Role of Mitochondrial Genomic Alterations in Epithelial Ovarian Tumors

描述（由申请人提供）：上皮性卵巢癌是美国女性妇科癌症死亡的主要原因。在分子水平上，散发性和遗传性卵巢癌都需要基因变化的积累，而这些变化的特点是高度的遗传改变。卵巢癌是根据形态学标准进行组织病理学分类的，形态学标准是指女性生殖系统中不同类型的上皮，包括浆液性、黏液性、子宫内膜样、透明细胞和布伦纳上皮。卵巢上皮性肿瘤亚型进一步分为良性、交界性和恶性，以反映其组织病理学。线粒体99%是通过卵母细胞从母体遗传而来，并参与一些必要的细胞途径，其中一些与肿瘤发生有关。在初步工作中，我们已经确定了细胞腺瘤中几种不同的线粒体DNA种系突变/多态性，在每一种上皮性卵巢肿瘤亚型和种族差异中，交界性和分期（1-IV） （Aikhionbare等人，Journal of carcingenesis 2007 and Diagnostic Pathology 2008）。该研究将采用多种分子技术，包括：随机扩增多态性DNA pcr （RAPD-PCR）、高分辨率限制性内切分析、等位基因特异性聚合酶链反应，然后是基于pcr的DNA测序和实时RT-PCR。这些技术将用于：1)鉴定和确定三种卵巢上皮性肿瘤亚型（n= 300个组织样本，浆液性=100个，黏液性=100个，子宫内膜样=100个）线粒体DNA突变/多态性的分布和频率。2)确定线粒体DNA多态性/突变在非裔美国人和白种人女性侵袭性卵巢上皮肿瘤易感性中的作用。本项目将为进一步研究线粒体新的下游靶基因提供更深入的见解和更初步的数据，最终有助于卵巢上皮性肿瘤亚型和分期的诊断和预后。

DESCRIPTION (provided by applicant): Epithelial ovarian cancer is the major cause of gynecologic cancer mortality in women in the United States. At the molecular level, both sporadic and hereditary ovarian cancer requires the accumulation of genetic changes, and these changes are characterized by a high degree of genetic alterations. Ovarian carcinoma is histopathologically classify on morphological criteria, which is the different types of epithelia in the female reproductive system, including serous, mucinous, endometrioid, clear cell, and Brenner. Epithelial ovarian tumor subtype has been further subclassified into benign, borderline and malignant to reflect their histopathology. Mitochondria are 99% inherited from the mother through the egg (oocyte) and involved in essential cellular pathways, some of which have been associated with tumorigenesis. In preliminary work, we have identified several differential mitochondrial DNA germline mutations/polymorphisms in cytoadenomas, borderline and stages (1-IV) within each of the epithelial ovarian tumor subtype and ethnic difference (Aikhionbare et al., Journal of Carcinogenesis 2007 and Diagnostic Pathology 2008). The proposed study would employ various molecular techniques, including: Random Amplified Polymorphic DNA-PCR (RAPD-PCR), High-Resolution Restriction analysis, Allelic-Specific Polymerase Chain Reaction, then followed by PCR-based DNA Sequencing and real-time RT-PCR. These techniques would be used to: 1) Identify and determine the distributions and frequencies of mitochondrial DNA mutation(s)/polymorphism(s) in three epithelial ovarian tumor subtypes (n= 300 tissue samples; serous=100, mucinous=100, endometrioid=100). 2) Determine the role of mitochondrial DNA polymorphisms/mutations among African-American and Caucasian women susceptibility to invasive epithelial ovarian tumor. This project will provide insight and more preliminary data for further study of a novel downstream target gene of mitochondria, which may ultimately facilitate the diagnosis and prognosis of the epithelial ovarian tumor subtypes and stages. PUBLIC HEALTH RELEVANCE: Mitochondria plays a role in the initiation of cells death and cancer cells growth. This project will identify and determine scientifically whether altered mitochondria gene could be associated with the different subtypes and early stages of the ovarian tumors progression, which may be involved in racial difference. Results from this aim may have significant clinical implications in the development of novel diagnostic approaches for biologically aggressive ovarian cancer from diverse racial origin.