Pharmacogenetics in Ovarian Cancer

描述（由申请人提供）： 卵巢癌仍然是妇科恶性肿瘤死亡的主要原因，也是美国妇女中第五大常见癌症。绝大多数患者在诊断时表现为晚期疾病，其生存率很低，需要接受以铂为基础的联合化疗。以前很少有卵巢癌研究集中在遗传多态性和卵巢癌预后。我们不知道任何先前的工作，采用了一个全面的方法，集中在多态性基因相关的化疗药物的代谢，保护治疗产生的活性氧（ROS）或DNA损伤，和耐药性。这些关键基因的遗传变异与化疗药物的潜在有效性直接相关，这可能有助于解释卵巢癌患者对治疗反应和结局的差异。这项研究的目的是为卵巢癌的全面药物遗传学研究奠定基础。我们打算进行一项试验性研究，旨在调查一组与卵巢癌化疗直接相关的候选多态性基因对在我们研究所治疗的患者的临床结局指标的影响。我们进一步建议通过比较从肿瘤组织和血液样本中分离的配对DNA样本中我们的候选基因多态性的等位基因分布来评估使用肿瘤组织进行卵巢癌药物遗传学研究的适当性。我们将利用来自一项正在进行的卵巢癌人群病例对照研究的患者样本。具体来说，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。我们在这项研究中的参与率和献血率非常令人鼓舞（分别为81%和97%），冷冻肿瘤样本可用于专利后（92%）。我们将从我们的组织采购机构获得肿瘤组织，并使用微阵列和基因组学机构的基因分型部门进行基因分型分析。将从病历审查中收集临床结局信息。拟议研究的结果应为旨在研究药物遗传学对卵巢癌预后影响的更大R01应用奠定坚实基础，因为结果将a）提供初步数据，B）确定存档组织库是否可用于此类研究。

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.