EXLPLOITATION OF NEW DIAGNOSTIC PROCEDURES OF HUMAN ENDOMETRIAL CANCERS IN RELATION TO CYTOGENETIC MECHANISMS OF MULTI-STEP CARCINOGENESIS ELUCIDATED WITH CGH

我们分析了29例子宫内膜癌组织中转化生长因子βRII、BAX和PTEN/MMAC1基因的突变状态以及微卫星不稳定性(MI)。为了检测携带这些基因的染色体区域的拷贝数丢失，我们使用了比较基因组杂交(CGH)分析。CGH分析可以提供与肿瘤相关的基因组失衡的全基因组概览。在9例表现为MI+表型的肿瘤中，4例(44%)PTEN/MMAC1基因发生了显著突变，并伴有明显的氨基酸改变。CGH分析显示，4例肿瘤(100%)均有该基因位点附近的染色体拷贝数丢失，而在7例PTEN/MMAC1突变的肿瘤中，有4例(57%)在MI癌中出现染色体丢失或双突变。转化生长因子βRII和bax基因作为MI+表型的靶基因在子宫内膜癌中的作用有限，因为在MI+的子宫内膜癌中检测到了几个突变，但CGH只在一个突变的子宫内膜癌中发现了染色体丢失。根据CGH结果，在1q、9q、2q、12q存在染色体不平衡。在这一系列子宫内膜中，β-连环蛋白的胞浆/胞核异常聚集频繁。

We analyzed the mutational status of the TGFβRII, BAX, and PTEN/MMAC1 genes as well as microsatellite instability (MI) in 29 consecutive cases of endometrial carcinoma operated on at our Institute. To examine copy number loss at the chromosomal regions bearing these genes, we used comparative genomic hybridization (CGH) analysis. CGH analysis may provides a genome-wide overview about tumor-associated genomic imbalances. Among nine tumors that showed the MI+ phenotype, four (44%) demonstrated a significant mutation with a definite amino acid change in PTEN/MMAC1 gene. CGH analysis demonstrated that all the four tumors (100%) showed chromosomal copy number loss around the locus of this gene, whereas four (57%) of seven tumors with PTEN/MMAC1 mutations showed chromosomal loss or double mutations in MI- carcinomas. The role of TGFβRII and BAX genes is limited as a target gene of MI+ phenotype in endometrial cancer, because several mutations of these genes were detected but a chromosomal loss was demonstrated by CGH in only one tumor in MI+ endometrial cancers with mutation. According to CGH results, chromosomal imbalances were demonstrated at 1q, 9q, 2q, 12q. Frequent abnormal cytoplasmic/ nuclear accumulation of β-catenin was observed in this endometrial series.