| Co-Investigator(Kenkyū-buntansha) |
AOKI Daisuke Keio University, School of Medicine, Professor, 医学部, 教授 (30167788)
BANNO Kouji Keio University, School of Medicine, Assistant Professor, 医学部, 助手 (70265875)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
In order to indivisualize the post-operative adjuvant treatment of patients with advanced endometrial cancers, we analyzed genetic/epigenetic change of DNA mismatch repair genes using histologic and cytologic specimens and checked sensitivities of anti-cancer drugs and progesterone hormone. We obtained some important findings as described below.
(1)Microsatellite instability (MSI) ;
1.MSI-high (MSI-H) was recognized in 28.5% cases of endometrial cancer.
2.Immunohistochemical study revealed that decreased expression of hMLH1, hMSH2, hMSH6 was recognized in 54%, 12%, 18% in MSI-positive endometrial cancers. Either decrease of the three MMR proteins was recognized in 73% of MSI-positive cases. Especially, decreased expression of hMLH1 is significantly related to MSI, and promoter of hMLH1 gene is highly (92%) methylated.
3.Analysis of germ-line mutation of MMR genes revealed tendency of high mutation rates in hMLH1 and hMSH6 genes in MSI-positive cases.
4.In the analysis of surgical specimens
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of endometrial cancers, hypermethylation of promoter lesions of hMLH1, APC, E-cadherin, PAR- β-, p16 genes is involved in the carcinogenesis of endometrium. Especially, hypermethylation of promoter lesions of hMLH1 is highly (40%) involved (Banno K, et al. Oncol Rep. 2006).
(2)Sensitivity of anti-cancer drugs ;
1.Using CDDST method with pleural effusions and ascites of patients with endometrial cancers, we could judge sensitivity to cisplatin, paclitaxel and docetaxel.
2.In the investigation of hypermethylation of CHFR gene, one of the cell cycle check point gene, with cell lines derived from endometrial cancers, hypermethylation of CHFR gene was related to high sensitivity to taxanes and demethylation caused decrease in sensitivity to taxanes. We recognized for the first time that methylation of CHFR gene may regulate the sensitivity to taxanes in endometrial cancer (Yanokura M, et al. Oncol Rep. 2007).
3.Using immunohistochemistry about cytotoxic CD8-positive lymphocytes infiltrating into the cancer nests (TIL), we recognized that the number of TILs (more than 15/HPF) is significant increased in MSI-H tumors and found that prognosis of the cases with increased TILs (more than 15/HPF) was significantly better than that with decrease TILs. In addition, there was a tendency that sensitivity to cisplatin was high in increased TILs cases.
(3)Sensitivity to Progesterone ;
1.Sixty-seven cases with early stage endometrial cancer were treated by high-dose medroxyprogesterone acetate (MPA) in order to preserve fertility. Remission rates in atypical endometrial hyperplasia, complex, and grade 1 endometrioid adenocarcinoma were 100% and 93.7%, respectively. In some cases, repeated MPA therapy was performed after recurrence in endometrial cavity. Six cases got pregnant and delivered.
2.Recurrence in endometrial cavity tended to occur in high rates in cases with decreased expression of hMLH1 of in cases with persistent genomic alterations detected by two-color FISH (Susumu N, et al. Int J Gynecol Cancer 2005) at the time of termination of MPA therapy. Less
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