PREDISPOSING/MODIFYING GENES IN HEREDITARY COLON CANCER

描述：(改编自调查员摘要)易感性 遗传性非息肉病性结肠癌(HNPCC)与生殖系相关 5个具有DNA错配修复功能的基因突变。以前的研究 已经表明，这些基因占HNPCC家庭会议的三分之二 国际上对该病的诊断标准和表现 微卫星不稳定性是肿瘤的一种特征性异常。其基础是 因为在剩下的三分之一的家庭中，癌症易感性是未知的 有微卫星不稳定性，在大多数家庭中没有这种异常。 此外，在具有可检测到的突变的亲缘关系中，甚至在共享 易感性，临床表型在之间和内部有很大的不同 个别家庭，原因很大程度上不得而知。 本研究的主要目标是确定基因和机制。 与癌症易感性和表型测定有关 非息肉性结肠癌。这些基因的检测是至关重要的。 鉴于据估计有一半的西方人口患有结肠癌 肿瘤在他们的一生中。重要的是，这些病变的进展到 癌症可以通过早期干预和增加遗传标记来预防 需要癌症风险来确定谁将是第一个受益的队列 这样的预防措施。具体目标1集中在有 非息肉病性结肠癌中目前已知的突变 与HNPCC相关的DNA错配修复基因已通过测序排除。一个 全基因组搜索的目的是识别与之相关的新基因 这些人有患癌症的倾向。具体目标2侧重于 具有共同易感突变的独特家族系列。观察到的 共同易感背景下的临床变异表明 存在额外的表型决定因素。其目的是识别基因 这可能会改变HNPCC的临床表型，利用 在这些遗传同质性中基于关联和连锁的方法 HNPCC患者的亚群。

DESCRIPTION: (Adapted from investigator's abstract) Susceptibility to hereditary nonpolyposis colon cancer (HNPCC) is associated with germline mutations in five genes with DNA mismatch repair function. Previous studies have shown that these genes account for two-thirds of HNPCC kindreds meeting the international diagnostic criteria for the disorder and displaying microsatellite instability as a characteristic abnormality in tumors. The basis for cancer susceptibility is unknown in the remaining one-third of kindreds with microsatellite instability and in most families without this abnormality. Furthermore, in kindreds with detectable mutations and even with shared predispositions, the clinical phenotype varies a lot between and within individual families, the reasons for which are largely unknown. The broad objective of the present study is to identify genes and mechanisms associated with cancer susceptibility and phenotype determination in non-polypotic colon cancer. The detection of such genes is of prime importance given the fact that half the Western population is estimated to develop a colon tumor during their lifetime. Importantly, the progression of those lesions to cancer can be prevented by early intervention, and genetic markers of increased cancer risk are needed to define the cohorts who would be the first to benefit from such preventive measures. The Specific Aim 1 focuses on kindreds with non-polyposis colon cancer in which mutations in the presently known HNPCC-associated DNA mismatch repair genes have been ruled out by sequencing. A genome-wide search is applied with the goal to identify novel genes associated with cancer predisposition in these kindreds. The Specific Aim 2 focuses on a unique series of families with shared predisposing mutations. The observation of clinical variation in the setting shared predisposition suggests the existence of additional phenotype determinants. The aim is to identify genes that might modify the clinical phenotype of HNPCC, taking advantage of association and linkage-based approaches in these genetically homogeneous subsets of HNPCC patients.