Project 3: Ovarian Cancer

摘要 我们建议使用问卷调查数据，生物样本， 以及来自护士健康研究（NHS）、NHSII和 新英格兰病例对照研究（仅针对肿瘤组织）。虽然关于卵巢的几个假设 虽然癌症的病因已经被提出，但目前确认的危险因素很少是容易改变的。因此，一个主要的 目前建议的重点是在两个关键但尚未探索的途径中可改变或可治疗的因素 卵巢癌病因学：脂质和炎症。对于脂质途径，我们将检查血浆总 胆固醇、HDL和LDL，因为这些标志物可以通过药物或生活方式的改变而改变， 其他几种有前途的脂质类，溶血磷脂酰胆碱和鞘磷脂， 建议作为早期检测标志物，在病因学上也很重要。这些将在一个 经过验证的半靶向代谢组学平台;这也将使我们能够进行全面的发现- 基于其他小分子代谢物的分析，这些代谢物可能在卵巢癌发生中起重要作用。的 炎症目标将建立在当前P01和与项目2的跨项目合作的基础上 （结肠直肠癌），采取创新的方法，考虑炎症环境的多个方面， 包括生活方式因素（促炎饮食、久坐行为、力量训练）、镇痛相关 因素（绝经前NSAID使用，尿中的前列腺素）和衣原体感染状态。重要的是我们 将通过评估风险因素相关性来探索潜在的潜在生物学作用机制， 肿瘤侵袭性、肿瘤相关巨噬细胞浸润量和总体肿瘤基因 表达以鉴定具有不同炎症暴露的患者的肿瘤中的转录改变。 我们建议在诊断后对可改变的因素进行第一次详细的评估，包括身体因素。 活动、吸烟、非甾体抗炎药和促炎饮食与I/II期患者的生存率;无循证证据 目前已有建议。本研究的主要优点包括样本量大，高达40 多年的问卷调查数据（病例诊断前和诊断后收集的数据），存档的血浆和尿液样本， 详细的医疗记录数据以及卵巢癌病例的肿瘤组织，允许仔细检查 与疾病风险和存活率相关的暴露时间。累积起来，这些丰富的资源将使我们能够 检查新的可改变或可治疗的风险因素，从预防到早期发现到生存。而且我们 将受益于与本计划项目中跨癌症的类似研究的整合和协同作用， 来自多个领域和机构的研究人员，包括一个杰出的临床癌症中心-提供 通过在科学和生物信息学上的交叉施肥来增加价值，最终产生新的标志， 癌症发展的潜在或共同途径，以及快速临床转化的可能性。

Abstract We propose to evaluate risk factors for epithelial ovarian cancer using questionnaire data, biological samples, and paraffin-embedded ovarian tumor tissue from women in the Nurses' Health Study (NHS), NHSII, and the New England Case-Control Study (tumor tissue aims only). Although several hypotheses regarding ovarian cancer etiology have been proffered, few currently confirmed risk factors are easily modifiable. Thus, a major focus of the current proposal is on modifiable or treatable factors within two key, yet underexplored, pathways in ovarian cancer etiology: lipids and inflammation. For the lipid pathway, we will examine plasma total cholesterol, HDL, and LDL as these markers can be altered by medication or lifestyle changes, as well as several other promising lipid classes, lysophosphatidylcholines and sphingomyelins, which have been suggested as early detection markers and also be important etiologically. These will be measured on a validated, semi-targeted metabolomics platform; this also will allow us to conduct a comprehensive discovery- based analysis of other small molecule metabolites that may be important in ovarian carcinogenesis. The inflammation aims will build on work from the current P01 and cross-project collaboration with Project 2 (colorectal cancer), taking an innovative approach that considers multiple facets of the inflammatory milieu, including lifestyle factors (pro-inflammatory diet, sedentary behavior, strength training), analgesic related factors (premenopausal NSAID use, urinary prostaglandins), and chlamydia infection status. Importantly, we will explore potential underlying biologic mechanisms of action by evaluating risk factor associations by tumor aggressiveness, the amount of tumor-associated macrophage infiltration, and global tumor gene expression to identify transcriptional alterations in tumors of patients with varying inflammatory exposures. We propose to provide the first detailed evaluation of modifiable factors after diagnosis, including physical activity, smoking, NSAIDs, and a pro-inflammatory diet, and survival in stage I/II patients; no evidence-based recommendations currently are available. Major strengths of this study include the large sample size, up to 40 years of questionnaire data (collected pre- and post-diagnosis in cases), archived plasma and urine samples, detailed medical record data as well as tumor tissue from ovarian cancer cases, allowing careful examination of timing of exposure in relation to disease risk and survival. Cumulatively, these rich resources will allow us to examine novel modifiable or treatable risk factors from prevention to early detection to survival. Moreover, we will benefit from integration and synergy with similar research across cancers in this Program Project as well as investigators from multiple fields and institutions, including a pre-eminent clinical cancer center - providing added value by enabling cross-fertilization in science and bioinformatics, eventually yielding new insignts into underlying or common pathways in cancer development, and the possibility of rapid clinical translation.