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: HSPA1A

Gene summary for HSPA1A

Gene summary.

Gene information	Species	Human
	Gene symbol	HSPA1A
	Gene ID	3303
	Gene name	heat shock protein family A (Hsp70) member 1A
	Gene Alias	HEL-S-103
	Cytomap	6p21.33
	Gene Type	protein-coding
	GO ID	GO:0000122
	UniProtAcc	A8K5I0

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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
3303	HSPA1A	GSM4909277	Human	Breast	Precancer	2.27e-02	8.21e-01	0.0177
3303	HSPA1A	GSM4909280	Human	Breast	Precancer	2.73e-04	7.99e-01	0.0305
3303	HSPA1A	GSM4909281	Human	Breast	IDC	9.93e-09	3.81e-01	0.21
3303	HSPA1A	GSM4909282	Human	Breast	IDC	5.87e-04	-4.70e-01	-0.0288
3303	HSPA1A	GSM4909285	Human	Breast	IDC	7.85e-08	-4.17e-01	0.21
3303	HSPA1A	GSM4909286	Human	Breast	IDC	8.98e-17	-8.38e-01	0.1081
3303	HSPA1A	GSM4909287	Human	Breast	IDC	3.42e-04	-4.81e-01	0.2057
3303	HSPA1A	GSM4909290	Human	Breast	IDC	1.14e-02	-7.30e-02	0.2096
3303	HSPA1A	GSM4909291	Human	Breast	IDC	3.53e-11	5.59e-01	0.1753
3303	HSPA1A	GSM4909293	Human	Breast	IDC	2.68e-09	-7.07e-01	0.1581
3303	HSPA1A	GSM4909294	Human	Breast	IDC	1.15e-06	-5.93e-01	0.2022
3303	HSPA1A	GSM4909297	Human	Breast	IDC	1.28e-04	3.11e-01	0.1517
3303	HSPA1A	GSM4909299	Human	Breast	IDC	2.86e-03	2.23e-01	0.035
3303	HSPA1A	GSM4909302	Human	Breast	IDC	7.55e-07	-5.92e-01	0.1545
3303	HSPA1A	GSM4909304	Human	Breast	IDC	5.79e-15	3.22e-01	0.1636
3303	HSPA1A	GSM4909305	Human	Breast	IDC	1.10e-08	3.59e-02	0.0436
3303	HSPA1A	GSM4909306	Human	Breast	IDC	9.30e-08	1.32e-01	0.1564
3303	HSPA1A	GSM4909308	Human	Breast	IDC	5.59e-07	2.04e-02	0.158
3303	HSPA1A	GSM4909311	Human	Breast	IDC	3.53e-10	-4.71e-01	0.1534
3303	HSPA1A	GSM4909312	Human	Breast	IDC	4.88e-14	-7.52e-01	0.1552

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Breast		IDC: Invasive ductal carcinoma
		DCIS: Ductal carcinoma in situ
		Precancer(BRCA1-mut): Precancerous lesion from BRCA1 mutation carriers
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Colorectum (GSE201348)		FAP: Familial adenomatous polyposis
		CRC: Colorectal cancer
Colorectum (HTA11)		AD: Adenomas
		SER: Sessile serrated lesions
		MSI-H: Microsatellite-high colorectal cancer
		MSS: Microsatellite stable colorectal cancer
Endometrium		AEH: Atypical endometrial hyperplasia
		EEC: Endometrioid Cancer
Esophagus		ESCC: Esophageal squamous cell carcinoma
		HGIN: High-grade intraepithelial neoplasias
		LGIN: Low-grade intraepithelial neoplasias
GC		CAG: Chronic atrophic gastritis
		CAG with IM: Chronic atrophic gastritis with intestinal metaplasia
		CSG: Chronic superficial gastritis
		GC: Gastric cancer
		SIM: Severe intestinal metaplasia
		WIM: Wild intestinal metaplasia
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
Oral Cavity		EOLP: Erosive Oral lichen planus
		LP: leukoplakia
		NEOLP: Non-erosive oral lichen planus
		OSCC: Oral squamous cell carcinoma
Prostate		BPH: Benign Prostatic Hyperplasia
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:003021823	Breast	DCIS	erythrocyte differentiation	22/1390	120/18723	6.60e-05	1.31e-03	22
GO:003133124	Breast	DCIS	positive regulation of cellular catabolic process	54/1390	427/18723	8.34e-05	1.58e-03	54
GO:003243614	Breast	DCIS	positive regulation of proteasomal ubiquitin-dependent protein catabolic process	18/1390	90/18723	9.33e-05	1.71e-03	18
GO:200006014	Breast	DCIS	positive regulation of ubiquitin-dependent protein catabolic process	20/1390	107/18723	1.05e-04	1.90e-03	20
GO:003206922	Breast	DCIS	regulation of nuclease activity	8/1390	22/18723	1.13e-04	2.00e-03	8
GO:000700622	Breast	DCIS	mitochondrial membrane organization	21/1390	116/18723	1.16e-04	2.03e-03	21
GO:004361823	Breast	DCIS	regulation of transcription from RNA polymerase II promoter in response to stress	12/1390	47/18723	1.22e-04	2.11e-03	12
GO:004564621	Breast	DCIS	regulation of erythrocyte differentiation	12/1390	47/18723	1.22e-04	2.11e-03	12
GO:004690222	Breast	DCIS	regulation of mitochondrial membrane permeability	14/1390	63/18723	1.71e-04	2.84e-03	14
GO:007005922	Breast	DCIS	intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	14/1390	63/18723	1.71e-04	2.84e-03	14
GO:007135622	Breast	DCIS	cellular response to tumor necrosis factor	33/1390	229/18723	1.84e-04	3.00e-03	33
GO:004563921	Breast	DCIS	positive regulation of myeloid cell differentiation	19/1390	103/18723	1.86e-04	3.03e-03	19
GO:000640123	Breast	DCIS	RNA catabolic process	38/1390	278/18723	1.91e-04	3.08e-03	38
GO:000640223	Breast	DCIS	mRNA catabolic process	33/1390	232/18723	2.35e-04	3.70e-03	33
GO:200123723	Breast	DCIS	negative regulation of extrinsic apoptotic signaling pathway	18/1390	97/18723	2.52e-04	3.89e-03	18
GO:003312023	Breast	DCIS	positive regulation of RNA splicing	10/1390	37/18723	2.68e-04	4.06e-03	10
GO:005125814	Breast	DCIS	protein polymerization	39/1390	297/18723	3.64e-04	5.15e-03	39
GO:001082122	Breast	DCIS	regulation of mitochondrion organization	23/1390	144/18723	3.86e-04	5.36e-03	23
GO:009734521	Breast	DCIS	mitochondrial outer membrane permeabilization	9/1390	32/18723	3.91e-04	5.40e-03	9
GO:190223622	Breast	DCIS	negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	7/1390	20/18723	4.01e-04	5.48e-03	7

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0502016	Breast	Precancer	Prion disease	95/684	273/8465	1.39e-37	1.46e-35	1.12e-35	95
hsa0513414	Breast	Precancer	Legionellosis	19/684	57/8465	4.62e-08	9.12e-07	6.98e-07	19
hsa030408	Breast	Precancer	Spliceosome	39/684	217/8465	1.44e-06	2.27e-05	1.74e-05	39
hsa0414118	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0491518	Breast	Precancer	Estrogen signaling pathway	28/684	138/8465	4.10e-06	5.39e-05	4.13e-05	28
hsa0541718	Breast	Precancer	Lipid and atherosclerosis	37/684	215/8465	7.64e-06	9.29e-05	7.12e-05	37
hsa0461218	Breast	Precancer	Antigen processing and presentation	19/684	78/8465	9.61e-06	1.12e-04	8.62e-05	19
hsa0502017	Breast	Precancer	Prion disease	95/684	273/8465	1.39e-37	1.46e-35	1.12e-35	95
hsa0513415	Breast	Precancer	Legionellosis	19/684	57/8465	4.62e-08	9.12e-07	6.98e-07	19
hsa0304013	Breast	Precancer	Spliceosome	39/684	217/8465	1.44e-06	2.27e-05	1.74e-05	39
hsa0414119	Breast	Precancer	Protein processing in endoplasmic reticulum	33/684	174/8465	2.78e-06	3.83e-05	2.94e-05	33
hsa0491519	Breast	Precancer	Estrogen signaling pathway	28/684	138/8465	4.10e-06	5.39e-05	4.13e-05	28
hsa0541719	Breast	Precancer	Lipid and atherosclerosis	37/684	215/8465	7.64e-06	9.29e-05	7.12e-05	37
hsa0461219	Breast	Precancer	Antigen processing and presentation	19/684	78/8465	9.61e-06	1.12e-04	8.62e-05	19
hsa0502023	Breast	IDC	Prion disease	102/867	273/8465	3.70e-34	4.01e-32	3.00e-32	102
hsa0491523	Breast	IDC	Estrogen signaling pathway	35/867	138/8465	2.55e-07	5.18e-06	3.88e-06	35
hsa0461223	Breast	IDC	Antigen processing and presentation	24/867	78/8465	4.61e-07	8.33e-06	6.23e-06	24
hsa0513422	Breast	IDC	Legionellosis	19/867	57/8465	1.89e-06	3.07e-05	2.29e-05	19
hsa0414124	Breast	IDC	Protein processing in endoplasmic reticulum	36/867	174/8465	2.73e-05	2.86e-04	2.14e-04	36
hsa0304023	Breast	IDC	Spliceosome	40/867	217/8465	1.53e-04	1.42e-03	1.06e-03	40

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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

HSPA1A

SNV

Missense_Mutation

novel

c.14C>T

p.Ala5Val

p.A5V

P0DMV8

protein_coding

tolerated_low_confidence(0.15)

benign(0)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HSPA1A

SNV

Missense_Mutation

novel

c.1694C>T

p.Ala565Val

p.A565V

P0DMV8

protein_coding

tolerated_low_confidence(0.08)

benign(0.146)

TCGA-2W-A8YY-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Chemotherapy

cisplatin

HSPA1A

SNV

Missense_Mutation

novel

c.1451G>T

p.Gly484Val

p.G484V

P0DMV8

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-NH-A5IV-01

Colorectum

colon adenocarcinoma

Female

>=65

I/II

Unknown

HSPA1A

SNV

Missense_Mutation

novel

c.1690N>A

p.Glu564Lys

p.E564K

P0DMV8

protein_coding

tolerated_low_confidence(0.08)

benign(0.022)

TCGA-A5-A0G2-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unknown

HSPA1A

SNV

Missense_Mutation

novel

c.1841N>T

p.Ala614Val

p.A614V

P0DMV8

protein_coding

deleterious_low_confidence(0.03)

benign(0.031)

TCGA-A5-A1OF-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

HSPA1A

SNV

Missense_Mutation

c.1876N>T

p.Gly626Cys

p.G626C

P0DMV8

protein_coding

deleterious_low_confidence(0.05)

possibly_damaging(0.455)

TCGA-AP-A05N-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

HSPA1A

SNV

Missense_Mutation

novel

c.1625N>C

p.Leu542Pro

p.L542P

P0DMV8

protein_coding

deleterious_low_confidence(0)

probably_damaging(1)

TCGA-AP-A1DK-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

I/II

Unknown

HSPA1A

SNV

Missense_Mutation

novel

c.4G>A

p.Ala2Thr

p.A2T

P0DMV8

protein_coding

tolerated_low_confidence(0.08)

benign(0.226)

TCGA-AX-A0J1-01

Endometrium

uterine corpus endometrioid carcinoma

Female

>=65

I/II

Unknown

HSPA1A

SNV

Missense_Mutation

novel

c.4G>A

p.Ala2Thr

p.A2T

P0DMV8

protein_coding

tolerated_low_confidence(0.08)

benign(0.226)

TCGA-AX-A1C5-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Unspecific

Carboplatin

HSPA1A

SNV

Missense_Mutation

novel

c.1771N>A

p.Glu591Lys

p.E591K

P0DMV8

protein_coding

deleterious_low_confidence(0)

probably_damaging(0.999)

TCGA-EO-A3AV-01

Endometrium

uterine corpus endometrioid carcinoma

Female

<65

III/IV

Chemotherapy

carboplatin

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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
3303	HSPA1A	DRUGGABLE GENOME		carbamazepine	CARBAMAZEPINE	16538175
3303	HSPA1A	DRUGGABLE GENOME		AIMPILA

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