Defining a Pre-Malignant Phenotype in Fallopian Tube Epithelium

摘要 缺乏卵巢癌可识别的前驱病变阻碍了合理设计的尝试 对这种致命疾病的监测和化学预防。事实上，目前还不确定哪些是特定的细胞 转化为卵巢和原发性腹膜恶性肿瘤的女性生殖道。更好地理解 卵巢肿瘤发生的早期步骤将有助于新的筛查和预防的发展 谋略。BRCA1基因的遗传突变导致大约40%的卵巢、输卵管 或者腹膜癌。目前对BRCA1突变女性的临床建议包括风险- 在完成生育后将输卵管卵巢切除术(RRSO)减少到40岁。我们的团队和其他人 在BRCA1突变携带者的输卵管中发现高级别浆液性肿瘤 正在经历RRSO。隐匿性输卵管肿瘤的发生率高于卵巢肿瘤。 详细的手术和病理方案。我们假设大多数卵巢癌和腹膜癌 BRCA1突变携带者起源于输卵管肿瘤细胞。这 这一现象可能对散发性和遗传性卵巢的发展具有重要的意义。 癌症。目前建议的总体目标是确定患有输卵管癌前病变的女性的表型。 遗传性BRCA1突变。这项建议的具体目标是： 1.BRCA1基因突变未受影响的妇女和BRCA1基因突变妇女的输卵管上皮细胞的特征 伴发或散发性卵巢癌和腹膜癌。 2.鉴定和表征与癌前病变相关的基因表达特征 BRCA1突变妇女的病理正常输卵管上皮。 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。

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.