel

c.426N>A

p.Asp142Glu

p.D142E

P34896

protein_coding

deleterious(0)

probably_damaging(0.964)

TCGA-EW-A2FR-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

epirubicin

SHMT1

insertion

Nonsense_Mutation

novel

c.217_218insG

p.Tyr73Ter

p.Y73*

P34896

protein_coding

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

SHMT1

insertion

In_Frame_Ins

novel

c.216_217insAGGTCAGTGTCATCTGAGGGATGCTGCAGAAGG

p.Lys72_Tyr73insArgSerValSerSerGluGlyCysCysArgArg

p.K72_Y73insRSVSSEGCCRR

P34896

protein_coding

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

SHMT1

insertion

Nonsense_Mutation

novel

c.501_502insATTATAAAATAAGGTTTGTGTTTGACTATCTTGCCCAGTGGAG

p.Glu168IlefsTer4

p.E168Ifs*4

P34896

protein_coding

TCGA-BH-A0HX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adrimycin

SHMT1

SNV

Missense_Mutation

rs778033192

c.1186N>G

p.Leu396Val

p.L396V

P34896

protein_coding

deleterious(0.02)

benign(0.289)

TCGA-DR-A0ZM-01

Cervix

cervical & endocervical cancer

Female

<65

III/IV

Unspecific

Cisplatin

SHMT1

SNV

Missense_Mutation

novel

c.1449N>G

p.Phe483Leu

p.F483L

P34896

protein_coding

tolerated_low_confidence(0.76)

benign(0)

TCGA-Q1-A73O-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SHMT1

SNV

Missense_Mutation

c.695N>C

p.Ile232Thr

p.I232T

P34896

protein_coding

deleterious(0.02)

possibly_damaging(0.884)

TCGA-AA-A01P-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Unknown

SHMT1

SNV

Missense_Mutation

c.137N>C

p.Val46Ala

p.V46A

P34896

protein_coding

tolerated(0.29)

benign(0.014)

TCGA-AZ-6598-01

Colorectum

colon adenocarcinoma

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
6470	SHMT1	ENZYME		fluorouracil	FLUOROURACIL	22044939
6470	SHMT1	ENZYME		leucovorin	LEUCOVORIN	22044939
6470	SHMT1	ENZYME		methotrexate	METHOTREXATE	20386493,18322994,15797993,22838948,18368069
6470	SHMT1	ENZYME		bevacizumab	BEVACIZUMAB	22044939
6470	SHMT1	ENZYME		irinotecan	IRINOTECAN	22044939

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