Molecular Correlates of Outcomes in Clinical Trials of Colon Cancer

描述（由申请人提供）：尽管在早期发现和治疗方面取得了进展，但结肠癌仍然是美国癌症死亡的主要原因。传统的临床和病理特征不足以预测结肠癌的生存。患者特征，如种系遗传变异，可能提供额外的预后信息。迄今为止，只有少数研究使用候选基因和途径方法来确定与癌症预后相关的种系遗传因素，并且尚未进行全面的全基因组研究来评估与结肠癌诊断后预后相关的更广泛的遗传变异。随机临床试验（rct）提供了一个强大的环境，以解决这方面的知识差距，因为患者群体具有良好的特征，治疗是标准化的，随访是统一的。拟议研究的总体目标是确定与结肠癌临床结果相关的遗传因素，并评估遗传变异的合并是否改善了现有的预后模型。为了实现这一目标，我们将利用nci赞助的三个结肠癌III期随机对照试验的资源，以及最近批准的与遗传疾病研究中心的合作。我们建议使用基于发现的宿主全基因组单核苷酸多态性数据搜索超过6500名II-III期结肠癌患者，这些患者都接受了5-氟尿嘧啶/亚叶酸钙/奥沙利铂（FOLFOX）化疗，有或没有辅助治疗，以检查与临床结果的关联。具体而言，我们将评估II-III期结肠癌患者的常见遗传变异与无病生存和总生存之间的关系（目的1）。我们还将评估生殖系遗传变异与治疗相关的严重不良事件的关系（目的2）。最后，我们将评估将遗传数据添加到现有的基于网络的、公开可用的预后模型中的影响，以确定生殖系遗传位点是否可以结合患者特征和临床因素来更准确地预测结肠癌的预后（目标3）。这些预后模型将在来自三个随机对照试验的1,000例II-III期结肠癌患者的独立样本中进行验证。这些调查产生的数据将是第一个描述与结肠癌预后相关的全基因组生殖系遗传因素的数据。这些结果在预测预后方面具有很高的转化潜力，增强了当前依赖于传统临床因素的策略和结合体细胞分子改变信息的新兴策略。此外，识别与结肠癌诊断后临床结果相关的基因座可能为癌症进展和转移提供机制洞察，潜在地阐明可用于临床转化的新治疗靶点。

DESCRIPTION (provided by applicant): Despite advances in early detection and treatment, colon cancer remains a leading cause of cancer death in the United States. Traditional clinical and pathological features of colon cancer are inadequate in predicting survival. Patient characteristics, such as germline genetic variation, may provide additional prognostic information. To date, only a few studies have used candidate gene and pathway approaches to identify germline genetic factors related to cancer outcomes, and no comprehensive genome-wide studies have been conducted to assess broader genetic variation in relation to outcomes after colon cancer diagnosis. Randomized clinical trials (RCTs) provide a powerful setting in which to address this gap in knowledge, because the patient populations are well-characterized, treatment is standardized, and follow-up is uniform. The overarching goal of the proposed study is to identify genetic factors associated with colon cancer clinical outcomes and to assess whether incorporation of genetic variants improves existing prognostic models. To achieve this goal, we will leverage the resources of three NCI-sponsored phase III RCTs of colon cancer and a recently approved collaboration with the Center for Inherited Disease Research. We propose to use a discovery-based search of host genome-wide single nucleotide polymorphism data in over 6,500 stage II-III colon cancer patients participating in three RCTs, all of whom received 5-fluorouracil / leucovorin / oxaliplatin (FOLFOX) chemotherapy with or without adjuvant therapy, to examine associations with clinical outcomes. Specifically, we will evaluate associations between common genetic variation and disease-free and overall survival among patients with stage II-III colon cancer (Aim 1). We will also evaluate germline genetic variation in relation to treatment-associated serious adverse events (Aim 2). Finally, we will evaluate the impact of adding genetic data into existing web-based, publicly available prognostic models to determine if germline genetic loci can be used, in combination with patient characteristics and clinical factors, to more accurately predict colon cancer outcomes (Aim 3). These prognostic models will be validated in an independent sample of 1,000 stage II-III colon cancer patients from the three RCTs. Data yielded by these investigations will be among the first describing genome-wide germline genetic factors associated with colon cancer prognosis. These results have high translational potential for informing prognosis, augmenting both current strategies that rely on traditional clinical factors and emerging strategies that incorporate information on somatic molecular alterations. Moreover, identifying loci associated with clinical outcomes after colon cancer diagnosis may provide mechanistic insight into cancer progression and metastasis, potentially illuminating new therapeutic targets that can be exploited for clinical translation.