| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
1.To elucidate the real incidence of GISTs in the stomach, 100 whole stomachs, resected from patients with gastric cancer, were sectioned at 5 mm intervals, and hematoxyline and eosin-stained slides (a mean 130 slides for each case) were examined for microscopic GISTs. KIT (CD117), CD34 and desmin expression of the incidental tumors was evaluated by immunohistochemistry, and genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissues was analyzed for c-kit gene mutations in exon 11. In 35 of the 100 whole stomachs, we found a total of 50 microscopic GISTs, all of which were positive for KIT and/or CD34, and negative for desmin and two of the 25 (8%) microscopic GISTs had c-kit gene mutations. These results indicate that microscopic GISTs are common in the upper portion of the stomach. Considering the annual incidence of clinical GISTs, only a few microscopic GISTs may grow to a clinical size with malignant potential. Further studies are required to clarify the genetic ev
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ents responsible for the transformation of microscopic to clinical GISTs.
2.To investigate additional alterations to c-kit or PDGFRA gene in GISTs, we analyzed for methylation status of GISTs and compared those results according to malignant potential or mutation types of GISTs. Thirty-five GISTs (25 cases with c-kit mutations, 7 cases with PDGFRA mutations and 3 cases lacking either mutations) were subjected to the analysis of methylation-specific polymerase chain reaction (MSP) to detect methylation status of nine independent CpG islands (p15, p16, p73, MGMT, E-cadherin, hMLH1, MINT (methylated in tumors) 1, MINT2, MINT31). Aberrant DNA methylation of these loci was found in 94% of all GISTs. The rate of hypermethylation in each locus was as follows : hMLH1(60%), MINT2(51%), MGMT(49%), p73(49%), p16(20%), E-cadeherin(14%), MINT1(9%), p15(6%) and MINT31(0%). Although the numbers of cases were few, GISTs lacking any mutations showed higher rate of methylation (3.3 loci on average) than that in GISTs with c-kit or PDGFRA gene (2.5 loci on average). Aberrant methylation of CpG islands, especially such as mismatch repair genes, may participate play an important role in the early stage of tumor development of GISTs addition to c-kit or PDGFRA gene or GISTs without those mutations. Less
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