Correlation of microsatellite instability (MSI) and sensitivity for anti-cancer drugs in endometrial cancer

子宫内膜癌微卫星不稳定性（MSI）与抗癌药物敏感性的相关性

• 批准号: 15591778
• 负责人: SUSUMU Nobuyuki
• 金额: $ 2.3万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591778/
• 关键词: endometrial cancer; Microsatellite instability(MSJ); DNA Mismatch Repair(MMR) gene; hMLH1; methylation; immunohistochemistry; drug sensitivity test; Histoculture Drug Response Assay(HDRA)

In advanced endometrial cancers, adjuvant chemotherapy is often needed for preventing from recurrence, however, no evidence has been established about which adjuvant therapy is better, chemotherapy or radiotherapy. We, therefore, examined whether microsatellite instability(MSI) is useful maker or not for individualized treatment for patients with endometrial cancers.1 MSI : (1)We analyzed MSI state of clinically obtained specimens of endometrial cancers and several cell lines derived from endometrial cancers by methylation-specific PCR in several MSI markers, and found that 35% cases of endometrial cancers showed MSI and this rate was higher than that of colorectal cancers. (2)In immunohistochemical studies using antibodies against DNA mismatch repair(MMR) proteins of hMLH1, hMSH2, hMSH6, MSI cases showed the reduction of either MMR protein in significantly high rate. However, non-sense mutation of hMLH1 was found only 1 case (6% of MSI cases) and methylation of hMLH1 promoter region w … More as recognized in a significantly higher rate than in microsatellite stability (MSS) cases. Therefore, we considered that the cause of high MSI rate in endometrial cancers is derived from methylation of hMLH1 promoter region.2 Anti-cancer drugs sensitivity test by Histoculture Drug Response Assay(HDRA)By calculating the IC_<50> value in use of MMT assay for cytotoxic effects of cisplatin against tumor tissues obtained from endometrial cancer tissues, we divides those cases into two categories, high-sensitivity group and low-sensitivity group. In 15 MSI cases, 14 cases(93%) were judged as less sensitive. This rate was significantly higher than that of MSS cases. In addition, we confirmed that the low-sensitivities of endometrial cancer cell lines for cisplatin were recovered by adding unmethylation procedures by using Collagen gel droplet enbedded drug sensitivity test (CDDST).Thus, we demonstrated the fact that MSI cases is less sensitive for the first time. Furthermore, we showed that the methylation state of hMLH1 promoter region is an important information in choosing the adjuvant therapy(chemotherapy or radiation therapy). Less

在晚期子宫内膜癌中，通常需要辅助化疗以防止复发，然而，没有证据表明化疗或放疗哪个辅助治疗更好。因此，我们研究了微卫星不稳定性（MSI）是否是子宫内膜癌患者个体化治疗的有用标记。1 MSI：（1）采用甲基化特异性PCR技术，对临床上获得的子宫内膜癌标本和子宫内膜癌细胞系的MSI状态进行了分析，结果发现35%的子宫内膜癌患者存在MSI，其比例高于结直肠癌。(2)In免疫组化检测hMLH1、hMSH2、hMSH6、MSI的DNA错配修复（MMR）蛋白表达，发现MMR蛋白表达明显减少。hMLH1基因无义突变仅1例（占MSI的6%），hMLH1基因启动子区甲基化阳性率为100%。 ...更多信息 如在显著高于微卫星稳定性（MSS）的情况下所识别的。因此，我们认为子宫内膜癌中高MSI率的原因来自于hMLH1启动子区域的甲基化。2通过组织培养药物反应测定（HISTORY）进行的抗癌药物敏感性试验通过<50>使用MMT测定计算顺铂对从子宫内膜癌组织获得的肿瘤组织的细胞毒性作用的IC_值，我们将这些病例分为两类，高敏感组和低敏感组。在15例MSI病例中，14例（93%）被判定为不敏感。这一比率明显高于MSS病例。此外，我们通过胶原凝胶液滴包埋药敏试验（CDDST）证实了子宫内膜癌细胞系对顺铂的低敏感性通过增加去甲基化程序而恢复，从而首次证实了MSI病例对顺铂的敏感性降低的事实。此外，我们还发现，hMLH1启动子区甲基化状态是选择辅助治疗（化疗或放疗）的重要信息。少

项目成果

妊娠・出産にかかわる婦人科疾患 婦人科悪性疾患

与妊娠、分娩相关的妇科疾病 妇科恶性疾病

• 发表时间: 2003
• 期刊: ペリネイタルケア 22(11)
• 作者: N.Suzuki;D.Aoki;Y.Tamada;N.Susumu;K.Orikawa;K.Tsukazaki;M.Sakayori;A.Suzuki;T.Fukuchi;M.Mukai;K.Kojima-Aikawa;I.Ishida;S.Nozawa;N.Suzuki;K.Banno;S.Nozawa;Nao Suzuki;青木大輔;進 伸幸;青木大輔;青木大輔;N.Masumoto;N.Susumu;K.Banno;A.Hirasawa;E.Saito;A.Hirasawa;阪埜浩司;阪埜浩司;青木大輔;青木大輔
• 通讯作者: 青木大輔

A.Hirasawa: "Unfavorable prognostic factors associated with high frequency of microsatellite instability and comparative genomic hybridization analysis in endometrial cancer"Clinical Cancer Research. 9(15). 5675-5682 (2003)

A.Hirasawa：“子宫内膜癌中与高频率微卫星不稳定性相关的不利预后因素和比较基因组杂交分析”临床癌症研究。

阪埜 浩司: "遺伝性子宮内膜癌とは-特にDNAミスマッチ修復遺伝子について"産婦人科の世界. 55(8). 3-10 (2003)

Koji Sakano：“什么是遗传性子宫内膜癌 - 特别是关于 DNA 错配修复基因”《妇产科世界》55(8) (2003)。

Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets.

• 发表时间: 2003-06
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: A. Hirasawa;F. Saito-Ohara;J. Inoue;D. Aoki;N. Susumu;T. Yokoyama;S. Nozawa;J. Inazawa;I. Imoto

Diagnostic clinical application of two-color fluorescence in situ hybridization that detects chromosome 1 and 17 alterations to direct touch smear and liquid-based thin-layer cytologic preparations of endometrial cancers.

双色荧光原位杂交检测 1 号和 17 号染色体改变的诊断临床应用，用于子宫内膜癌的直接接触涂片和液基薄层细胞学制剂。

• 发表时间: 2005
• 期刊: Int J Gynecol Cancer 15・1
• 作者: Susumu N.;Aoki D.;Inazawa J;et al.
• 通讯作者: et al.