用于识别由DNA错配修复基因种系突变引起的早发性结直肠癌的微卫星不稳定性标志物。

Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes.

作者信息

Mead Leeanne J, Jenkins Mark A, Young Joanne, Royce Simon G, Smith Letitia, St John D James B, Macrae Finlay, Giles Graham G, Hopper John L, Southey Melissa C

机构信息

Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.

出版信息

Clin Cancer Res. 2007 May 15;13(10):2865-9. doi: 10.1158/1078-0432.CCR-06-2174.

DOI:10.1158/1078-0432.CCR-06-2174

PMID:17504984

Abstract

PURPOSE

Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes.

EXPERIMENTAL DESIGN

Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel.

RESULTS

The National Cancer Institute five-marker panel system scored 31 (29%) as (NCI)MSI-High, 13 (12%) as (NCI)MSI-Low, and 63 (59%) as (NCI)MS-Stable. The 10-marker panel classified 18 (17%) as (10)MSI-High, 17 (16%) as (10)MSI-Low, and 72 (67%) as (10)MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all (10)MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored (10)MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored (10)MSI-High).

CONCLUSIONS

In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.

摘要

目的

对结直肠癌肿瘤进行微卫星不稳定性（MSI）检测，作为一种筛查工具，以识别最有可能是错配修复（MMR）基因突变携带者的患者。我们想研究目前用于检测MSI的哪些微卫星标记物能最好地预测由MMR基因种系突变引起的早发性结直肠癌。

实验设计

从107例45岁前诊断为结直肠癌的人群样本中获取侵袭性原发性肿瘤，检测其MLH1、MSH2、MSH6和PMS2的种系突变以及MMR蛋白表达，并使用美国国立癌症研究所（NCI）的检测板和一个扩展的包含10个微卫星标记物的检测板对这些肿瘤进行MSI筛查。

结果

NCI的五标记物检测板系统将31例（29%）判定为（NCI）MSI-High，13例（12%）判定为（NCI）MSI-Low，63例（59%）判定为（NCI）MS-Stable。10标记物检测板将18例（17%）判定为（10）MSI-High，17例（16%）判定为（10）MSI-Low，72例（67%）判定为（10）MS-Stable。在26例至少缺乏一种MMR基因表达的癌症中，24例（92%）在某种程度上MSI呈阳性（使用任一微卫星检测板）。单核苷酸重复序列Bat26、Bat40和Myb在所有（10）MSI-High癌症以及所有MLH1和MSH2突变携带者中均不稳定（敏感性为100%）。Bat40和Bat25在所有MSH6突变携带者的肿瘤中均不稳定（敏感性为100%）。Bat40在所有MMR基因突变携带者中均不稳定（敏感性为100%）。通过将七个单核苷酸重复标记物纳入10标记物检测板，我们能够区分MSH6突变携带者（均判定为（10）MSI-Low）和MLH1及MSH2突变携带者（均判定为（10）MSI-High）。