Abstract
About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets.Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes.Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression.Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract
The aim of this study is a genome analysis for the characterization of individual metastatic KIT exon 11-mutant GIST, to better understand the range of additional aberrations occurring in each tumor and eventually find simultaneous molecular events that are responsible for tumor progression and may represent potential new drug target candidates
In order to identify novel single nucleotide variations (SNVs), all variants found in the dbSNP131 or 1000 Genomes Project with MAF greater than 0.01 were excluded
Summary
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. About 90% of GISTs are associated with KIT or PDGFRα gene mutations. The remaining 10-15% of GISTs do not harbor identified receptor tyrosine-kinase mutations (KIT/ PDGFRα wild-type GIST) and are very different from mutant GISTs in their clinical and molecular profiles, to the extent that they are considered a separate pathological entity with wide heterogeneity [1, 2]. The in-depth understanding of GIST pathogenesis led to the development of molecular targeted therapies with tyrosine kinase inhibitors (TKIs). KIT and PDGFRα mutational status predicts clinical response to imatinib and molecular sub-classification of GISTs is essential to recognize patients who will benefit from therapy [3,4]. Even imatinib-responsive patients quite invariably acquire resistance after a median time of about 24 months [5]. The mechanisms of secondary resistance are divided between those associated with KIT/PDGFRα receptors, among which secondary mutations are believed to be most prevalent and frequent, and those mechanisms independent from KIT/PDGFRα receptors, such as (i) chromosomal alterations (such as loss of chromosomes 1p, 14q or 22q), (ii) pharmacokinetic variables, and (iii) tumor differentiation (such as sarcomatoid differentiation)
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