de Leeuw W J, Dierssen J, Vasen H F, Wijnen J T, Kenter G G, Meijers-Heijboer H, Brocker-Vriends A, Stormorken A, Moller P, Menko F, Cornelisse C J, Morreau H
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
J Pathol. 2000 Nov;192(3):328-35. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH701>3.0.CO;2-2.
Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes.
在遗传性非息肉病性结直肠癌（HNPCC）背景下发生的结直肠癌和结肠外恶性肿瘤（主要是子宫内膜肿瘤）中，已观察到微卫星重复序列的不稳定性。微卫星不稳定性（MSI）作为人类DNA错配修复（MMR）驱动的子宫黏膜肿瘤发生的一个特征，主要在散发性肿瘤中进行了研究，这些肿瘤主要表现为MLH1的体细胞高甲基化。本研究表明，来自MLH1和MSH2种系突变携带者的所有子宫内膜癌（n = 12）均表现出MSI高表型，涉及所有类型的重复标记，而在来自MSH6突变携带者的子宫内膜癌中，只有36%（11例中的4例）表现出MSI高表型。有趣的是，在来自MSH2突变携带者的子宫内膜增生中发现了MSI高表型，与之形成对比的是，来自MLH1突变携带者的增生表现出MSI稳定表型。在来自MSH6突变携带者的子宫内膜癌和增生中，仅发现单核苷酸重复标记的不稳定性。在31个子宫内膜肿瘤病灶中的29个（94%）中，MSI与MLH1、MSH2和MSH6的免疫组织化学分析相结合，可以预测已鉴定的种系突变。在子宫内膜增生中观察到MSI以及MMR基因蛋白染色改变，支持了MMR基因失活是子宫内膜肿瘤发生早期事件的观点。发现MSI的程度和水平变化与癌的发病年龄之间存在相关性，提示肿瘤进展速率存在差异。仅在MSH2突变携带者中发现增生中MSI频率较高，这可能表明肿瘤进展更快，与癌的发病年龄较早相关。本研究表明，对子宫内膜肿瘤的蛋白染色改变进行评估并结合MSI分析，可能指导MMR基因的突变分析。
