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: TM9SF4

Gene summary for TM9SF4

Gene summary.

Gene information	Species	Human
	Gene symbol	TM9SF4
	Gene ID	9777
	Gene name	transmembrane 9 superfamily member 4
	Gene Alias	dJ836N17.2
	Cytomap	20q11.21
	Gene Type	protein-coding
	GO ID	GO:0001666
	UniProtAcc	A0A024QYR3

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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
9777	TM9SF4	LZE4T	Human	Esophagus	ESCC	2.34e-13	5.00e-01	0.0811
9777	TM9SF4	LZE5T	Human	Esophagus	ESCC	1.87e-02	2.10e-01	0.0514
9777	TM9SF4	LZE7T	Human	Esophagus	ESCC	2.16e-05	4.94e-01	0.0667
9777	TM9SF4	LZE8T	Human	Esophagus	ESCC	1.09e-08	1.95e-01	0.067
9777	TM9SF4	LZE20T	Human	Esophagus	ESCC	3.18e-11	3.48e-01	0.0662
9777	TM9SF4	LZE22T	Human	Esophagus	ESCC	5.57e-05	3.19e-01	0.068
9777	TM9SF4	LZE24T	Human	Esophagus	ESCC	1.31e-23	7.72e-01	0.0596
9777	TM9SF4	P1T-E	Human	Esophagus	ESCC	1.68e-06	5.86e-01	0.0875
9777	TM9SF4	P2T-E	Human	Esophagus	ESCC	1.53e-23	4.29e-01	0.1177
9777	TM9SF4	P4T-E	Human	Esophagus	ESCC	2.29e-21	5.45e-01	0.1323
9777	TM9SF4	P5T-E	Human	Esophagus	ESCC	1.20e-16	2.98e-01	0.1327
9777	TM9SF4	P8T-E	Human	Esophagus	ESCC	1.73e-42	7.11e-01	0.0889
9777	TM9SF4	P9T-E	Human	Esophagus	ESCC	6.42e-17	2.62e-01	0.1131
9777	TM9SF4	P10T-E	Human	Esophagus	ESCC	7.99e-36	6.76e-01	0.116
9777	TM9SF4	P11T-E	Human	Esophagus	ESCC	5.35e-19	7.76e-01	0.1426
9777	TM9SF4	P12T-E	Human	Esophagus	ESCC	2.81e-37	7.13e-01	0.1122
9777	TM9SF4	P15T-E	Human	Esophagus	ESCC	7.54e-35	6.52e-01	0.1149
9777	TM9SF4	P16T-E	Human	Esophagus	ESCC	2.92e-40	8.02e-01	0.1153
9777	TM9SF4	P17T-E	Human	Esophagus	ESCC	6.73e-13	4.90e-01	0.1278
9777	TM9SF4	P20T-E	Human	Esophagus	ESCC	4.91e-28	7.15e-01	0.1124

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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
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:003238618	Esophagus	ESCC	regulation of intracellular transport	243/8552	337/18723	3.20e-23	7.25e-21	243
GO:1903829111	Esophagus	ESCC	positive regulation of cellular protein localization	199/8552	276/18723	2.99e-19	3.45e-17	199
GO:0033157110	Esophagus	ESCC	regulation of intracellular protein transport	169/8552	229/18723	3.31e-18	3.23e-16	169
GO:0032388110	Esophagus	ESCC	positive regulation of intracellular transport	152/8552	202/18723	7.89e-18	7.36e-16	152
GO:1904951111	Esophagus	ESCC	positive regulation of establishment of protein localization	216/8552	319/18723	1.01e-15	6.86e-14	216
GO:009031617	Esophagus	ESCC	positive regulation of intracellular protein transport	122/8552	160/18723	2.45e-15	1.49e-13	122
GO:0051222111	Esophagus	ESCC	positive regulation of protein transport	204/8552	303/18723	1.56e-14	8.38e-13	204
GO:0070482111	Esophagus	ESCC	response to oxygen levels	218/8552	347/18723	6.91e-11	2.17e-09	218
GO:0036293111	Esophagus	ESCC	response to decreased oxygen levels	201/8552	322/18723	8.37e-10	2.04e-08	201
GO:0001666111	Esophagus	ESCC	response to hypoxia	192/8552	307/18723	1.59e-09	3.69e-08	192
GO:003252714	Esophagus	ESCC	protein exit from endoplasmic reticulum	37/8552	48/18723	8.99e-06	8.65e-05	37
GO:00700711	Esophagus	ESCC	proton-transporting two-sector ATPase complex assembly	12/8552	15/18723	7.31e-03	2.63e-02	12
GO:00708615	Esophagus	ESCC	regulation of protein exit from endoplasmic reticulum	19/8552	27/18723	8.35e-03	2.95e-02	19
GO:00512227	Liver	NAFLD	positive regulation of protein transport	55/1882	303/18723	1.07e-05	3.35e-04	55
GO:19049517	Liver	NAFLD	positive regulation of establishment of protein localization	55/1882	319/18723	4.79e-05	1.14e-03	55
GO:00903166	Liver	NAFLD	positive regulation of intracellular protein transport	29/1882	160/18723	1.24e-03	1.41e-02	29
GO:00325273	Liver	NAFLD	protein exit from endoplasmic reticulum	12/1882	48/18723	2.30e-03	2.19e-02	12
GO:00331576	Liver	NAFLD	regulation of intracellular protein transport	37/1882	229/18723	2.55e-03	2.36e-02	37
GO:0070861	Liver	NAFLD	regulation of protein exit from endoplasmic reticulum	8/1882	27/18723	3.97e-03	3.34e-02	8
GO:00323866	Liver	NAFLD	regulation of intracellular transport	49/1882	337/18723	5.34e-03	4.11e-02	49

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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

TM9SF4

SNV

Missense_Mutation

c.1532T>C

p.Phe511Ser

p.F511S

Q92544

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TM9SF4

SNV

Missense_Mutation

novel

c.1724C>A

p.Ser575Tyr

p.S575Y

Q92544

protein_coding

deleterious(0)

probably_damaging(0.995)

TCGA-AO-A03T-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cyclophosphamide

TM9SF4

SNV

Missense_Mutation

c.1124G>A

p.Arg375Gln

p.R375Q

Q92544

protein_coding

deleterious(0.03)

probably_damaging(0.972)

TCGA-D8-A1XQ-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

TM9SF4

insertion

In_Frame_Ins

novel

c.1375_1376insCTTTATATATATATT

p.Ile459delinsThrLeuTyrIleTyrPhe

p.I459delinsTLYIYF

Q92544

protein_coding

TCGA-A7-A0CJ-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

TM9SF4

insertion

In_Frame_Ins

novel

c.1292_1293insCTTTTTTTTGAGACG

p.Leu431delinsPhePhePheLeuArgArg

p.L431delinsFFFLRR

Q92544

protein_coding

TCGA-AO-A0JB-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

cyclophosphamide

TM9SF4

SNV

Missense_Mutation

c.1444N>T

p.Arg482Cys

p.R482C

Q92544

protein_coding

deleterious(0)

probably_damaging(0.998)

TCGA-A6-2686-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

TM9SF4

SNV

Missense_Mutation

rs750795353

c.1195C>T

p.Arg399Cys

p.R399C

Q92544

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-AA-3680-01

Colorectum

colon adenocarcinoma

Female

>=65

III/IV

Chemotherapy

folinic

TM9SF4

SNV

Missense_Mutation

c.1300T>C

p.Phe434Leu

p.F434L

Q92544

protein_coding

tolerated(0.78)

benign(0.323)

TCGA-D5-6529-01

Colorectum

colon adenocarcinoma

Male

>=65

I/II

Chemotherapy

oxaliplatinum+

TM9SF4

SNV

Missense_Mutation

rs777279514

c.1912N>A

p.Ala638Thr

p.A638T

Q92544

protein_coding

deleterious(0)

possibly_damaging(0.835)

TCGA-AG-4015-01

Colorectum

rectum adenocarcinoma

Female

>=65

I/II

Unknown

TM9SF4

SNV

Missense_Mutation

c.1871N>T

p.Gly624Val

p.G624V

Q92544

protein_coding

deleterious(0)

probably_damaging(0.991)

TCGA-AG-A01J-01

Colorectum

rectum 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

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