One patient had three tumors, one had five, and one had greater than 10 tumor nodules, all of which demonstrated histologic features characteristic of gastrointestinal stromal tumors and stained strongly for CD117 and CD34.
Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings.
Most KIT mutations occur in untreated GISTs in the juxtamembrane exon 11 and only rarely in the kinase domain, whereas in imatinib-treated patients secondary mutations are frequent in exons encoding for the ATP/imatinib binding pocket or the kinase activation loop.
We evaluated GISTs from three females with incomplete Carney triad for KIT and PDGFRA mutations and studied the DNA by comparative genomic hybridization (CGH).
In conclusion, contrasting with the regulation of other tyrosine kinase receptors, KIT overexpression in GISTs is rarely related to a gene amplification, which suggests a deregulation of KIT gene transcription.
Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-α mutation (n. 2) and exon 18 PDGFR-α mutation (n. 4).
From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations.
Approximately 85% of GISTs are driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT or platelet-derived growth factor receptor alpha.
Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option.
Gastrointestinal stromal tumors (GIST) are stromal or mesenchymal subepithelial neoplasms affecting the gastrointestinal tract and frequently contain activating gene mutations in either KIT or platelet-derived growth factor A (PDGFRA).
The clinico-pathological and genetic factors influencing disease-free survival (DFS) in 335 patients with primary CD117-immunopositive tumors (group A; calculated from primary tumor resection) and progression-free survival (PFS) in 232 metastatic/unresectable GIST patients treated with IM (group B; calculated from the start of imatinib therapy) were analyzed.
Mutations in exon 9 of KIT were present in 5.1% of the gastrointestinal stromal tumors, and mutations of the PDGFR were present in 11% of the KIT -nonmutated tumors.
As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias.