Pharmacogenetics in Ovarian Cancer

描述(申请人提供)：卵巢癌仍然是妇科恶性肿瘤的主要死因，也是美国女性第五大常见癌症。绝大多数患者在确诊时患有晚期疾病，其存活率很低，并建议使用铂类联合化疗。以往的卵巢癌研究很少集中在基因多态与卵巢癌预后的关系上。据我们所知，以前的任何工作都没有采用全面的方法，专注于与化疗药物代谢相关的多态基因，保护免受治疗产生的活性氧物种(ROS)或DNA损伤，以及耐药。这些与化疗药物潜在疗效直接相关的关键基因的遗传变异可能有助于解释卵巢癌患者对治疗和结果的反应差异。这项拟议研究的目标是为卵巢癌的全面药物遗传学研究奠定基础。我们打算进行一项初步研究，旨在调查一组与卵巢癌化疗直接相关的候选多态基因对在我们研究所接受治疗的患者的临床结果的影响。我们进一步建议通过比较我们的候选基因多态在从肿瘤组织和血液样本中分离的成对DNA样本中的等位基因分布来评估利用肿瘤组织进行卵巢癌药物遗传学研究的适宜性。我们将利用正在进行的一项基于人群的卵巢癌病例对照研究中的患者样本。具体地说，我们将包括在罗斯威尔公园癌症研究所接受治疗的卵巢癌患者。在这项研究中，我们有非常令人鼓舞的参与率和献血率(分别为81%和97%)，冷冻的肿瘤样本可用于专利申请后(92%)。我们将从我们的组织采购设施获得肿瘤组织，并使用微阵列和基因组设施的基因分型部门进行基因分型分析。临床结果信息将从病历审查中收集。拟议研究的结果应该是更大规模的R01应用的坚实基础，目的是调查药物遗传学对卵巢癌预后的影响，因为结果将a)提供初步数据，b)将决定存档的组织库是否可以用于此类研究。

DESCRIPTION (provided by applicant): Ovarian cancer continues to be the leading cause of death from gynecological malignancies and the fifth most common cancer among US women. The vast majority of patients present with advanced disease at diagnosis, for which survival rates are poor and for which platinum-based combination chemotherapy is indicated. Very few previous ovarian cancer studies focused on genetic polymorphisms and ovarian cancer prognosis. We are unaware of any prior work that employed a comprehensive approach focusing on polymorphic genes related to the metabolism of chemotherapeutic agents, protection from treatment- generated reactive oxygen species (ROS) or DNA damage, and drug resistance. Genetic variability in such key genes that are directly related to the potential effectiveness of chemotherapeutic agents may help to explain the differences in response to treatment and outcomes among ovarian cancer patients. The goal of the proposed study is to build a foundation for a comprehensive pharmacogenetic study of ovarian cancer. We intend to conduct a pilot study aimed at investigating the effect of a panel of candidate polymorphic genes, directly relevant to ovarian cancer chemotherapy, on clinical outcome measures among patients treated at our institute. We further propose to evaluate the appropriateness of using tumor tissue for pharmacogenetic investigations in ovarian cancer by comparing the allele distribution of our candidate genetic polymorphisms in paired DNA samples isolated from tumor tissue and from blood samples. We will utilize patient samples from an ongoing population-based case-control study of ovarian cancer. Specifically, we will include ovarian cancer patients who were treated at Roswell Park Cancer Institute. We have had very encouraging participation and blood donation rates in this study (81% and 97%, respectively) and frozen tumor samples are available for post patents (92%). We will obtain tumor tissue from our Tissue Procurement Facility and use the Genotyping Division of the Microarray and Genomics Facility for genotyping analyses. Clinical outcome information will be collected from medical records review. Results from the proposed study should be a solid foundation for a larger R01 application aimed at investigating pharmacogenetic influences on ovarian cancer prognosis, as results will a) provide preliminary data, and b) will determine if archived tissue banks can be utilized for such research.