Defining a Pre-Malignant Phenotype in Fallopian Tube Epithelium

描述（由申请人提供）：缺乏卵巢癌的可识别的前体病变阻碍了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促进新的筛查和预防策略的发展。BRCA1基因的遗传突变导致卵巢癌、输卵管癌或腹膜癌的终生风险约为40%。目前对BRCA1突变妇女的临床建议包括在生育结束后40岁前进行降低风险的输卵管卵巢切除术（RRSO）。我们的研究小组和其他研究人员已经发现，BRCA1突变携带者接受RRSO的输卵管高级别浆液性瘤变的发生率很高。当使用详细的手术和病理协议时，隐性输卵管瘤变的频率超过卵巢瘤变。我们假设BRCA1突变携带者中产生的大多数卵巢癌和腹膜癌是由输卵管中产生的肿瘤细胞播撒而来的。这一现象可能对散发性和遗传性卵巢癌的发展具有重要意义。当前建议的总体目标是确定具有遗传性BRCA1突变的女性的癌前输卵管表型。本建议的具体目的是：1。描述未受影响的BRCA1突变妇女和BRCA1相关或散发性卵巢癌和腹膜癌妇女的输卵管上皮。2. 鉴定和描述BRCA1突变女性病理正常输卵管上皮癌前病变相关的基因表达特征。3. 评估特异性靶蛋白2在遗传性和散发性卵巢癌和腹膜癌中的优先基因。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。识别卵巢癌和腹膜癌的前驱病变并证明其恶性进展的可能性，将有助于在高危妇女中进行化学预防试验，并为早期发现提供新的靶点。

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.