Defining a Pre-Malignant Phenotype in Fallopian Tube Epithelium

定义输卵管上皮的癌前表型

基本信息

批准号：
8068733
负责人：
ELIZABETH MARY SWISHER
金额：
$ 31.4万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-08 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068733
关键词：
Age Alleles BRCA1 Mutation BRCA1 gene CDKN1B gene CDKN1C gene Carcinoma Cells Chemoprevention Child Clinical Development Disease Early Diagnosis Epithelial Epithelium Female Frequencies Gene Expression Profile Genes Genital system Goals Health Hereditary Ovarian Carcinoma High Risk Woman Immunohistochemistry Inherited Lead Lesion Location Malignant - descriptor Malignant Neoplasms Mammalian Oviducts Microinvasive Molecular Profiling Mutation Neoplasms Operative Surgical Procedures Ovarian Ovarian Carcinoma Peritoneal Phenotype Premalignant Prevention Prevention strategy Preventive Proteins Protocols documentation Quantitative Reverse Transcriptase PCR Recommendation Risk Salpingo-Oophorectomy Screening procedure Serous Specimen Time Woman design fimbria high risk improved lifetime risk malignant phenotype mutation carrier neoplastic cell novel strategies ovarian neoplasm protein expression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The lack of an identifiable precursor lesion for ovarian carcinoma hinders attempts to design rational surveillance and chemoprevention for this deadly disease. Indeed, it is uncertain which are the specific cells in the female genital tract that transform into ovarian and primary peritoneal malignancies. A better understanding of the early steps in ovarian tumorigenesis would facilitate the development of new screening and prevention strategies. Inherited mutations in the BRCA1 gene result in an approximate 40% lifetime risk of ovarian, tubal or peritoneal carcinoma. Current clinical recommendations for women with BRCA1 mutations include risk-reducing salpingo-oophorectomy (RRSO) by age 40 after completion of child-bearing. Our group and others have identified a high rate of high-grade serous neoplasia in the fallopian tubes of BRCA1 mutation carriers undergoing RRSO. The frequency of occult tubal neoplasia exceeds that of ovarian neoplasia when using a detailed surgical and pathological protocol. We hypothesize that most ovarian and peritoneal carcinomas arising in BRCA1 mutation carriers are seeded from neoplastic cells arising in the fallopian tubes. This phenomenon could have important implications for the development of sporadic as well as hereditary ovarian carcinoma. The overall goal of the current proposal is to define a premalignant tubal phenotype in women with inherited BRCA1 mutations. The specific aims of this proposal are: 1. Characterize tubal epithelium in unaffected women with BRCA1 mutations and in women with BRCA1- associated or sporadic ovarian and peritoneal carcinomas. 2. Identify and characterize a gene expression signature associated with premalignant alterations in pathologically normal tubal epithelium from women with BRCA1 mutations. 3. Evaluate priority genes from Specific Aim 2 in inherited and sporadic ovarian and peritoneal carcinomas. PUBLIC HEALTH RELEVANCE: An improved understanding of the early steps in ovarian carcinoma development is needed to facilitate rational and novel strategies for screening and prevention. Identification of a pre-cursor lesion for ovarian and peritoneal carcinoma and proof of its potential for malignant progression would facilitate chemoprevention trials in high-risk women and provide new targets for early detection.

描述（由申请人提供）：卵巢癌缺乏可识别的前体病变，阻碍了针对这种致命疾病设计合理的监测和化学预防的尝试。事实上，目前尚不清楚女性生殖道中哪些特定细胞会转化为卵巢和原发性腹膜恶性肿瘤。更好地了解卵巢肿瘤发生的早期步骤将有助于制定新的筛查和预防策略。 BRCA1 基因的遗传性突变导致一生中患卵巢癌、输卵管癌或腹膜癌的风险约为 40%。目前针对 BRCA1 突变女性的临床建议包括在完成生育后 40 岁时进行降低风险的输卵管卵巢切除术 (RRSO)。我们的团队和其他人发现，接受 RRSO 的 BRCA1 突变携带者的输卵管中高级别浆液性肿瘤发生率很高。当采用详细的手术和病理方案时，隐匿性输卵管肿瘤的发生率超过卵巢肿瘤。我们假设大多数 BRCA1 突变携带者中产生的卵巢癌和腹膜癌是由输卵管中产生的肿瘤细胞播种的。这种现象可能对散发性和遗传性卵巢癌的发展具有重要意义。当前提案的总体目标是定义具有遗传性 BRCA1 突变的女性的癌前输卵管表型。该提案的具体目标是： 1. 表征具有 BRCA1 突变的未受影响女性以及患有 BRCA1 相关或散发性卵巢癌和腹膜癌的女性的输卵管上皮。 2. 鉴定并表征与 BRCA1 突变女性的病理正常输卵管上皮癌前改变相关的基因表达特征。 3. 评估遗传性和散发性卵巢癌和腹膜癌中特定目标 2 的优先基因。公共卫生相关性：需要更好地了解卵巢癌发展的早期步骤，以促进合理和新颖的筛查和预防策略。卵巢癌和腹膜癌前驱病变的鉴定并证明其恶性进展的潜力将有助于高危女性的化学预防试验，并为早期检测提供新的目标。