Role of Mitochondrial Genomic Alterations in Epithelial Ovarian Tumors

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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.