Calcium and Colorectal Cancer: Gene-Environment Interactions and Molecular Pathways

 描述(申请人提供)：尽管结肠镜检查的使用越来越多，治疗也有所改善，但结直肠癌(CRC)仍然是美国男性和女性第三常见的癌症和癌症相关死亡病例。我的长期职业目标是成为一名独立的学术研究员，有能力应用分子病理流行病学和遗传流行病学方法来开发新的结直肠癌预防和控制策略。我渴望在流行病学工作中观察到的与CRC病因和预后的联系之间架起桥梁，从而阐明新的生物学机制，并最终降低CRC的发病率和死亡率。为了实现这一目标，K07奖将使我能够在分子病理流行病学、肿瘤组织收集和使用、癌症生存以及遗传流行病学方法方面接受新的培训。培训将包括指导研究、原发肿瘤组织数据收集、病理学实验室实习、参与建立多中心癌症幸存者队列、授课课程、在同行评议期刊上发表我的研究成果、出席科学会议以及提交R01拨款。这项拟议的研究解决了关于钙在结直肠癌病因学和预后中的作用的三个关键知识空白：结直肠癌亚型的病因学异质性(目标1)、基因-环境相互作用对结直肠癌风险的影响(目标2)以及对结直肠癌生存的预后影响(目标3)。为了弥补这些差距，我提出了一种新的综合方法，将利用四项独特和丰富的基于人群的研究：护士健康研究、护士健康研究II、卫生专业人员跟踪研究以及结直肠癌联合会(GECCO)的遗传学和流行病学。这项研究将是研究钙与肿瘤病理标志物和基因变异在结直肠癌病因和预后中的联合作用的最大规模的研究。它的发现可能具有重大的病因学和临床意义，包括1)揭示新的预后标志和生物机制；2)为未来降低结直肠癌风险的饮食指南提供信息；3)为提高美国120万患有这种致命疾病的人的存活率提供新的见解。这项培训和研究得到了哈佛一群经验丰富的导师的支持。爱德华·乔瓦努奇博士将监督培训和研究的各个方面。我将与小野修二博士一起接受分子病理流行病学方面的新培训，与查尔斯·富克斯博士一起接受癌症生存方面的培训，并与彼得·克拉夫特博士一起接受遗传流行病学方法方面的培训。哈佛大学的唐娜·斯皮格尔曼博士和弗雷德·哈钦森癌症研究中心的乌里克·彼得斯博士也承诺与我合作。在完成该奖项后，我有信心实现研究独立，并显著增强我以创新和重要的方式为结直肠癌流行病学领域做出贡献的能力。

 DESCRIPTION (provided by applicant): Despite the increasing use of colonoscopy and improved treatment, colorectal cancer (CRC) remains the third most common cancer and cancer-related death in both US men and women. My long-term career goal is to become an independent academic investigator with the ability to apply molecular pathological epidemiology and genetic epidemiology methods to develop new prevention and control strategies for CRC. I aspire to bridge the associations observed in epidemiological work with CRC etiology and prognosis, thereby illuminating new biological mechanisms and, ultimately, decreasing CRC incidence and mortality. To achieve this goal, this K07 award will enable me to receive new training in molecular pathological epidemiology, tumor tissue collection and usage, cancer survivorship, as well as genetic epidemiology methods. The training will include mentored research, primary tumor tissue data collection, pathology laboratory internship, involvement in establishing a multi-center cancer survivor cohort, didactic coursework, publication of my research in peer- reviewed journals, attendance at scientific meetings, and submission of an R01 grant. The proposed research addresses three critical gaps in knowledge regarding the role of calcium in CRC etiology and prognosis: the etiologic heterogeneity of CRC sub-types (Aim 1), gene-environment interaction on CRC risk (Aim 2), and prognostic implications for CRC survival (Aim 3). To address these gaps, I propose a novel and integrated approach that will leverage four unique and rich population-based studies: the Nurses' Health Study, Nurses' Health Study II, Health Professionals Follow-Up Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). This study will be the largest to examine the role of calcium in combination with tumor pathological markers and genetic variants on the etiology and prognosis of CRC. Its findings could have significant etiologic and clinical implications, including 1) revealing new prognostic markers and biological mechanisms; 2) informing future dietary guidelines to lower the risk of CRC; and 3) offering new insights for improving survival among the 1.2 million people in the US who are afflicted by this deadly disease. This training and research is supported by a group of experienced mentors at Harvard. Dr. Edward Giovannucci will supervise all aspects of the training and research. I will obtain new training in molecular pathological epidemiology with Dr. Shuji Ogino, cancer survivorship with Dr. Charles Fuchs, and genetic epidemiology methods with Dr. Peter Kraft. I also have a pledge of collaboration from Drs. Donna Spiegelman at Harvard and Ulrike Peters at the Fred Hutchinson Cancer Research Center. At the completion of the award, I am confident to achieve research independence and significantly enhance my ability to contribute to the field of CRC epidemiology in innovative and important ways.