Baldinu Paola, Cossu Antonio, Manca Antonella, Satta Maria P, Pisano Marina, Casula Milena, Dessole Salvatore, Pintus Adriana, Tanda Francesco, Palmieri Giuseppe
Institute of Molecular Genetics, C.N.R., Località Tramariglio, Santa Maria La Palma (Sassari), Italy.
Cancer. 2002 Jun 15;94(12):3157-68. doi: 10.1002/cncr.10606.
Microsatellite instability (MSI) is due mostly to a defective DNA mismatch repair (MMR). Inactivation of the two principal MMR genes, hMLH1 and hMSH2, and the PTEN tumor suppressor gene seems to be involved in endometrial tumorigenesis. In this study, Sardinian patients with endometrial carcinoma (EC) were analyzed to assess the prevalence of both the mutator phenotype (as defined by the presence of MSI and abnormal MMR gene expression at the somatic level) and the hMLH1, hMSH2, and PTEN germline mutations among patients with MSI positive EC.
Paraffin embedded tissue samples from 116 consecutive patients with EC were screened for MSI by polymerase chain reaction-based microsatellite analysis. Immunohistochemistry (IHC) with anti-hMLH1 and anti-hMSH2 antibodies was performed on MSI positive tumor tissue sections. Germline DNA was used for mutational screening by denaturing high-performance liquid chromatography analysis and automated sequencing.
Thirty-nine patients with EC (34%) exhibited MSI; among them, 25 tumor samples (64%) showed negative immunostaining for hMLH1/hMSH2 proteins (referred to as IHC negative). No disease-causing mutation within the coding sequences of the hMLH1/hMSH2 and PTEN genes was found in patients with EC who had the mutator phenotype (MSI positive and IHC negative), except for a newly described hMLH1 missense mutation, Ile655Val, that was observed in 1 of 27 patients (4%). Although MSI was more common among patients with advanced-stage EC and increased as the tumor grade increased, no significant correlation with disease free survival or overall survival was observed among the two groups (MSI positive or MSI negative) of patients with EC.
In patients with MSI positive EC, epigenetic inactivations rather than genetic mutations of the MMR genes seem to be involved in endometrial tumorigenesis. No prognostic value was demonstrated for MSI in patients with EC.
微卫星不稳定性（MSI）主要归因于DNA错配修复（MMR）缺陷。两个主要的MMR基因hMLH1和hMSH2以及PTEN肿瘤抑制基因的失活似乎与子宫内膜肿瘤发生有关。在本研究中，对撒丁岛子宫内膜癌（EC）患者进行分析，以评估突变体表型（由MSI的存在和体细胞水平上异常的MMR基因表达定义）以及MSI阳性EC患者中hMLH1、hMSH2和PTEN种系突变的患病率。
通过基于聚合酶链反应的微卫星分析，对116例连续的EC患者的石蜡包埋组织样本进行MSI筛查。对MSI阳性肿瘤组织切片进行抗hMLH1和抗hMSH2抗体的免疫组织化学（IHC）检测。通过变性高效液相色谱分析和自动测序，将种系DNA用于突变筛查。
39例EC患者（34%）表现出MSI；其中，25个肿瘤样本（64%）显示hMLH1/hMSH2蛋白免疫染色阴性（称为IHC阴性）。在具有突变体表型（MSI阳性和IHC阴性）的EC患者中，未在hMLH1/hMSH2和PTEN基因的编码序列中发现致病突变，但在27例患者中的1例（4%）中观察到一个新描述的hMLH1错义突变Ile655Val。尽管MSI在晚期EC患者中更常见，且随着肿瘤分级增加而增加，但在两组（MSI阳性或MSI阴性）EC患者中，未观察到与无病生存期或总生存期有显著相关性。
在MSI阳性的EC患者中，MMR基因的表观遗传失活而非基因突变似乎参与了子宫内膜肿瘤发生。未证明MSI对EC患者有预后价值。
