Allelic Loss of 14q and 22q, NF2 Mutation, and Genetic Instability Occur Independently of c-kit Mutation in Gastrointestinal Stromal Tumor

Department of Pathology, GraduateSchool of Medicine, The Tokyo University, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointes-tinal tract. Since c-kit mutation occurs only in one-third of GIST, there might be other molecularmechanisms. Loss of heterozygosity (LOH), microsatellite instability (MSI) and NF2 gene mutationwere investigated in 22 GISTs (9 low-risk and 13 high-risk tumors). LOH and MSI were evaluatedusing 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 frequencieswere similar in low-risk and high-risk tumors, and were unrelated with gastric or intestinal origin.Two other abnormalities, additional LOH on other chromosomes and MSI at more than two loci,were characteristic of the high-risk tumors (P<0.05). NF2 gene mutation was identified in twocases showing 22q-LOH (8 bp deletion on the splice donor site of exon 7, and 1 bp insertion at posi-tion 432 of exon 4, which resulted in nonsense mutation). There was no significant correlationbetween these results and c-kit gene mutation, which was observed in 8 of 22 tumors. Suppressorgenes on 14q and 22q may be involved, independently of c-kit gene mutation, in the development ofGIST. NF2 contributes as a tumor suppressor in a small subset of GIST. These abnormalities arepresumably followed by increased genetic instability.Key words: Gastrointestinal stromal tumor — Allelic loss — Genetic instability — NF2 — c-kit