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: SLC46A1

Gene summary for SLC46A1

Gene summary.

Gene information	Species	Human
	Gene symbol	SLC46A1
	Gene ID	113235
	Gene name	solute carrier family 46 member 1
	Gene Alias	G21
	Cytomap	17q11.2
	Gene Type	protein-coding
	GO ID	GO:0000041
	UniProtAcc	A0A024QZ44

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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
113235	SLC46A1	HCC1_Meng	Human	Liver	HCC	2.99e-33	5.09e-02	0.0246
113235	SLC46A1	HCC1	Human	Liver	HCC	4.41e-04	1.69e+00	0.5336
113235	SLC46A1	HCC2	Human	Liver	HCC	1.64e-03	1.33e+00	0.5341
113235	SLC46A1	S027	Human	Liver	HCC	1.44e-03	3.82e-01	0.2446
113235	SLC46A1	S028	Human	Liver	HCC	4.52e-17	6.04e-01	0.2503
113235	SLC46A1	S029	Human	Liver	HCC	5.64e-12	4.63e-01	0.2581

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		NAFLD: Non-alcoholic fatty liver disease

∗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:000657521	Liver	HCC	cellular modified amino acid metabolic process	119/7958	188/18723	6.47e-09	1.67e-07	119
GO:00436482	Liver	HCC	dicarboxylic acid metabolic process	68/7958	96/18723	1.73e-08	4.14e-07	68
GO:00425581	Liver	HCC	pteridine-containing compound metabolic process	28/7958	33/18723	6.57e-07	1.03e-05	28
GO:00067601	Liver	HCC	folic acid-containing compound metabolic process	22/7958	26/18723	1.23e-05	1.39e-04	22
GO:005507612	Liver	HCC	transition metal ion homeostasis	81/7958	138/18723	8.87e-05	7.72e-04	81
GO:0042168	Liver	HCC	heme metabolic process	30/7958	42/18723	1.40e-04	1.13e-03	30
GO:0006767	Liver	HCC	water-soluble vitamin metabolic process	39/7958	59/18723	2.14e-04	1.63e-03	39
GO:00330131	Liver	HCC	tetrapyrrole metabolic process	39/7958	59/18723	2.14e-04	1.63e-03	39
GO:00067781	Liver	HCC	porphyrin-containing compound metabolic process	33/7958	49/18723	3.86e-04	2.62e-03	33
GO:004691611	Liver	HCC	cellular transition metal ion homeostasis	67/7958	115/18723	4.64e-04	3.08e-03	67
GO:0042440	Liver	HCC	pigment metabolic process	51/7958	84/18723	5.74e-04	3.65e-03	51
GO:19026007	Liver	HCC	proton transmembrane transport	87/7958	157/18723	7.27e-04	4.42e-03	87
GO:0046655	Liver	HCC	folic acid metabolic process	12/7958	14/18723	1.17e-03	6.54e-03	12
GO:00000411	Liver	HCC	transition metal ion transport	59/7958	105/18723	3.18e-03	1.47e-02	59
GO:0015886	Liver	HCC	heme transport	9/7958	11/18723	9.51e-03	3.60e-02	9
GO:00068261	Liver	HCC	iron ion transport	34/7958	58/18723	9.66e-03	3.63e-02	34
GO:005507211	Liver	HCC	iron ion homeostasis	47/7958	85/18723	1.17e-02	4.28e-02	47
GO:0006766	Liver	HCC	vitamin metabolic process	57/7958	106/18723	1.25e-02	4.53e-02	57
GO:00508926	Liver	HCC	intestinal absorption	25/7958	41/18723	1.31e-02	4.69e-02	25

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa01523	Liver	HCC	Antifolate resistance	21/4020	30/8465	1.06e-02	2.71e-02	1.51e-02	21
hsa015231	Liver	HCC	Antifolate resistance	21/4020	30/8465	1.06e-02	2.71e-02	1.51e-02	21

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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

SLC46A1

SNV

Missense_Mutation

rs781998047

c.1241A>C

p.Tyr414Ser

p.Y414S

Q96NT5

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-AN-A0G0-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC46A1

SNV

Missense_Mutation

c.610N>T

p.Arg204Trp

p.R204W

Q96NT5

protein_coding

deleterious(0)

probably_damaging(0.911)

TCGA-D8-A141-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicine

SLC46A1

insertion

Frame_Shift_Ins

novel

c.564_565insAGAGT

p.Gly189ArgfsTer33

p.G189Rfs*33

Q96NT5

protein_coding

TCGA-AN-A04C-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC46A1

insertion

Frame_Shift_Ins

novel

c.393_394insTG

p.Val132TrpfsTer89

p.V132Wfs*89

Q96NT5

protein_coding

TCGA-B6-A0I5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC46A1

insertion

Frame_Shift_Ins

novel

c.392_393insATTATCCATGGGAATATTAAGAAGCCTGATGTGGGTGA

p.Val132LeufsTer101

p.V132Lfs*101

Q96NT5

protein_coding

TCGA-B6-A0I5-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC46A1

insertion

Frame_Shift_Ins

novel

c.864_865insT

p.Thr289TyrfsTer4

p.T289Yfs*4

Q96NT5

protein_coding

TCGA-B6-A0I6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC46A1

insertion

Nonsense_Mutation

novel

c.863_864insGTGACATGGGTTTCATTTTCCACAGTTGACAG

p.Thr289Ter

p.T289*

Q96NT5

protein_coding

TCGA-B6-A0I6-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

SLC46A1

SNV

Missense_Mutation

novel

c.1043N>C

p.Val348Ala

p.V348A

Q96NT5

protein_coding

deleterious(0)

probably_damaging(0.994)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SLC46A1

SNV

Missense_Mutation

novel

c.443N>A

p.Arg148His

p.R148H

Q96NT5

protein_coding

deleterious(0)

probably_damaging(0.993)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SLC46A1

SNV

Missense_Mutation

c.560G>T

p.Ser187Ile

p.S187I

Q96NT5

protein_coding

tolerated(0.1)

benign(0.075)

TCGA-D5-6930-01

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
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		178103302
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		PREMETREXED
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		178101283
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME	inhibitor	135650390	INDOMETHACIN
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		178103300
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		PEMETREXED	PEMETREXED	26317331,21879757
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		178103301
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		Folic Acid
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		Methotrexate	METHOTREXATE
113235	SLC46A1	CELL SURFACE, TRANSPORTER, DRUGGABLE GENOME		178101388

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