Role of Mitochondrial Genomic Alterations in Epithelial Ovarian Tumors

线粒体基因组改变在上皮性卵巢肿瘤中的作用

• 批准号: 7688902
• 负责人: Felix O Aikhionbare
• 金额: $ 14万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688902
• 关键词: Accounting; Address; African American; Age; Alabama; Apoptosis; Apoptotic; Area; Asians; Award; Back; Base Sequence; Behavioral Research; Benign; Biochemical; Biological Markers; Biological Markers; Cancer Biology; Cancer Burden; Cancer Cell Growth; Cancer Control; Cancerous; Caucasians; Caucasoid Race; Cause of Death; Cell Death; Cessation of life; Classification; Clear Cell; Clinical; Clinical Research; Communication; Critiques; DNA; DNA Restriction Enzymes; DNA Sequence; DNA-Directed DNA Polymerase; Data; Detection; Development; Development Plans; Diagnosis; Diagnostic; Digestion; Disease; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Enrollment; Epithelial; Epithelial ovarian cancer; Epithelium; Ethnic Origin; Evaluation; Evolution; Faculty; Frequencies; Funding; Future; Gene Expression Profiling; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Population Study; Genomics; Germ-Line Mutation; Goals; Grant; Growth; Hispanic Americans; Hispanics; Histopathology; Impairment; Inherited; Inner mitochondrial membrane; Institution; Intervention; Investigation; Ions; Joints; Journals; Lead; Lesion; Link; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Manuscripts; Measurement; Mentors; Metabolic; Minority; Mitochondria; Mitochondrial DNA; Molecular; Molecular Epidemiology; Monitor; Mothers; Mucinous; Mutation; National Cancer Institute; Native Americans; Necrosis; Oocytes; Outcome; Outcome Study; Ovarian; Ovarian Carcinoma; Ovarian Surface Epithelial-Stromal Tumor; Oxidative Phosphorylation; Pacific Island Americans; Pathogenicity; Pathologist; Pathology; Pathway interactions; Patients; Peer Review; Permeability; Persons; Pilot Projects; Play; Polymerase Chain Reaction; Population; Population Group; Predictive Factor; Predisposition; Premalignant; Principal Investigator; Procedures; Process; Productivity; Publications; Publishing; Race; Random Amplified Polymorphic DNA Technique; Reporting; Reproduction spores; Research; Research Methodology; Research Personnel; Research Project Grants; Research Proposals; Research Support; Research Training; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Schools; Science; Screening procedure; Series; Serous; Staging; Students; Suggestion; System; Techniques; Technology; Time; Tissue Sample; Tissues; Training; Training Programs; Tumor Cell Line; Tumor Subtype; Underrepresented Minority; United States; United States National Institutes of Health; Universities; University of Alabama at Birmingham Cancer Center; Variant; Videoconferences; Videoconferencing; Woman; Work; Writing; adenoma; anticancer research; base; cancer cell; cancer health disparity; carcinogenesis; career; career development; cell type; effective intervention; egg; ethnic difference; experience; female reproductive system; field study; follow-up; gene function; health disparity; improved; innovation; insight; medical schools; meetings; member; mitochondrial DNA mutation; mitochondrial genome; molecular pathology; mortality; mutant; novel; novel diagnostics; outcome forecast; ovarian neoplasm; population based; programs; public health relevance; racial and ethnic; racial difference; racial/ethnic difference; repaired; research study; response; segregation; skills; solute; tumor; tumor progression; tumorigenesis

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.

描述(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，无论是散发性卵巢癌还是遗传性卵巢癌，都需要基因改变的积累，而这些改变的特点是高度的基因改变。卵巢癌是根据形态标准进行组织病理学分类的，卵巢癌是女性生殖系统中不同类型的上皮细胞，包括浆液性、粘液性、子宫内膜样癌、透明细胞和布伦纳细胞。卵巢上皮性肿瘤的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%是通过卵子(卵母细胞)从母亲那里遗传过来的，参与了基本的细胞途径，其中一些与肿瘤的发生有关。在初步工作中，我们已经在卵巢上皮性肿瘤亚型和种族差异的细胞腺瘤、交界性和分期(1-IV)的细胞腺瘤中发现了几种不同的线粒体DNA种系突变/多态(Aikhionbaar等，癌症发生杂志2007和诊断病理学2008)。该研究将采用多种分子技术，包括：随机扩增多态性DNA-聚合酶链式反应、高分辨率限制性内切酶分析、等位基因特异性聚合酶链式反应、DNA测序和实时定量RT-PCR。1)检测卵巢上皮性肿瘤三种亚型(浆液性100例、粘液性100例、子宫内膜样癌100例)中线粒体基因突变(S)/多态(S)的分布和频率。2)确定线粒体DNA多态/突变在非裔美国人和高加索女性对卵巢侵袭性上皮性肿瘤易感性中的作用。本项目将为进一步研究线粒体下游靶基因提供洞察力和更多的初步数据，最终可能有助于卵巢上皮性肿瘤亚型和分期的诊断和预后。 与公共健康相关：线粒体在启动细胞死亡和癌细胞生长中发挥作用。该项目将科学地鉴定和确定线粒体基因改变是否与卵巢肿瘤进展的不同亚型和早期阶段相关，这可能涉及种族差异。这一目标的结果可能对开发不同种族来源的具有生物学侵袭性的卵巢癌的新诊断方法具有重要的临床意义。