Lifestyle Factors and Survival Outcomes for Colorectal Cancer Molecular Subtypes

描述(由申请人提供)：激励我研究的首要目标一直是表征癌症中的生物异质性及其对癌症流行病学的影响。作为华盛顿大学(UW)的一名流行病学博士生，我开发了一个研究组合，描述了三阴性乳腺癌的风险因素--一种预后较差、人们对乳腺癌亚型知之甚少的乳腺癌亚型。2010年我从威斯康星大学毕业后，我的研究从乳腺癌研究过渡到结直肠癌(CRC)研究，从癌症风险研究过渡到癌症生存研究。在将我的研究扩展到CRC生存研究的过程中，激励我工作的目标保持不变，但我的特定研究兴趣已经演变到包括我以前从未参与过的领域。特别是，我对临床流行病学和基础研究产生了兴趣。 在临床试验环境中。为这个职业发展奖建议的研究和培训活动将使我获得必要的技能、经验和合作，以启动癌症生存的独立学术生涯，并将我的研究转变为更具翻译性的领域。将我的博士后、博士后和拟议的研究统一在一起的是对癌症生物学和癌症流行病学之间的关系的兴趣。像乳腺癌一样，结直肠癌是一种异质性疾病，可以分为不同的生物学亚型。然而，与乳腺癌不同的是，分子定义的结直肠癌亚型尚未得到广泛的表征。根据微卫星不稳定性(MSI)、CpG岛甲基化(CIMP)、BRAF突变和KRAS突变等四种肿瘤标志物的信息，最近提出了结直肠癌亚型的分子分类。这四种标志物的不同组合被认为反映了结直肠癌发展的不同途径。这些标志物定义的CRC亚型之间的生物学差异也可能转化为预后和预后因素的差异，尽管这种差异尚未得到很好的描述。这项建议的研究目标是评估由MSI/CIMP/BRAF/KRAS联合状态定义的CRC分子亚型的预后意义，并评估可改变的生活方式因素对这些亚型疾病患者CRC诊断后临床结果的影响。这项研究的最终目标是确定将具有 影响结直肠癌存活率的临床意义。为了追求这些研究目标，我将利用两项非常丰富但非常不同的研究的数据，这两项研究是我现有的合作伙伴：西雅图结肠癌家族登记中心(S-CCFR)和III期结肠癌的III期随机临床试验(N0147)。这两项研究都用流行病学数据和有关结直肠癌患者MSI、CIMP、BRAF和KRAS突变状态的信息进行了很好的诠释。通过提议的研究活动，我将使用这两项研究的数据来表征四个不同的可改变的生活方式因素(目标1a)和存活率(目标1b)的差异 由联合MSI/CIMP/BRAF/KRAS状态定义的CRC亚型。我还将使用这些数据来评估几种生活方式因素(例如，吸烟、饮酒、体育活动)与这四种亚型结直肠癌患者(目标2-3)的生存率之间的关系。在观察性研究(S-CCFR)和临床试验(N0147)中进行平行分析将提供机会，在具有互补优势和局限性的研究环境中比较和对比结果。这种平行和互补的分析方法也将为我提供在不同研究环境中收集的临床结果数据和临床试验工作的经验。在进行拟议的研究时，将受益于弗雷德·哈钦森癌症研究中心(FHCRC)的丰富资源和合作环境。作为世界领先的癌症研究中心之一，FHCRC聚集了大量杰出的流行病学家、临床研究人员和实验室科学家，他们可以提供有针对性的指导。特别是，我将受益于Polly Newcomb博士(主要导师)的指导，他在结直肠癌流行病学和癌症生存观察研究方面拥有丰富的专业知识，是S-中国癌症研究中心的PI。我还将得到Noel Weiss博士(共同导师)的指导，他是流行病学方法和临床流行病学方面的经验丰富的专家。为了获得进一步的指导，我征集了外部咨询委员会的专业知识，该委员会的专家包括进行肿瘤学临床试验的专家(Steven Alberts博士，他也是N0147研究主席)、跨研究环境下进行相关科学的专家(Paul Limburg博士)、结直肠癌的流行病学和治疗专家(Andrew Chan博士)以及结直肠癌病理学的专家(Christophe Roustin博士)。为了补充我的研究和进一步的职业发展，我还将与Weiss博士合作开发和实施研究生水平的流行病学方法系列课程的教学材料。通过这个项目获得的实践经验和专业知识将得到结果研究、药物流行病学和临床试验方法学方面的正式课程的补充，以及通过FHCRC、华盛顿大学和其他项目提供的定期研究研讨会。FHCRC和UW都特别重视为早期职业科学家提供职业发展机会，提供正式的指导机制、定期职业发展研讨会、期刊俱乐部、课程评估和其他网络资源。因此，FHCRC的环境，以及与之密切相关的华盛顿大学，为我开始独立的学术研究生涯提供了一个极好的环境。

DESCRIPTION (provided by applicant): The overarching goal motivating my research has been to characterize biological heterogeneity in cancer and its impact on cancer epidemiology. As an epidemiology doctoral student at the University of Washington (UW), I developed a research portfolio characterizing risk factors for triple-negative breast cancer - a poor prognosis poorly understood breast cancer subtype. Following my graduation from UW in 2010, my research transitioned from the study of breast cancer to the study of colorectal cancer (CRC), and from the study of cancer risk to the study of cancer survival. In extending my research to the study of CRC survival, the goal motivating my work has remained the same but my specific research interests have evolved to encompass areas in which I have not previously been involved. In particular, I have developed an interest in clinical epidemiology and in studies based in the clinical trial setting. The research and training activities proposed for this career development award will allow me to gain the skills, experience, and collaborations necessary to launch an independent academic career in cancer survival, and to transition my research into a more translational realm. Unifying my predoctoral, postdoctoral, and proposed research is an interest in the relationship between cancer biology and cancer epidemiology. Like breast cancer, CRC is a heterogeneous disease that can be classified into biologically distinct subtypes. Unlike breast cancer, however, molecularly-defined subtypes of CRC have not yet been widely characterized. Molecular classifications for CRC subtypes were recently proposed, using information on four tumor markers: microsatellite instability (MSI), CpG island methylation (CIMP), mutations in BRAF, and mutations in KRAS. Different combinations of these four markers are thought to reflect distinct pathways of CRC development. Biological distinctions between CRC subtypes defined by these markers also likely translate to differences in prognosis and prognostic factors, although such differences have not yet been well described. The research objectives of this proposal are to assess the prognostic significance of CRC molecular subtypes defined by joint MSI / CIMP / BRAF / KRAS status, and to assess the impact of modifiable lifestyle factors on clinical outcomes after CRC diagnosis for patients with these subtypes of disease. The ultimate goal of this research is to identify factors that will have clinical relevance in informing CRC survival. In pursuit of these research objectives, I will leverage data from two very rich but very different studies with which I have existing collaborations: the Seattle Colon Cancer Family Registry (S-CCFR) and a phase III randomized clinical trial of stage III colon cancer (N0147). Both studies are well annotated with epidemiologic data and information on MSI, CIMP, and BRAF and KRAS mutation status in CRC patients. Through the proposed research activities, I will use data from both studies to characterize differences in modifiable lifestyle factors (Aim 1a) and survival (Aim 1b) across four CRC subtypes defined by joint MSI / CIMP / BRAF / KRAS status. I will also use these data to assess the relationship between several lifestyle factors (e.g., smoking, alcohol consumption, physical activity) and survival in patients with these four subtypes of CRC (Aims 2-3). Conducting parallel analyses in an observational study (S-CCFR) and in a clinical trial (N0147) will provide opportunities for comparing and contrasting results across study settings with complementary strengths and limitations. This approach of parallel and complementary analyses will also provide me with experience in working with clinical outcomes data collected in different study settings and in working with clinical trials. In conducting the proposed research, will benefit from the rich resources and collaborative environment of the Fred Hutchinson Cancer Research Center (FHCRC). As one of the world's leading cancer research centers, the FHCRC is home to a large number of distinguished epidemiologists, clinical researchers, and laboratory scientists who can provide directed guidance. In particular, I will benefit from the mentorship of Dr. Polly Newcomb (primary mentor), who has considerable expertise in CRC epidemiology and observational studies of cancer survival and who is PI of the S-CCFR. I will also be mentored by Dr. Noel Weiss (co-mentor), who is a seasoned expert in epidemiologic methods and clinical epidemiology. For further guidance, I have enlisted the expertise of an external advisory committee, comprised of specialists in the conduct of oncology clinical trials (Dr. Steven Alberts, who is also the N0147 Study Chair), in the conduct of correlative science across study settings (Dr. Paul Limburg), in the epidemiology and treatment of CRC (Dr. Andrew Chan), and in CRC pathology (Dr. Christophe Rosty). To complement my research and further my career development, I will also work with Dr. Weiss to develop and implement materials for teaching a graduate-level epidemiologic methods course series. The hands-on experience and expertise gained through this project will be supplemented by formal coursework in outcomes research, pharmacoepidemiology, and clinical trial methodologies, and by regular research seminars offered through the FHCRC, the UW, and other programs. Both the FHCRC and the UW place particular emphasis on providing early career scientists with career development opportunities, offering formal mechanisms for mentoring, regular career development seminars, journal clubs, curriculum evaluation, and other networking resources. Thus, the environment of the FHCRC, and the closely affiliated UW, provides an excellent setting in which to launch my independent academic research career.