INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', 184 rue du Faubourg Saint-Antoine, Paris F-75012, France.
Br J Cancer. 2010 Dec 7;103(12):1840-5. doi: 10.1038/sj.bjc.6605988. Epub 2010 Nov 16.
microsatellite instability (MSI) is commonly screened using a panel of two mononucleotide and three dinucleotide repeats as recommended by a consensus meeting on MSI tumours held at the National Cancer Institute (Bethesda, MD, USA). According to these recommendations, tumours are classified as MSI-H when at least two of the five microsatellite markers show instability, MSI-L when only one marker shows instability and MSS when none of the markers show instability. Almost all MSI-H tumours are characterised by alterations in one of the four major proteins of the mismatch repair (MMR) system (MLH1, MSH2, MSH6 or PMS2) that renders them MMR deficient, whereas MSI-L and MSS tumours are generally MMR proficient. However, tumours from patients with a pathogenic germline mutation in MSH6 can sometimes present an MSI-L phenotype with the NCI panel. The MSH6 protein is not involved in the repair of mismatches of two nucleotides in length and consequently the three dinucleotide repeats of the NCI panel often show stability in MSH6-deficient tumours.
a pentaplex panel comprising five mononucleotide repeats has been recommended as an alternative to the NCI panel to determine tumour MSI status. Several studies have confirmed the sensitivity, specificity and ease of use of the pentaplex panel; however, its sensitivity for the detection of MSH6-deficient tumours is so far unknown. Here, we used the pentaplex panel to evaluate MSI status in 29 tumours known to harbour an MSH6 defect.
MSI-H status was confirmed in 15 out of 15 (100%) cases where matching normal DNA was available and in 28 out of 29 (97%) cases where matching DNA was not available or was not analysed.
these results show that the pentaplex assay efficiently discriminates the MSI status of tumours with an MSH6 defect.
微卫星不稳定性 (MSI) 通常使用由美国国立癌症研究所 (马里兰州贝塞斯达) 举行的 MSI 肿瘤共识会议推荐的两个单核昔酸和三个二核昔酸重复的面板进行筛选。根据这些建议，如果五个微卫星标记中的至少两个显示不稳定，则将肿瘤分类为 MSI-H，如果只有一个标记显示不稳定，则分类为 MSI-L，如果没有标记显示不稳定，则分类为 MSS。几乎所有的 MSI-H 肿瘤都具有错配修复 (MMR) 系统的四个主要蛋白之一的改变（MLH1、MSH2、MSH6 或 PMS2），使其 MMR 缺陷，而 MSI-L 和 MSS 肿瘤通常是 MMR 功能正常。然而，来自 MSH6 种系突变致病性患者的肿瘤有时可能会出现 MSI-L 表型，使用 NCI 面板。MSH6 蛋白不参与两个核苷酸长度的错配修复，因此 NCI 面板的三个二核昔酸重复通常在 MSH6 缺陷肿瘤中显示稳定性。
已经推荐了包含五个单核昔酸重复的五重面板作为替代 NCI 面板来确定肿瘤 MSI 状态。几项研究已经证实了五重面板的敏感性、特异性和易用性；然而，其检测 MSH6 缺陷肿瘤的敏感性迄今为止尚不清楚。在这里，我们使用五重面板评估了 29 个已知存在 MSH6 缺陷的肿瘤的 MSI 状态。
在有匹配正常 DNA 的 15 例病例中，确认了 MSI-H 状态，在 29 例病例中，有匹配 DNA 不可用或未进行分析的情况下，确认了 28 例（97%）MSI-H 状态。
这些结果表明，五重检测法能够有效地鉴别具有 MSH6 缺陷的肿瘤的 MSI 状态。
