Microsatellite instability in aberrant crypt foci from patients without concurrent colon cancer
Microsatellite instability in aberrant crypt foci from patients without concurrent colon cancer
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DOI：
10.1093/carcin/bgl209
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发表时间：
2007-04-01
期刊：
影响因子：
4.7
通讯作者：
Heinen, Christopher D.
中科院分区：
文献类型：
--
作者：
Greenspan, Emily J.;Cyr, Jennifer L.;Heinen, Christopher D.
异常隐窝病灶(ACF)是一种显微镜下的表面异常，可能是结直肠癌(CRC)的先兆。ACF表现出与腺瘤和结直肠癌相似的组织和分子异常，可能是癌症风险的有用生物标记物。微卫星不稳定性(MSI)是在CRC患者并发ACF中发现的一种分子异常，可能预示着进展的风险。为了确定是否可以在非癌症受试者的ACF中检测到MSI，我们检查了20名接受结肠镜检查的受试者的45例ACF。这组患者包括12名根据结直肠癌家族史或个人结直肠癌病史或晚期腺瘤病史而患结直肠癌风险升高的患者，以及8名没有已知危险因素的患者。用近焦放大色内窥镜检查ACF，并进行原位活检。用激光捕获显微切割技术分离ACF和邻近的正常结肠上皮，提取基因组DNA，并进行MSI分析。来自结直肠癌高风险患者的30个病变中有9个(30%)至少有一个标志物被确定，而来自中等风险患者的15个病变中有2个(13%)被确定为MSI。利用甲基化特异的PCR分析，我们还检测了ACF对DNA修复基因hMLH1和MGMT启动子的超甲基化，发现中度变化(分别为8/39和3/32)。虽然我们发现hMLH1高甲基化与MSI之间的关系有限，但所有MGMT高甲基化的病变都表现出MSI低的表型。这些病变可能是MSI-low CRC的先兆，为评估癌症预防策略的效果提供了一个潜在的早期生物标志物。
Aberrant crypt foci (ACF) are microscopic surface abnormalities that are putative precursors to colorectal cancer (CRC). ACF exhibit similar histological and molecular abnormalities to adenomas and CRC and potentially represent useful biomarkers of cancer risk. Microsatellite instability (MSI) is one molecular abnormality identified in concurrent ACF from CRC patients that may indicate a risk for progression. To determine if MSI can be detected in ACF from cancer-free subjects, we examined 45 ACF from 20 subjects undergoing colonoscopies. The group included 12 patients at elevated risk for CRC based on family history of CRC or personal history of CRC or advanced adenoma and 8 patients with no known risk factors. ACF were identified using close-focus magnifying chromendoscopy and collected by biopsy in situ. Genomic DNA was prepared from ACF and adjacent normal colonic epithelium isolated by laser capture microdissection and analyzed for MSI. MSI was identified in at least one marker from 9 of 30 (30%) lesions from patients at elevated risk for CRC and in 2 of 15 (13%) lesions from average risk patients. Using methylation-specific PCR analysis, we also examined the ACF for promoter hypermethylation of the DNA repair genes hMLH1 and MGMT and found moderate changes (8/39 and 3/32, respectively). Although we found only a limited relationship between hMLH1 hypermethylation and MSI, all the lesions with MGMT hypermethylation displayed an MSI-low phenotype. These lesions may be precursors to MSI-low CRC, providing a potential early biomarker to assess the effects of cancer prevention strategies.