6533b82cfe1ef96bd128fe25

RESEARCH PRODUCT

Homozygous mutations in exon 11 of c-KIT in GIST define a group of high risk patients

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Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the gastrointestinal tract. Gain of function mutations of tyrosine kinase receptors, c-KIT, and PDGFRa have been identified in most GIST; c-KIT exon 11 mutations are the most common. The type of c-KIT or PDGFRa mutation indicates tumor responsiveness to imatinib treatment or progression, although GIST with homozygous mutation has been poorly studied. We analyzed 145 GIST at the immunohistopathologic and genetic levels. Formalin-fixed, paraffin-embedded sections were used for our studies. The histological variables included: mitotic count per 50 HPF, necrosis, pleomorphism, and cell type. The immunophenotype was defined using a battery of antibodies. Furthermore, DNA was extracted and intronic PCR primers were used to amplify exons 9, 11, 13, and 17 of c-KIT and 12 and 18 of PDGFRa. Bidirectional sequencing with specific primers was performed on an ABI 310 sequencer using the BigDye Terminator v1.1 kit. A total of 96 mutations was observed, and from them five cases showed homozygous mutations in exon 11 of c-KIT. No homozygous mutations were observed in other exons of c-KIT or PDGFRa. The five homozygous mutations were: two deletions of codons 557e558, the same deletion plus V559D, deletion of codons 559e573, and deletion of codons 554e559; all mutations were located in the part 50 of the exon 11. Four cases were male, the median age being 59 years (range, 38e78 years). The median tumor size was 15 cm (range, 8e16 cm); four were gastric tumors, and one was derived from the small bowel. The mitotic count was 20 mitoses per 50 HPF (range, 7e32 cm); spindle cell type was present in four cases, and one case showed an epithelioid phenotype. All cases were classified as high risk and expressed c-KIT. Moreover all tumors progressed, and two patients died from the disease. Homozygous mutations in c-KIT define a subgroup of GIST of high risk and poor prognosis. However, more studies with more cases are needed to confirm the aggressiveness of the homozygous mutations in GISTs and the clinical implications. Supported by the following grants: AECC and FIVO, Valencia, Spain. COMPARISON OF CYTOGENETIC AND MOLECULAR GENETIC TOOLS TO ASCERTAIN PROGNOSTIC CHROMOSOMAL ABERRATIONS IN UVEAL MELANOMA