Defining a Pre-Malignant Phenotype in Fallopian Tube Epithelium

描述(由申请人提供)：缺乏卵巢癌可识别的前驱病变，阻碍了为这种致命疾病设计合理的监测和化学预防的尝试。事实上，目前还不确定女性生殖道中哪些特定细胞会转化为卵巢和原发腹膜恶性肿瘤。更好地了解卵巢肿瘤发生的早期步骤将有助于开发新的筛查和预防策略。BRCA1基因的遗传突变导致大约40%的终生卵巢癌、输卵管癌或腹膜癌风险。目前对BRCA1突变女性的临床建议包括在完成生育后40岁之前进行降低风险的输卵管卵巢切除术(RRSO)。我们小组和其他人发现，在接受RRSO治疗的BRCA1突变携带者的输卵管中，高级别浆液性肿瘤的发生率很高。使用详细的手术和病理方案时，隐匿性输卵管肿瘤的发生率高于卵巢肿瘤。我们假设大多数发生在BRCA1突变携带者身上的卵巢癌和腹膜癌是从发生在输卵管中的肿瘤细胞中播种的。这一现象可能对散发性和遗传性卵巢癌的发展有重要意义。目前建议的总体目标是确定具有遗传性BRCA1突变的妇女的癌前输卵管表型。这项建议的具体目的是：1.研究BRCA1基因突变未受影响的妇女和BRCA1相关或散发性卵巢癌和腹膜癌妇女的输卵管上皮细胞的特征。2.鉴定和表征BRCA1突变妇女的病理正常输卵管上皮癌前病变相关的基因表达特征。3.评价遗传性和散发性卵巢癌和腹膜癌中特异性靶基因2的优势基因。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光标前病变并证明其恶性进展的可能性将有助于在高危女性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.