GENETIC MECHANISM OF BRCA LINKED OVARIAN TUMORIGENESIS

BRCA相关卵巢肿瘤发生的遗传机制

基本信息

  • 批准号:
    6497770
  • 负责人:
  • 金额:
    $ 28.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-02-01 至 2005-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION: (Adapted from the investigator's abstract) Approximately 10 percent of all ovarian cancers are associated with autosomal dominant genetic predispostion. It is now well established that the great majority of these hereditary ovarian cancers are attributable to inherited mutations in the recently cloned and characterized tumor suppressor genes BRCA1 or BRCA2. The long-term goals of this project are to determine the molecular genetic mechanism through which BRCA-linked ovarian cancers develop and to define the clinical and biological features of these cancers. Specifically, this project will focus on two major aims, the first of which is to test the hypothesis that pathologically normal ovarian tissues from BRCA heterozygotes exhibit preclinical histologic, molecular genetic, and cell biological alterations. Ovaries removed prophylactically from women with deleterious germline BRCA mutations will be compared to those removed from women not at increased risk for ovarian cancer with regard to the prevalence of histological features that may represent premalignant alterations, and the ratio of proliferating to apoptotic epithelial cells. Using a combination of microdissection, PCR-based DNA analyses, and immunohistochemical techniques, ovaries from BRCA heterozygotes will be further analyzed for regional loss of the wild-type BRCA allele and TP53 mutation, the order in which these events occur, and the correlation of these events with regions of abnormal histologic variation. It is anticipated that these studies will lead to an improved understanding of the early molecular genetic events in heretidary ovarian tumorigenesis specifically, and to greater insight into the cell or region of origin of ovarian carcinoma generally. This information should prove useful in the development of new approaches for the early detection of ovarian cancer. The second major aim is to address the hypothesis that BRCA proteins function in the cellular response to therapeutic DNA damaging agents (chemical and physical), and further, to determine whether this function is specific for a particular type of DNA damage (e.g., double-strand DNA breaks). This aim will be accomplished by examining the effect of BRCA expression on the cellular response to several different classes of cytotoxic chemotherapeutic agents and radiation, using three experimental strategies for the comparison of BRCA-expressing and BRCA-nonexpressing cells: 1) conditional BRCA expression in BRCA-deficient human tumor cell lines; 2) direct comparison of BRCA-deficient and BRCA-wild-type tumor cell lines, and; 3) antisense-mediated BRCA depletion in BRCA-wild-type tumor cell lines. Data from these studies may lead to the development of more effective therapeutic strategies for genetically-defined subsets of ovarian cancer patients.
描述:(改编自研究者摘要)约10例 %的卵巢癌与常染色体显性遗传有关。 倾向性现在已经确定,其中绝大多数 遗传性卵巢癌是由于遗传性突变, 最近克隆并鉴定了肿瘤抑制基因BRCA 1或BRCA 2。的 该项目的长期目标是确定分子遗传 BRCA相关卵巢癌的发生机制,并确定 这些癌症的临床和生物学特征。具体来说,这个项目 将集中在两个主要目标,其中第一个是测试的假设, BRCA杂合子的病理正常卵巢组织表现出 临床前组织学、分子遗传学和细胞生物学改变。 卵巢从有害生殖系BRCA的女性中切除 突变将与那些从没有增加风险的女性中移除的突变进行比较。 对于卵巢癌的组织学特征的患病率, 可能代表癌前病变,增殖与 凋亡上皮细胞。使用显微切割、基于PCR的 BRCA卵巢的DNA分析和免疫组织化学技术 杂合子将进一步分析野生型BRCA的区域丢失 等位基因和TP 53突变、这些事件发生的顺序以及 这些事件与异常组织学变异区域的相关性。它 预计这些研究将有助于更好地了解 遗传性卵巢肿瘤发生的早期分子遗传事件 具体来说,并更深入地了解细胞或起源区域 卵巢癌一般。这一信息应证明是有用的 卵巢癌早期诊断的新方法。的 第二个主要目标是解决BRCA蛋白在 细胞对治疗性DNA损伤剂(化学和 物理的),并且进一步地,确定该功能是否特定于 特定类型的DNA损伤(例如,双链DNA断裂)。这一目标将 通过检查BRCA表达对细胞增殖的影响, 对几种不同类型的细胞毒性化疗剂的反应, 辐射,使用三种实验策略进行比较, BRCA表达和BRCA非表达细胞:1)条件性BRCA表达, BRCA缺陷型人肿瘤细胞系; 2)直接比较BRCA缺陷型人肿瘤细胞系和BRCA缺陷型人肿瘤细胞系。 和BRCA-野生型肿瘤细胞系,和; 3)反义介导的BRCA耗竭 在BRCA野生型肿瘤细胞系中。这些研究的数据可能会导致 开发更有效的治疗策略, 卵巢癌患者的子集。

项目成果

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JEFFREY ALLEN BOYD其他文献

JEFFREY ALLEN BOYD的其他文献

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{{ truncateString('JEFFREY ALLEN BOYD', 18)}}的其他基金

The Molecular Genetics of MUC16
MUC16 的分子遗传学
  • 批准号:
    6952119
  • 财政年份:
    2005
  • 资助金额:
    $ 28.14万
  • 项目类别:
Molecular Classification of Endometrial Carcinomas
子宫内膜癌的分子分类
  • 批准号:
    6877995
  • 财政年份:
    2004
  • 资助金额:
    $ 28.14万
  • 项目类别:
Molecular Classification of Endometrial Carcinomas
子宫内膜癌的分子分类
  • 批准号:
    7217239
  • 财政年份:
    2004
  • 资助金额:
    $ 28.14万
  • 项目类别:
Molecular Classification of Endometrial Carcinomas
子宫内膜癌的分子分类
  • 批准号:
    7026927
  • 财政年份:
    2004
  • 资助金额:
    $ 28.14万
  • 项目类别:
Molecular Classification of Endometrial Carcinomas
子宫内膜癌的分子分类
  • 批准号:
    6780644
  • 财政年份:
    2004
  • 资助金额:
    $ 28.14万
  • 项目类别:
GENETIC MECHANISM OF BRCA LINKED OVARIAN TUMORIGENESIS
BRCA相关卵巢肿瘤发生的遗传机制
  • 批准号:
    6628320
  • 财政年份:
    2001
  • 资助金额:
    $ 28.14万
  • 项目类别:
GENETIC MECHANISM OF BRCA LINKED OVARIAN TUMORIGENESIS
BRCA相关卵巢肿瘤发生的遗传机制
  • 批准号:
    6700738
  • 财政年份:
    2001
  • 资助金额:
    $ 28.14万
  • 项目类别:
GENETIC MECHANISM OF BRCA LINKED OVARIAN TUMORIGENESIS
BRCA相关卵巢肿瘤发生的遗传机制
  • 批准号:
    6261180
  • 财政年份:
    2001
  • 资助金额:
    $ 28.14万
  • 项目类别:
MOLECULAR CLASSIFICATION OF OVARIAN CANCERS
卵巢癌的分子分类
  • 批准号:
    6350458
  • 财政年份:
    2000
  • 资助金额:
    $ 28.14万
  • 项目类别:
MOLECULAR CLASSIFICATION OF OVARIAN CANCERS
卵巢癌的分子分类
  • 批准号:
    6702604
  • 财政年份:
    2000
  • 资助金额:
    $ 28.14万
  • 项目类别:

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