Prognostic relevance of genetic aberrations in gastrointestinal stromal tumors.

Abstract

49 Background: Gastrointestinal stromal tumours (GISTs) contain oncogenic KIT or PDGFRA tyrosine kinase (TK) mutations leading to disturbance of downstream signaling pathways that contribute to GIST pathogenesis. Additional genetic aberrations were found in GISTs, demonstrating the involvement of other genes important in tumor progression. The aim of the study was to evaluate the prognostic relevance of different TK mutations in GISTs and to analyze the additional genetic aberrations in GISTs according to mutational status. Methods: 180 GIST patients were examined for KIT (9, 11, 13, 17 exons) and PDGFRA mutations (12, 14, 18 exons) by direct sequencing of DNA obtained from microdissected tumor sections. Tumor tissue DNA from 44 GISTs patients was screened for loss of heterozygosity (LOH) at 11 microsatellite loci on 1p, 9p, 14q, 15q and 22q arms. Results: KIT and PDGFRA mutations were identified in 76.1% and 10% of GISTs, respectively. 13.9% GISTs had no mutations (wild type). Most of KIT mutations were located in exon 11 (65%) and exon 9 (9.4%). Prognostic significance of TK mutations was evaluated. There was a trend of better survival for patients with PDGFRA mutation then with KIT mutation or wild type GISTs. The higher overall survival prior to target therapy was shown for patients with duplication or point mutation in KIT exon 11 in comparison to exon 11 deletion. Analysis of LOH revealed allelic deletions in 85% of GISTs, more frequently at 14q arm. There was a different LOH pattern in subgroups of GISTs. GISTs with PDGFRA mutation and with KIT exon 11 point mutation had LOH at 14q, while GISTs with KIT exon 11 deletions revealed high LOH frequency also on 22q, 15q and 1p arms. LOH in wild type GISTs occurred on all chromosomes with low frequency. LOH on 9p was found exclusively in metastatic and recurrent GISTs. Specific gene loci of frequent LOH were identified on 9p, 15q and 22q that may be contributed to GIST progression. Conclusions: Specific mutations are associated with GISTs prognosis. Tumors with point mutations and duplications in KIT exon 11 are associated with a better survival then GISTs with other KIT mutations. Specific pattern of allelic deletions was identified in subgroups of GISTs according to type of mutation and tumor progression. No significant financial relationships to disclose.

Does Immunohistochemistry Provide Additional Prognostic Data in Gastrointestinal Stromal Tumors?

“…Tumor size, origin and mitotic activity are the leading features that have been widely approved as being predictive of clinical outcome for resected GIST patients (Dematteo et al, 2008). The discovery of the particular molecular abnormalities and mutational analyses provided to define certain GIST subtypes that demonstrate divergent responses to TKI therapy and had different clinical behavior (Mazurenko et al, 2011). Previous studies demonstrated that KIT exon 11 mutations show the greatest benefit from imatinib treatment, while the patients with exon 9 mutations require a higher imatinib dosage to reach a higher response and are associated with a worse course than the patients with exon 11 mutations (Singer et al, 2002;Debiec-Rychter et al, 2006).…”

Current management and prognostic features for gastrointestinal stromal tumor (GIST)

“…In patients with KIT mutations, point mutations and duplication in KIT axon 11 had better survival than GIST with other KIT mutations [111]. …”