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Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib.

ABSTRACT: Gastrointestinal stromal tumors carry in about 85% of the cases activating mutations in KIT gene. Generally only one KIT mutation is found in primary tumors and the majority of mutations affecting KIT exon 11 is sensitive to Imatinib. We report upon a GIST case harboring a double-mutant KIT gene at exon 11, which expresses a receptor bearing the known activating W557G mutation and a newly discovered missense Y578C alteration. The relative affinities for ATP and Imatinib of each single (W557G, Y578C) and double (W557G/Y578C) mutant KITs were predicted by in silico studies (computer-based molecular simulations), and compared with those obtained for known Imatinib sensitive and resistant KIT mutants. In parallel, biochemical analysis of the single and double KIT mutants expressed in mammalian cells was performed. Both the in-silico/in-vitro investigations showed constitutive activation and sensitivity to Imatinib of the yet mentioned Y578C mutation as well as of the double mutant, providing evidence that the concomitant presence of the W557G and Y578C mutations does not affect Imatinib response compare to the single mutations, in line with what observed in Imatinib treated patient.

SUBMITTER: Conca E

PROVIDER: S-EPMC5528426 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib.

Conca Elena E Miranda Claudia C Dal Col Valentina V Fumagalli Elena E Pelosi Giuseppe G Mazzoni Mara M Fermeglia Maurizio M Laurini Erik E Pierotti Marco A MA Pilotti Silvana S Greco Angela A Pricl Sabrina S Tamborini Elena E

Molecular oncology 20130321 4

Gastrointestinal stromal tumors carry in about 85% of the cases activating mutations in KIT gene. Generally only one KIT mutation is found in primary tumors and the majority of mutations affecting KIT exon 11 is sensitive to Imatinib. We report upon a GIST case harboring a double-mutant KIT gene at exon 11, which expresses a receptor bearing the known activating W557G mutation and a newly discovered missense Y578C alteration. The relative affinities for ATP and Imatinib of each single (W557G, Y5 ...[more]

PMID: 23567324

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Project description:BACKGROUND: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813-3825, 2004; Hematol Oncol Clin North Am 23:15-34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. METHODS: We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. RESULTS: We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). CONCLUSION: We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors.

Dataset Information

Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib.

Publications

Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib.

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