| Co-Investigator(Kenkyū-buntansha) |
OSANAI Takayuki Tokyo Medical & Dental University, instructor, 大学院・医歯学総合研究科, 助手 (50301164)
ICHIKAWA Wataru Tokyo Medical & Dental University, instructor, 大学院・医歯学総合研究科, 助手 (70282738)
飯田 聡 東京医科歯科大学, 医学部, 助手
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1998: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Despite a decreasing incidence, gastric cancer remains a major cause of cancer death worldwide. Recently, in three FGC kindreds in New Zealand, germ-line mutations of the E-cadherin gene were found. To determine whether or not nerm-line mutation of the E-cadherin gene is also responsible for the predisposition to Japanese FGC, we analyzed all of the exons of E-cadherin by PCR-single-strand conformational polymorphism analysis in 16 patients from 14 Japanese familial gastric cancer(FGC)kindreds. However, no germ-line mutation was detected, suggesting that a predisposition to FGCs by E-dacherin gene mutation is infrequent in Japanese cases.
p 14^<ARF>, generated through an alternative splicing process that replaces the first exon, Ia, of p16^<1NK4a> with exon Ib, located > 15kb upstream of exon Ia, has been shown to function as a growth suppressor. We examined 11 gastric cancer cell lines for mRNA expression, homozygous deletion, mutation, and promoter methylation of the p 14^<ARF> gene. No mRNA expression was detected in 5 of the 7 diffuse-type cell lines. All intestinal cell lines displayed normal levels of expression except for one with a low level of expression. Of the 3 cell lines without expression, 3(MKN45, NUGC-2, and NUGC-4)and 1(KATO III)displayed homozygous deletion and methylation of the p 14^<ARF> gene, respectively. No mutation was found in the whole coding region of the p 14^<ARF> gene in 8 cell lines without homozygous deletion. Our results indicate that the p 14^<ARF> gene is more frequently inactivated by homozygous deletion or methylation in diffuse-type gastric cancer cell lines(5/7, 71.4%)than in intestinal ones(0/4, P=0.022). When we also analyzed 62 primary gastric cancers for the methylation status of the p 14^<ARF> promoter region, the methylation frequency tended to be higher in diffuse-type gastric cancers(15/33, 45.5%)than in intestinal ones(7/28, 25%). Thus, p 14^<ARF> alterations might be involved in diffuse-type gastric carcinogenesis.
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