PREDISPOSING/MODIFYING GENES IN HEREDITARY COLON CANCER

遗传性结肠癌的诱发/改变基因

• 批准号: 6377319
• 负责人: Paivi T Peltomaki
• 金额: $ 24.52万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-17 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377319
• 关键词: cancer risk; clinical research; colon neoplasms; colorectal neoplasms; family genetics; gene expression; gene mutation; genetic markers; genetic polymorphism; genetic screening; genetic susceptibility; human genetic material tag; human subject; linkage mapping; neoplasm /cancer genetics; nucleic acid sequence; oncogenes; phenotype

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.

描述：（改编自研究者摘要） 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激酶的三分之二， 该疾病的国际诊断标准和显示 微卫星不稳定性是肿瘤的特征性异常。基础 对于癌症易感性是未知的，在剩下的三分之一的激酶中， 微卫星不稳定性和大多数家庭没有这种异常。 此外，在具有可检测突变的kinetics中，甚至在具有可检测突变的kinetics中， 易感性，临床表型之间和内部变化很大 个别家庭，其原因在很大程度上是未知的。 本研究的主要目的是确定基因和机制 与癌症易感性和表型决定相关， 非息肉性结肠癌检测这些基因是至关重要的 鉴于一半的西方人口估计会发展成结肠， 一生中的肿瘤重要的是，这些病变的进展 癌症可以通过早期干预来预防，并且增加了遗传标记。 癌症风险需要确定谁将是第一个受益的队列 这些预防措施。具体目标1侧重于kinetics与 非息肉病性结肠癌，其中目前已知的 HNPC相关的DNA错配修复基因已通过测序排除。一 应用全基因组搜索的目的是识别与基因组相关的新基因。 与癌症易感性有关第二个目标是一个 一系列具有共同易感突变的独特家族观察 临床变异的共同倾向表明， 存在额外的表型决定因素。其目的是识别基因 可能改变HNPCC的临床表型，利用 在这些遗传上同质的， HNPCC患者的子集。

项目成果

The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.

• 发表时间: 2001-11
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Tao Liu;Hai Yan;S. Kuismanen;Antonio Percesepe;M. Bisgaard;M. Pedroni;P. Benatti;K. Kinzler;B. Vogelstein;M. P. D. Leon;P. Peltomäki;Annika Lindblom

Novel splicing associations of hereditary colon cancer related DNA mismatch repair gene mutations.

遗传性结肠癌相关DNA错配修复基因突变的新剪接关联。

• DOI: 10.1136/jmg.2003.017269
• 发表时间: 2004
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Renkonen,E;Lohi,H;Järvinen,HJ;Mecklin,J-P;Peltomäki,P
• 通讯作者: Peltomäki,P

Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.

• DOI: 10.1155/2004/305058
• 发表时间: 2004
• 期刊: Disease markers
• 作者: Peltomäki P;Vasen H
• 通讯作者: Vasen H

Nuclear and mitochondrial genome instability in human breast cancer.

• 发表时间: 2000-08
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Silvina M. Richard;G. Bailliet;Gerardo L. Páez;M. Bianchi;P. Peltomäki;Néstor O. Bianchi