Prospective Cohort Collaborative in Pancreatic Cancer Epidemiology & Pathogenesis

描述（由申请人提供）：胰腺癌是癌症相关死亡的第四大常见原因。尽管如此，对这种恶性肿瘤的发病机制和流行病学知之甚少。在之前的R 01资助（R 01 CA 86102）中，我们汇集了三项大型前瞻性队列研究的资源，即护士健康研究、卫生专业人员随访研究和医生健康研究，以研究胰腺癌的流行病学和发病机制。为了响应NIH计划公告PA-05- 040“饮食和胰腺癌预防的分子方法”，我们现在建议通过包括两个额外的大型前瞻性队列研究的资源来扩展我们的研究结果和我们的合作，这些研究具有广泛的库存饮食数据和生物标本，即妇女健康研究和妇女健康倡议。将这五项正在进行的大型前瞻性队列研究中的病例进行汇总，并进行长期随访，将允许对胰腺癌发病机制的假设进行严格的检查。我们建议检查胰腺癌发生的3个相互关联的致病途径：1）能量平衡，胰岛素和胰岛素样生长因子信号传导，2）炎症，3）维生素D相关途径。结合这五项队列研究的资源，我们将利用（1）前瞻性收集的饮食、体型、体力活动、镇痛剂使用和其他暴露的数据（2）营养和激素生物标志物，以及（3）与感兴趣的途径相关的遗传因素，研究相关暴露。将检查这些暴露、血浆生物标志物和遗传因素与胰腺癌发病率以及胰腺癌标本中特定分子改变的关系。这些分析的前瞻性设计将允许对这些风险因素进行严格检查，同时最大限度地减少胰腺癌回顾性研究中固有的潜在偏倚。通过更好地了解潜在的机制，剂量-反应关系，在类似途径中起作用的因素之间的相互关系，由于遗传易感性引起的反应变化，以及与特定肿瘤标志物相关的特异性，我们可以确定旨在降低这种高致死性恶性肿瘤的发病率和死亡率的建议。

DESCRIPTION (provided by applicant): Pancreatic cancer represents the fourth most common cause of cancer-related mortality. Nonetheless, relatively little is known about the pathogenesis and epidemiology of this malignancy. In a previous R01 grant (R01CA86102), we pooled the resources of three large prospective cohort studies, the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physician's Health Study to examine the epidemiology and pathogenesis of pancreatic cancer. In response to a NIH Program Announcement, PA-05- 040, "Molecular Approaches to Diet and Pancreatic Cancer Prevention," we now propose to extend our findings and our collaborations by including the resources of two additional large prospective cohort studies with extensive banked dietary data and biospecimens, the Women's Health Study and the Women's Health Initiative. Pooling of cases from these five large ongoing prospective cohort studies with long-term follow-up will allow a rigorous examination of hypotheses focusing on mechanisms of pancreatic cancer pathogenesis. We propose to examine 3 inter-related pathogenic pathways for pancreatic carcinogenesis: 1) energy balance, insulin and insulin-like growth factor signaling, 2) inflammation, and 3) vitamin D-related pathways. With the combined resources of these five cohort studies, we will study relevant exposures utilizing (1) prospectively collected data on diet, body habitus, physical activity, analgesic use, and other exposures (2) nutrient and hormonal biomarkers, and (3) genetic factors relevant to the pathways of interest. These exposures, plasma biomarkers, and genetic factors will be examined in relation to pancreatic cancer incidence as well as specific molecular alterations in pancreatic cancer specimens. The prospective design of these analyses will allow a rigorous examination of these risk factors while minimizing the potential biases that are inherent in retrospective studies of pancreatic cancer. By better understanding underlying mechanisms, dose-response relations, inter-relations among factors acting in similar pathways, variation in response due to genetic susceptibility, and specificity in associations to specific tumor markers, we can identify recommendations aimed at reducing the incidence and mortality from this highly lethal malignancy.