Abstract
Background: Gastrointestinal stromal tumors (GIST) are known to carry oncogenic KIT or PDGFRA mutations, or less commonly SDH or NF1 gene inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 10% of GISTs are devoid of any of such mutations and are characterized by very limited therapeutic opportunities and poor response to standard treatments.Methods: Twenty-six sporadic KIT/PDGFRA/SDH/RAS-pathway wild type GIST were profiled for the molecular status of genes frequently altered in GIST by a targeted next generation sequencing (NGS) approach. Molecular findings were validated by alternative amplicon-based targeted sequencing, immunohistochemistry, gene expression profiling and Sanger sequencing.Results: Three patients harboring NF1 inactivating mutations were identified and excluded from further analysis. Intriguingly, five patients carried cryptic KIT alterations, mainly represented by low-allele-fraction mutations (12–16% allele ratio). These mutations were confirmed by another targeted NGS approaches and supported by CD117 immuno-staining, gene expression profiling, Sanger sequencing, with peak signals at the level of background noise, and by the patients' clinical course assessment.Conclusion: This study indicates that ~20% patients diagnosed with a KIT/PDGFRA/SDH/RAS-pathway wild-type GIST are bona-fide carriers of pathogenic KIT mutations, thus expected to be eligible for and responsive to the various therapeutic lines of TK-inhibitors in use for KIT/PDGFRA-mutant GIST. The centralization for a second level molecular analysis of GIST samples diagnosed as wild-type for KIT and PDGFRA is once again strongly recommended.
Highlights
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors arising in the gastrointestinal tract [1]
Only private or hardly recurrent alterations have been identified in this GIST subgroup, such as ETV6-NTRK3, FGFR1, or FGF4 alterations, MAX, MEN1 [14,15,16,17], and still no conclusive result has been found on the actionable mutations for this subset of patients
The series consisted of 26 GIST specimens selected as negative for KIT/PDGFRA/BRAF/NRAS/KRAS mutations and with intact succinate dehydrogenase complex (SDH) complex, whose molecular characterization was performed by Sanger sequencing and immunohistochemistry
Summary
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors arising in the gastrointestinal tract [1]. This very heterogeneous category includes around 20–40% of cases that are succinate dehydrogenase complex (SDH)-deficient GIST, due to germline and/or somatic loss-of-function mutations in any of the four SDH subunits (A, B, C, or D) [7,8,9] Another subgroup of KIT/PDGFRA wild-type GIST with intact SDH complex, collectively defined as RAS-pathway (RAS-P)-mutant GIST, includes patients that either carry inactivating mutations in NF1 gene, often signaling an unrecognized NF1 syndromic condition [10, 11], or activating mutations in BRAF or more rarely a RAS gene [12, 13]. 10% of GISTs are devoid of any of such mutations and are characterized by very limited therapeutic opportunities and poor response to standard treatments
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