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: SLC4A1

Gene summary for SLC4A1

Gene summary.

Gene information	Species	Human
	Gene symbol	SLC4A1
	Gene ID	6521
	Gene name	solute carrier family 4 member 1 (Diego blood group)
	Gene Alias	AE1
	Cytomap	17q21.31
	Gene Type	protein-coding
	GO ID	GO:0002262
	UniProtAcc	P02730

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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
6521	SLC4A1	HCC1	Human	Liver	HCC	5.36e-21	1.23e+00	0.5336
6521	SLC4A1	HCC2	Human	Liver	HCC	2.54e-34	1.79e+00	0.5341
6521	SLC4A1	HCC5	Human	Liver	HCC	1.30e-53	1.94e+00	0.4932

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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:1902600	Colorectum	AD	proton transmembrane transport	66/3918	157/18723	1.59e-09	1.17e-07	66
GO:0021859	Colorectum	AD	pyramidal neuron differentiation	9/3918	13/18723	2.38e-04	3.03e-03	9
GO:0021860	Colorectum	AD	pyramidal neuron development	8/3918	11/18723	3.26e-04	3.85e-03	8
GO:0030004	Colorectum	AD	cellular monovalent inorganic cation homeostasis	36/3918	103/18723	6.80e-04	6.95e-03	36
GO:0009791	Colorectum	AD	post-embryonic development	29/3918	80/18723	1.13e-03	1.03e-02	29
GO:0030641	Colorectum	AD	regulation of cellular pH	29/3918	81/18723	1.42e-03	1.22e-02	29
GO:0051453	Colorectum	AD	regulation of intracellular pH	26/3918	75/18723	4.04e-03	2.82e-02	26
GO:0006885	Colorectum	AD	regulation of pH	30/3918	91/18723	4.95e-03	3.32e-02	30
GO:0055067	Colorectum	AD	monovalent inorganic cation homeostasis	45/3918	151/18723	6.19e-03	3.88e-02	45
GO:0015698	Colorectum	AD	inorganic anion transport	52/3918	180/18723	6.83e-03	4.22e-02	52
GO:19026002	Colorectum	MSS	proton transmembrane transport	57/3467	157/18723	1.00e-07	4.81e-06	57
GO:00097912	Colorectum	MSS	post-embryonic development	26/3467	80/18723	1.91e-03	1.66e-02	26
GO:00300042	Colorectum	MSS	cellular monovalent inorganic cation homeostasis	31/3467	103/18723	2.94e-03	2.27e-02	31
GO:0035264	Colorectum	MSS	multicellular organism growth	37/3467	132/18723	4.77e-03	3.34e-02	37
GO:00306412	Colorectum	MSS	regulation of cellular pH	25/3467	81/18723	4.97e-03	3.46e-02	25
GO:0035725	Colorectum	FAP	sodium ion transmembrane transport	44/2622	178/18723	9.31e-05	1.60e-03	44
GO:19026004	Colorectum	FAP	proton transmembrane transport	39/2622	157/18723	2.03e-04	2.92e-03	39
GO:00300043	Colorectum	FAP	cellular monovalent inorganic cation homeostasis	28/2622	103/18723	3.23e-04	4.15e-03	28
GO:0006814	Colorectum	FAP	sodium ion transport	54/2622	245/18723	3.98e-04	4.85e-03	54
GO:00514532	Colorectum	FAP	regulation of intracellular pH	22/2622	75/18723	4.38e-04	5.21e-03	22

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Enriched KEGG pathways.

Pathway ID

Tissue

Disease Stage

Description

Gene Ratio

Bg Ratio

pvalue

p.adjust

qvalue

Count

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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

SLC4A1

SNV

Missense_Mutation

rs28931585

c.2608N>T

p.Arg870Trp

p.R870W

P02730

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-A2-A3KC-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

adriamycin

SLC4A1

SNV

Missense_Mutation

c.2722N>A

p.Ala908Thr

p.A908T

P02730

protein_coding

tolerated(0.63)

benign(0)

TCGA-AN-A0AK-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SLC4A1

SNV

Missense_Mutation

rs775748758

c.2185G>A

p.Val729Met

p.V729M

P02730

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-C8-A12L-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

SLC4A1

SNV

Missense_Mutation

c.2147N>A

p.Ala716Asp

p.A716D

P02730

protein_coding

deleterious(0.01)

possibly_damaging(0.454)

TCGA-E2-A15R-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

SLC4A1

SNV

Missense_Mutation

c.1232N>C

p.Phe411Ser

p.F411S

P02730

protein_coding

deleterious(0.01)

probably_damaging(0.996)

TCGA-E2-A1L7-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

SLC4A1

SNV

Missense_Mutation

c.1778N>G

p.Asn593Ser

p.N593S

P02730

protein_coding

deleterious(0.02)

possibly_damaging(0.733)

TCGA-GM-A2DK-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

arimidex

SLC4A1

insertion

Frame_Shift_Ins

novel

c.2536_2537insGGGGAAATGA

p.Val846GlyfsTer47

p.V846Gfs*47

P02730

protein_coding

TCGA-AO-A0J5-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Other, specify in notesBisphosphonate

zoledronic

SLC4A1

insertion

Frame_Shift_Ins

novel

c.2534_2535insTGTGTCTTCATTTTGCTCACCTGTAA

p.Leu847SerfsTer13

p.L847Sfs*13

P02730

protein_coding

TCGA-AO-A0J5-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Other, specify in notesBisphosphonate

zoledronic

SLC4A1

SNV

Missense_Mutation

novel

c.1735N>A

p.Ala579Thr

p.A579T

P02730

protein_coding

tolerated(0.09)

benign(0.103)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

SLC4A1

SNV

Missense_Mutation

novel

c.856N>T

p.Ala286Ser

p.A286S

P02730

protein_coding

tolerated(1)

possibly_damaging(0.469)

TCGA-C5-A1ME-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
6521	SLC4A1	ENZYME, TRANSPORTER, CELL SURFACE, DRUGGABLE GENOME		metoprolol	METOPROLOL
6521	SLC4A1	ENZYME, TRANSPORTER, CELL SURFACE, DRUGGABLE GENOME		atenolol	ATENOLOL

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