MOLECULAR GENETICS OF HUMAN GYNECOLOGIC PATHOLOGY

人类妇科病理学的分子遗传学

• 批准号: 3755408
• 负责人: J A BOYD
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3755408
• 关键词: chemical carcinogen; chemical carcinogenesis; chromosome translocation; cytogenetics; developmental genetics; diethylstilbestrol; dioxins; endometriosis; female; gene expression; genetic mapping; halobiphenyl /halotriphenyl compound; human genetic material tag; human tissue; leiomyoma; molecular cloning; neoplasm /cancer genetics; nucleic acid structure; oncogenes; ovary neoplasms; tissue /cell culture; tumor suppressor genes; uterus neoplasms

The goals of this project center around the molecular genetic analysis of pathologic conditions of the human uterus, including endometrial carcinoma, endometriosis, and uterine leiomyoma (fibroids). Related studies include the molecular genetic analyses of human and rodent cancers associated with exposure in utero to diethylstilbestrol, human latent prostatic carcinomas, and hereditary breast and ovarian cancers with emphasis on the BRCA1 susceptibility locus. Significant progress has been made in defining the relevant oncogenes and tumor suppressor genes involved in the pathobiology of endometrial carcinoma. Several genes and chromosomal loci have been found to be predominantly involved in either type I, estrogen-related tumors, or type II, nonestrogen-related tumors. Notable among these are a gene on chromosome 2p responsible for a replication error phenotype (type I tumors), and a novel locus on chromosome 14q that is highly correlated with death from disease (type II tumors). Studies on endometriosis have identified a novel endometrial cDNA clone that is recognized by serum antibodies in women with endometriosis; the sequencing, characterization, and determination of clinical utility of this gene is in progress. Further studies were initiated that will attempt to correlate serum levels of organochlorine toxicants (e.g., dioxin, PCBs) with the presence or extent of endometriosis in human subjects. Efforts were begun to clone and characterize genes involved in uterine leiomyoma. The most frequent cytogenetic abnormality in these tumors is a balanced translocation involving chromosomes 12 and 14. A large number of candidate cDNAs have been cloned from the 12q15 region, and their characterization and possible involvement in myometrial tumorigenesis are under study. An analysis of human and rodent tumors induced by DES exposure has found an absence of mutations in the P53, RAS, and WT-1 genes. Future studies are designed to identify other, perhaps novel genomic loci relevant to DES carcinogenesis, as well as the molecular pathway of DES-induced genital tract developmental anomalies.

该项目的目标是围绕分子遗传学分析， 人类子宫的病理状况，包括子宫内膜 癌、子宫内膜异位症和子宫平滑肌瘤（纤维瘤）。 相关 研究包括人类和啮齿动物癌症的分子遗传学分析 与子宫内暴露于己烯雌酚有关，人类潜伏性 前列腺癌和遗传性乳腺癌和卵巢癌， BRCA 1易感基因座。了重大进展 在定义相关的癌基因和肿瘤抑制基因时， 参与子宫内膜癌的病理生物学。 一些基因和 已发现染色体基因座主要参与 I型，雌激素相关肿瘤，或II型，非雌激素相关肿瘤。 其中值得注意的是染色体2 p上的一个基因， 复制错误表型（I型肿瘤），以及一个新的基因座 染色体14 q与疾病死亡高度相关（II型 肿瘤）。 子宫内膜异位症的研究已经确定了一种新的子宫内膜 在患有乳腺癌的女性中被血清抗体识别的cDNA克隆 子宫内膜异位症;序列、特征和测定 该基因的临床应用正在进行中。 进一步研究 试图将有机氯的血清水平 毒物（例如，二恶英，多氯联苯）的存在或程度 子宫内膜异位症。 人们开始努力克隆， 描述子宫平滑肌瘤相关基因。 最常见的 这些肿瘤中的细胞遗传学异常是平衡易位 包括12号和14号染色体 大量的候选cDNA具有 从12 q15区域克隆，及其特征和可能的 参与子宫肌层肿瘤发生正在研究中。 分析 DES暴露诱导的人类和啮齿类动物肿瘤已经发现， P53、RAS和WT-1基因突变。 未来的研究旨在 鉴定与DES致癌作用相关的其他可能新的基因组位点， 以及DES诱导生殖道的分子途径 发育异常