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: TTN

Gene summary for TTN

Gene summary.

Gene information	Species	Human
	Gene symbol	TTN
	Gene ID	7273
	Gene name	titin
	Gene Alias	CMD1G
	Cytomap	2q31.2
	Gene Type	protein-coding
	GO ID	GO:0000070
	UniProtAcc	Q8WZ42

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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
7273	TTN	HCC1_Meng	Human	Liver	HCC	1.93e-02	-1.44e-01	0.0246
7273	TTN	HCC5	Human	Liver	HCC	6.34e-15	2.72e+00	0.4932
7273	TTN	S028	Human	Liver	HCC	7.08e-10	6.89e-01	0.2503
7273	TTN	S029	Human	Liver	HCC	1.04e-02	3.61e-01	0.2581
7273	TTN	RNA-P25T1-P25T1-1	Human	Lung	AIS	2.80e-10	5.59e-01	-0.2116
7273	TTN	RNA-P25T1-P25T1-2	Human	Lung	AIS	1.21e-06	7.26e-01	-0.1941
7273	TTN	RNA-P25T1-P25T1-3	Human	Lung	AIS	8.26e-07	6.77e-01	-0.2107
7273	TTN	RNA-P25T1-P25T1-4	Human	Lung	AIS	2.27e-10	6.99e-01	-0.2119
7273	TTN	HTA12-18-3	Human	Pancreas	PDAC	1.07e-02	5.78e-01	0.0716
7273	TTN	HTA12-25-1	Human	Pancreas	PDAC	2.02e-02	4.06e-01	0.313
7273	TTN	HTA12-26-1	Human	Pancreas	PDAC	1.84e-07	4.56e-01	0.3728
7273	TTN	HTA12-29-1	Human	Pancreas	PDAC	3.65e-29	6.66e-01	0.3722

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease
Lung		AAH: Atypical adenomatous hyperplasia
		AIS: Adenocarcinoma in situ
		IAC: Invasive lung adenocarcinoma
		MIA: Minimally invasive adenocarcinoma

∗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:00308388	Breast	IDC	positive regulation of actin filament polymerization	16/1434	99/18723	3.40e-03	2.83e-02	16
GO:003297024	Breast	DCIS	regulation of actin filament-based process	56/1390	397/18723	2.50e-06	8.74e-05	56
GO:003133423	Breast	DCIS	positive regulation of protein-containing complex assembly	40/1390	237/18723	8.13e-07	3.36e-05	40
GO:004325424	Breast	DCIS	regulation of protein-containing complex assembly	61/1390	428/18723	6.32e-07	2.71e-05	61
GO:190290524	Breast	DCIS	positive regulation of supramolecular fiber organization	37/1390	209/18723	6.31e-07	2.71e-05	37
GO:200123623	Breast	DCIS	regulation of extrinsic apoptotic signaling pathway	31/1390	151/18723	1.79e-07	9.04e-06	31
GO:009719123	Breast	DCIS	extrinsic apoptotic signaling pathway	40/1390	219/18723	9.43e-08	5.28e-06	40
GO:200123424	Breast	DCIS	negative regulation of apoptotic signaling pathway	48/1390	224/18723	1.70e-11	3.22e-09	48
GO:200123324	Breast	DCIS	regulation of apoptotic signaling pathway	81/1390	356/18723	3.51e-20	3.31e-17	81
GO:190300812	Breast	IDC	organelle disassembly	17/1434	114/18723	5.99e-03	4.31e-02	17
GO:00030125	Breast	IDC	muscle system process	50/1434	452/18723	5.52e-03	4.05e-02	50
GO:006172612	Breast	IDC	mitochondrion disassembly	15/1434	81/18723	1.13e-03	1.23e-02	15
GO:001082113	Breast	IDC	regulation of mitochondrion organization	23/1434	144/18723	5.96e-04	7.54e-03	23
GO:011005314	Breast	IDC	regulation of actin filament organization	37/1434	278/18723	7.01e-04	8.58e-03	37
GO:00322719	Breast	IDC	regulation of protein polymerization	32/1434	233/18723	9.19e-04	1.05e-02	32
GO:000042212	Breast	IDC	autophagy of mitochondrion	15/1434	81/18723	1.13e-03	1.23e-02	15
GO:00512589	Breast	IDC	protein polymerization	38/1434	297/18723	1.26e-03	1.34e-02	38
GO:00325358	Breast	IDC	regulation of cellular component size	45/1434	383/18723	2.72e-03	2.41e-02	45
GO:000155813	Breast	IDC	regulation of cell growth	49/1434	414/18723	1.55e-03	1.55e-02	49
GO:190290324	Breast	DCIS	regulation of supramolecular fiber organization	54/1390	383/18723	3.82e-06	1.16e-04	54

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa054142	Lung	AIS	Dilated cardiomyopathy	22/961	96/8465	9.02e-04	7.11e-03	4.55e-03	22
hsa054102	Lung	AIS	Hypertrophic cardiomyopathy	20/961	90/8465	2.25e-03	1.37e-02	8.80e-03	20
hsa054143	Lung	AIS	Dilated cardiomyopathy	22/961	96/8465	9.02e-04	7.11e-03	4.55e-03	22
hsa054103	Lung	AIS	Hypertrophic cardiomyopathy	20/961	90/8465	2.25e-03	1.37e-02	8.80e-03	20

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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

TTN

SNV

Missense_Mutation

c.15285G>T

p.Gln5095His

p.Q5095H

protein_coding

TCGA-91-7771-01

Lung

lung adenocarcinoma

Male

<65

I/II

Chemotherapy

cisplatin

TTN

SNV

Missense_Mutation

novel

c.89924N>G

p.Ala29975Gly

p.A29975G

protein_coding

TCGA-91-8499-01

Lung

lung adenocarcinoma

Female

>=65

I/II

Unknown

TTN

SNV

Missense_Mutation

novel

c.89923N>A

p.Ala29975Thr

p.A29975T

protein_coding

TCGA-91-8499-01

Lung

lung adenocarcinoma

Female

>=65

I/II

Unknown

TTN

SNV

Missense_Mutation

novel

c.72170N>A

p.Pro24057Gln

p.P24057Q

protein_coding

TCGA-91-8499-01

Lung

lung adenocarcinoma

Female

>=65

I/II

Unknown

TTN

SNV

Missense_Mutation

c.44802C>A

p.Asn14934Lys

p.N14934K

protein_coding

TCGA-91-A4BC-01

Lung

lung adenocarcinoma

Male

<65

I/II

Unknown

TTN

SNV

Missense_Mutation

c.69913N>C

p.Asp23305His

p.D23305H

protein_coding

TCGA-93-8067-01

Lung

lung adenocarcinoma

Male

>=65

I/II

Unknown

TTN

SNV

Missense_Mutation

c.90053N>A

p.Pro30018His

p.P30018H

protein_coding

TCGA-95-7039-01

Lung

lung adenocarcinoma

Female

<65

I/II

Unknown

TTN

SNV

Missense_Mutation

c.64534N>A

p.His21512Asn

p.H21512N

protein_coding

TCGA-95-7039-01

Lung

lung adenocarcinoma

Female

<65

I/II

Unknown

TTN

SNV

Missense_Mutation

c.63146N>A

p.Pro21049Gln

p.P21049Q

protein_coding

TCGA-95-7039-01

Lung

lung adenocarcinoma

Female

<65

I/II

Unknown

TTN

SNV

Missense_Mutation

c.56276N>G

p.Thr18759Ser

p.T18759S

protein_coding

TCGA-95-7039-01

Lung

lung 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
7273	TTN	DRUGGABLE GENOME, TYROSINE KINASE, SERINE THREONINE KINASE, KINASE, ENZYME		PROTEASE INHIBITORS		9648223

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