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Anatomic and transcriptional determinants of gastrointestinal stromal tumor

ABSTRACT: Anatomic and transcriptional determinants of gastrointestinal stromal tumor

PROVIDER: PRJNA635434 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11858937_1.fastq.gz	Fastqsanger.gz
	SRR11858937_2.fastq.gz	Fastqsanger.gz
	SRR11858938_1.fastq.gz	Fastqsanger.gz
	SRR11858938_2.fastq.gz	Fastqsanger.gz
	SRR11858939_1.fastq.gz	Fastqsanger.gz

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Anatomic and transcriptional determinants of gastrointestinal stromal tumor

Project description:Malignant transformation of the interstitial cells of Cajal (ICC) or their precursors gives rise to gastrointestinal stromal tumor (GIST). This mesenchymal neoplasm is characterized by activating mutations in the receptor tyrosine kinases KIT, or other less common mutational subtypes. GIST relies on a highly conserved core transcription factor (TF) network, with expression of accessory disease-state specific TFs. In this study, we define the divergent transcriptional programs supported by accessory TFs HAND1 and BARX1, with HAND1 modulating core TF and KIT gene expression to support GIST cell proliferation. HAND1 was expressed primarily in KIT mutant tumors, including the majority of metastatic tumors or those derived from small bowel, which intrinsically portend a more aggressive clinical course. Assessing archival GIST specimens, HAND1 and BARX1 expression patterns were superior predictors of relapse free survival compared to standard risk stratification. Metastatic tumors expressing HAND1 had a shorter progression free survival on first-line imatinib than those that were HAND1-negative. In contrast, BARX1 expression was enriched in more indolent forms of GIST. Signifying developmental origins of accessory TF expression, HAND1 was expressed solely in ICCs derived from the small intestine, while BARX1 expression was restricted to ICCs of the stomach. These results define the anatomic and transcriptional determinants of GIST clinical phenotypes, and may provide important biomarkers of disease risk stratification in GIST that will inform clinical decision making.

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