Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes
Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes
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DOI：
10.1158/1078-0432.ccr-06-2174
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发表时间：
2007-05-15
影响因子：
11.5
通讯作者：
Southey, Melissa C.
中科院分区：
文献类型：
--
作者：
Mead, Leeanne J.;Jenkins, Mark A.;Southey, Melissa C.
目的：结直肠癌微卫星不稳定性(MSI)检测是一种筛查工具，用于确定最有可能是错配修复(MMR)基因突变携带者的患者。我们想要检查目前用于检测MSI的哪些微卫星标记最能预测由MMR基因的胚系突变引起的早发性结直肠癌。实验设计：从107例45岁之前确诊的结直肠癌患者的基于人群的侵袭性原发肿瘤样本中检测MLH1、MSH2、MSH6和PMS2的胚系突变，并使用国家癌症研究所小组和扩展的10个微卫星标记小组对MSI进行筛查。结果：国家癌症研究所五个标记小组系统将31(29%)评分为(MSI)-M-NCI-High，13例(12%)为(MSI)-M-NCI-低，63例(59%)为NCIMS稳定。10项指标分为(MSI)-M-10-高18例(17%)，(MSI)-M-10-低17例(16%)，(MS)-M-10-稳定72例(67%)。在26个缺乏至少一个MMR基因表达的癌症中，24个(92%)的MSI呈不同程度的阳性(使用任何一个微卫星面板)。单核苷酸重复序列Bat26、Bat40和Myb在ALL(MSI)-M-10-High癌和所有MLH1和MSH2突变携带者(100%敏感)中不稳定。在MSH6突变携带者的所有肿瘤中，BAT40和BAT25不稳定(100%敏感)。BAT40在所有MMR基因突变携带者中均不稳定(100%敏感)。通过将7个单核苷酸重复序列标记引入10标记组，我们能够区分出MSH6突变携带者(MSI-M-10-Low)和MLH1和MSH2突变携带者(MSI-M-10-High)。结论：在早发性结直肠癌中，包含高比例单核重复序列的微卫星小组可以区分MLH1和MSH2突变引起的肿瘤和MSH6突变引起的肿瘤。
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 (MSI)-M-NCI- High, 13 (12%) as (MSI)-M-NCI-Low, and 63 (59%) as NCIMS-Stable. The 10-marker panel classified 18 (17%) as (MSI)-M-10-High, 17 (16%) as (MSI)-M-10-Low, and 72 (67%) as (MS)-M-10-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 (MSI)-M-10-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in Ell] 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 (MSI)-M-10-Low) from the MLH1 and MSH2 mutation carriers (all scored (MSI)-M-10-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.