MOLECULAR GENETICS OF HUMAN GYNECOLOGIC PATHOLOGY

人类妇科病理学的分子遗传学

• 批准号: 3777491
• 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/3777491
• 关键词: breast neoplasms; chemical carcinogen; chemical carcinogenesis; chromosome translocation; cytogenetics; diethylstilbestrol; dioxins; drug related neoplasm /cancer; embryo /fetus toxicology; endometriosis; environment related neoplasm /cancer; female; gene expression; gene mutation; halobiphenyl /halotriphenyl compound; human genetic material tag; human tissue; leiomyoma; molecular cloning; neoplasm /cancer genetics; 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人类基因组的分子遗传分析 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肌瘤(肌瘤)。相关 研究包括人类和啮齿动物癌症的分子遗传学分析。 与宫内接触己烯雌酚有关，人潜伏期 前列腺癌，遗传性乳腺癌和卵巢癌 重点关注BRCA1易感基因座。已经取得了重大进展 在定义相关癌基因和肿瘤抑制基因方面取得了进展 参与子宫内膜癌的病理生物学研究。几个基因和 人们已经发现，染色体基因座主要与这两种疾病有关 第一类是雌激素相关的肿瘤，第二类是非雌激素相关的肿瘤。 其中值得注意的是染色体2p上的一个基因，它负责 复制错误表型(I型肿瘤)和一个新的基因座 与疾病死亡(II型)高度相关的染色体14Q 肿瘤)。对子宫内膜异位症的研究发现了一种新的子宫内膜 慢性阻塞性肺病患者血清抗体可识别的基因克隆 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。进一步的研究是 将尝试将血清有机氯水平与 有毒物质(如二恶英、多氯联苯) 人类子宫内膜异位症。克隆和克隆的努力已经开始 描述与子宫肌瘤有关的基因。最频繁的 这些肿瘤的细胞遗传学异常是一种平衡易位。 涉及到12号和14号染色体。大量的候选cDNA 是从12q15区域克隆的，它们的特征和可能 参与子宫肌层肿瘤发生的研究正在进行中。一种分析 由DES诱发的人和啮齿动物肿瘤已发现缺乏 P53、RAS和WT-1基因突变。未来的研究旨在 确定其他可能与DES致癌相关的新的基因组基因座， 以及DES诱导生殖道的分子途径 发育异常。