The Microsatellite Instability Phenotype

微卫星不稳定性表型

基本信息

项目摘要

DESCRIPTION (provided by applicant): Hereditary non-polyposis colon cancer (HNPCC) is a cancer syndrome shown to be the result of a mutator effect - inheritance of gene or genes with mutations detracting from the cells' ability to correct damage to DNA. In HNPCC, dominantly inherited defects in mismatch repair (MMR) genes lead to microsatellite instability after loss of the normal allele function in affected tissue. This is seen in tumor tissue DNA by conducting PCR across a set of microsatellite loci and observing mutant fragments at a minimum of 40% of such loci. The molecular basis of the disease in such families is arrived at by identifying which MMR gene might be responsible by immunohistochemical staining (IHC) of the tumor, and then identifying a significant mutation in that MMR gene segregating with the disease. This works fine when the mutation in the MMR gene knocks out the level of IHC-detectable enzyme after LOH and when the resultant MSI is at high enough level to be detected by simple PCR. However, MMR mutations might produce IHC detectable proteins, which are inefficient but not totally ineffectual. Such "hypomorphic" mutations would allow mutant microsatellite fragments to accumulate but at levels not detectable by standard PCR. Consistent with that hypothesis, HNPCC has been shown to segregate in a significant proportion of families whose cancers do not meet the MSI-IHC-MMR mutation criteria. The molecular basis of their genetic disease can be approached by conducting PCR at the single molecule level in many aliquots of DNA from a sample. With appropriate statistics one can quantify mutant fragments at marker microsatellite loci and generate an MSI phenotype (weighted frequency of mutant alleles over all loci) for that sample. Such small pool PCR (SP-PCR) and will be used here to determine the MSI phenotypes in both the tumor and normal (PBLs) tissues relative to the type of MMR mutation (or lack thereof) in HNPCC pedigrees. We also intend to determine the ability of the procedure to identify individuals at risk in families where no MMR mutation has been identified, and to identify "sporadic" patients carrying germline mutation predisposing to cancer. Finally, we intend to determine the impact of inherited organism-dominant/cell recessive germline mutations on future generations.
描述(申请人提供):遗传性非息肉病性结肠癌(HNPCC)是一种癌症综合征,被证明是突变效应的结果--一个或多个基因的遗传导致细胞纠正DNA损伤的能力下降。在HNPCC中,主要遗传的错配修复(MMR)基因导致组织中正常等位基因功能丧失后导致微卫星不稳定性。在肿瘤组织DNA中可以看到这一点,方法是在一组微卫星基因座上进行聚合酶链式反应,并观察至少40%这样的基因座的突变片段。在这些家系中,疾病的分子基础是通过肿瘤的免疫组织化学染色(IHC)确定哪个MMR基因可能负责,然后确定与疾病分离的MMR基因中的一个显著突变。当MMR基因的突变敲除了LOH后IHC可检测到的酶的水平,并且所产生的MSI处于足够高的水平,可以通过简单的PCR检测时,这种方法效果很好。然而,MMR突变可能产生IHC可检测到的蛋白质,这些蛋白质效率低下,但并非完全无效。这种“亚型”突变将允许突变的微卫星片段积累,但水平无法被标准的聚合酶链式反应检测到。与这一假设一致,HNPCC已被证明在其癌症不符合MSI-IHC-MMR突变标准的相当大比例的家庭中分离。他们遗传病的分子基础可以通过对样本中多个等量DNA进行单分子水平的聚合酶链式反应来探讨。通过适当的统计,人们可以量化标记微卫星座位上的突变片段,并为该样本生成MSI表型(所有座位上突变等位基因的加权频率)。这种小池聚合酶链式反应(SP-PCR),并将在此用于确定肿瘤组织和正常(PBL)组织中与HNPCC家系中MMR突变类型(或缺失)相关的MSI表型。我们还打算确定该程序在未发现MMR突变的家庭中识别高危个体的能力,以及识别携带生殖系突变易患癌症的“零星”患者的能力。最后,我们打算确定遗传性生物显性/细胞隐性生殖系突变对后代的影响。

项目成果

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MICHAEL J SICILIANO其他文献

MICHAEL J SICILIANO的其他文献

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{{ truncateString('MICHAEL J SICILIANO', 18)}}的其他基金

The Microsatellite Instability Phenotype
微卫星不稳定性表型
  • 批准号:
    6985733
  • 财政年份:
    2005
  • 资助金额:
    $ 26.21万
  • 项目类别:
The Microsatellite Instability Phenotype
微卫星不稳定性表型
  • 批准号:
    7274262
  • 财政年份:
    2005
  • 资助金额:
    $ 26.21万
  • 项目类别:
The Microsatellite Instability Phenotype
微卫星不稳定性表型
  • 批准号:
    6606902
  • 财政年份:
    2002
  • 资助金额:
    $ 26.21万
  • 项目类别:
The Microsatellite Instability Phenotype
微卫星不稳定性表型
  • 批准号:
    6464696
  • 财政年份:
    2002
  • 资助金额:
    $ 26.21万
  • 项目类别:
CORE--MINIMAL DISEASE DETECTION BY FISH
核心——鱼类微小疾病检测
  • 批准号:
    6332468
  • 财政年份:
    2000
  • 资助金额:
    $ 26.21万
  • 项目类别:
GENOMIC INSTABILITY IN FAMILIAL CANCER SYNDROMES
家族性癌症综合征的基因组不稳定性
  • 批准号:
    6357986
  • 财政年份:
    2000
  • 资助金额:
    $ 26.21万
  • 项目类别:
CORE--HYPERMETAPHASE FISH AND PCR IN ACUTE MYELOGENOUS LEUKEMIA
核心--急性髓系白血病的超中期 Fish 和 PCR
  • 批准号:
    6338679
  • 财政年份:
    2000
  • 资助金额:
    $ 26.21万
  • 项目类别:
GENOMIC INSTABILITY IN FAMILIAL CANCER SYNDROMES
家族性癌症综合征的基因组不稳定性
  • 批准号:
    6198231
  • 财政年份:
    1999
  • 资助金额:
    $ 26.21万
  • 项目类别:
CORE--HYPERMETAPHASE FISH AND PCR IN ACUTE MYELOGENOUS LEUKEMIA
核心--急性髓系白血病的超中期 Fish 和 PCR
  • 批准号:
    6102719
  • 财政年份:
    1999
  • 资助金额:
    $ 26.21万
  • 项目类别:
CORE--MINIMAL DISEASE DETECTION BY FISH
核心——鱼类微小疾病检测
  • 批准号:
    6203154
  • 财政年份:
    1999
  • 资助金额:
    $ 26.21万
  • 项目类别:

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  • 批准号:
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