Mitochondrial DNA and Ovarian Cancer Risk and Survival

描述(申请人提供)：卵巢癌是最致命的妇科癌症。我们几乎在每一条战线上都受到这种复杂的恶性肿瘤的挑战：很少有可改变的风险因素被确定为初级预防，目前的筛查既不敏感也不敏感 目前的细胞毒治疗方案(单一或联合)延长了生存期，但最终是无效的，因为大多数卵巢癌患者仍然死于耐药复发疾病。需要对导致癌症发展和化疗耐药的关键因素有一个新的理解，以便为新的干预和治疗提供生物学基础。一种有趣的可能性是，线粒体和线粒体DNA(MtDNA)在卵巢癌的发生和发展中扮演着一个尚未确定的角色。我们的总体目标是了解如何使用mtDNA来预测卵巢癌风险较高的女性，这些女性可能受益于更密集的医疗检查，从而获得更早的诊断，并预测哪些女性最有可能从特定的治疗中受益。我们的工作假设是，与类似的非卵巢癌女性相比，患有卵巢癌的女性在血液和癌组织中将具有不同的mtDNA多态变异和/或不同的mtDNA拷贝数分布。我们还假设，这些线粒体DNA中的一个或多个特征将预测风险和生存。在验证我们的假设时，我们将使用艾伯塔省和不列颠哥伦比亚省卵巢癌(OVAL-BC)研究的广泛资源，这是一项基于人群的病例对照研究，从2002-2011年招募了约1235例病例和2070名对照。现有的数据/样本包括广泛的访谈信息和血液/口腔样本的DNA。我们将通过治疗和肿瘤组织学以及癌症组织样本的详细信息来增加这一资源。我们可以使用领先的下一代测序平台，使用索引标签作为分子条形码，一次对多达96个样本进行同步测序，从而对mtDNA变异进行系统和详细的表征，从而使我们能够对每个病例的血液或唾液中的mtDNA进行完整测序，并在病例中对来自癌组织的对照和mtDNA进行完整测序。我们独特的OVAL-BC研究资源、对医疗记录和组织的访问、专家病理学审查以及技术实力使我们能够独一无二地评估线粒体基因变异对卵巢癌风险和生存率的影响。因此，通过表征现有和特征良好的人群中的线粒体DNA和风险/生存，我们可以在短期内识别新的生物标记物，这些标记物可以在预防卵巢癌死亡的努力中得到进一步评估。最终，这些知识可以被用来引发更有效的卵巢癌预防和治疗。

DESCRIPTION (provided by applicant): Ovarian cancer is the most deadly gynecologic cancer. We are challenged on almost every front by this complex malignancy: few modifiable risk factor have been identified for primary prevention, current screening is neither sensitive nor specific enough to use at the population level, and current cytotoxic therapy regimens (single or combined) extend survival but ultimately are ineffective as most ovarian cancer patients still die of chemo- resistant recurrent disease. A new understanding of key factors that contribute to cancer development and chemo-resistance is needed to inform the biological basis for novel interventions and therapies. An intriguing possibility is that mitochondria and mitochondrial DNA (mtDNA) play a role, as yet undefined, in ovarian cancer development and progression. Our overall goal is to understand how mtDNA can be used to predict women at elevated risk for ovarian cancer who may benefit from more intensive medical workups resulting in earlier diagnosis and to predict women who are most likely to benefit from specific therapies. Our working hypothesis is that women with ovarian cancer will have different polymorphic variants of mtDNA and/or a different distribution of mtDNA copy number in blood and cancerous tissue than similar women without ovarian cancer. We also hypothesize that one or more of these mtDNA features will be predictive of risk and survival. In testing our hypotheses, we will use extensive resources of the Ovarian Cancer in Alberta and British Columbia (OVAL-BC) Study, a population-based case-control study with ~1235 cases and 2070 controls recruited from 2002-2011. Existing data/specimens include extensive interview information and DNA from blood/buccal samples. We will augment this resource with detailed information on treatment and tumor histology as well as cancerous tissue samples. We have access to a leading next-generation sequencing platform for systematic and detailed characterization of mtDNA variation using index tags that act as molecular barcodes for simultaneous sequencing of up to 96 samples at a time, allowing us to completely sequence mtDNA from blood or saliva in very case and control and mtDNA from cancerous tissue in the cases. Our exceptional OVAL-BC Study resource, access to medical records and tissue, expert pathology review, and technological strength makes us uniquely poised to assess the effect of mitochondrial genetic variation on ovarian cancer risk and survival. Thus, by characterizing mtDNA and risk/survival in an existing and well- characterized population, we may, in the short-term, identify new biomarkers that could be further assessed in efforts to prevent death from ovarian cancer. Ultimately, such knowledge can be used to elicit more effective ovarian cancer prevention and treatment.