Kanaya Taro, Kyo Satoru, Sakaguchi Junko, Maida Yoshiko, Nakamura Mitsuhiro, Takakura Masahiro, Hashimoto Manabu, Mizumoto Yasunari, Inoue Masaki
Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, Kanazawa, Japan.
Am J Clin Pathol. 2005 Jul;124(1):89-96. doi: 10.1309/PAACLG8DXDK0X2B1.
We studied mismatch repair deficiency and PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutations in endometrial cancers and hyperplasias in a Japanese population. Methylation-sensitive restriction enzyme polymerase chain reaction revealed MLH1 hypermethylation in 21 (38%) of 56 endometrial cancers. Sequencing analysis revealed PTEN mutations in 22 patients with cancer (39%) in exons 5 and 8. A PTEN frameshift mutation was associated significantly with MLH1 hypermethylation (P = .01) and a highly positive phenotype with microsatellite instability (P < .001) but not with a PTEN missense mutation. In hyperplasia, MLH1 hypermethylation was similarly observed (11/27 [41%]), but the PTEN mutation was less frequent (5/27 [19%]), observed only in atypical hyperplasias; among the 5 patients with a PTEN mutation, the 2 patients with frameshift mutations had MLH1 hypermethylation, but the 3 patients with missense mutations had unmethylated MLH1. These findings indicate that MLH1 hypermethylation is an early event frequently occurring in hyperplasia without atypia, whereas the PTEN mutation occurs later, mostly in atypical hyperplasia, possibly caused by MLH1 hypermethylation.
我们在日本人群中研究了子宫内膜癌和子宫内膜增生中的错配修复缺陷及PTEN（第10号染色体缺失的磷酸酶及张力蛋白同源物）突变情况。甲基化敏感限制性内切酶聚合酶链反应显示，56例子宫内膜癌中有21例（38%）存在MLH1高甲基化。测序分析显示，22例癌症患者（39%）的第5和第8外显子存在PTEN突变。PTEN移码突变与MLH1高甲基化显著相关（P = 0.01），与微卫星不稳定性的高度阳性表型显著相关（P < 0.001），但与PTEN错义突变无关。在增生中，同样观察到MLH1高甲基化（11/27 [41%]），但PTEN突变较少见（5/27 [19%]），仅在非典型增生中观察到；在5例有PTEN突变的患者中，2例有移码突变的患者存在MLH1高甲基化，而3例有错义突变的患者MLH1未甲基化。这些发现表明，MLH1高甲基化是增生（无非典型增生）中频繁发生的早期事件，而PTEN突变发生较晚，主要发生在非典型增生中，可能由MLH1高甲基化引起。
