Allelic loss of 14q and 22q, NF2 mutation, and genetic instability occur independently of c-kit mutation in gastrointestinal stromal tumor

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Since c-kit mutation occurs only in one-thir d of GIST, there might be other molecular mechanisms. Loss of heterozygosit y (LOH), microsatellite instability (MSI) and NF2 gene mutation were invest igated in 22 GISTs (9 low-risk and 13 high-risk tumors). LOH and MSI were e valuated using 41 markers on 21 chromosomal arms, and NF2 gene mutation was examined by PCR-SSCP. High frequency of LOH was observed on 14q (9/19, 47% ), and 22q (17/22, 77%). The frequencies were similar in low-risk and high- risk tumors, and were unrelated with gastric or intestinal origin. Two othe r abnormalities, additional LOH on other chromosomes and MSI at more than t wo loci, were characteristic of the high-risk tumors (P<0.05). NF2 gene mut ation was identified in two cases showing 22q-LOH (8 bp deletion on the spl ice donor site of exon 7, and 1 bp insertion at position 432 of exon 4, whi ch resulted in nonsense mutation). There was no significant correlation bet ween these results and c-kit gene mutation, which was observed in 8 of 22 t umors. Suppressor genes on 14q and 22q may be involved, independently of c- kit gene mutation, in the development of GIST. NF2 contributes as a tumor s uppressor in a small subset of GIST. These abnormalities are presumably fol lowed by increased genetic instability.