Defining a Pre-Malignant Phenotype in Fallopian Tube Epithelium

摘要 缺乏可识别的卵巢癌前病变阻碍了设计合理的治疗方案的尝试。 监测和化学预防这种致命的疾病。事实上，不确定哪些是特定的细胞， 女性生殖道转化为卵巢和原发性腹膜恶性肿瘤。更好地理解 卵巢肿瘤发生的早期步骤将促进新的筛查和预防的发展， 策略BRCA 1基因的遗传性突变导致大约40%的卵巢、输卵管和卵巢癌的终生风险。 或腹膜癌。目前对BRCA 1突变女性的临床建议包括风险- 在40岁之前减少输卵管卵巢切除术（RRSO）。我们集团和其他 已经确定BRCA 1突变携带者输卵管中高级别浆液性肿瘤的发生率很高 进行RRSO。当使用一种药物时，隐匿性输卵管肿瘤的发生率超过卵巢肿瘤。 详细的手术和病理方案我们假设大多数卵巢癌和腹膜癌 BRCA 1突变携带者中产生的肿瘤细胞是从输卵管中产生的肿瘤细胞中接种的。这 这种现象可能对散发性和遗传性卵巢癌的发展有重要意义。 carcinoma.目前的建议的总体目标是确定一个癌前输卵管表型的妇女， 遗传性BRCA 1突变这项建议的具体目标是： 1.表征未受影响的BRCA 1突变女性和BRCA 1- 相关或散发的卵巢癌和腹膜癌。 2.鉴定和表征与乳腺癌癌前病变相关的基因表达特征 病理正常的输卵管上皮来自BRCA 1突变的女性。 3.评估遗传性和散发性卵巢癌和腹膜癌中特异性目标2的优先基因。

Abstract 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 facillitate the development of new screening and prevention stratgies. Inherited mutations in the BRCA1 gene results 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.