Molecular Correlates of Outcomes in Clinical Trials of Colon Cancer

描述（由申请人提供）：尽管在早期检测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。结肠癌的传统临床和病理特征不足以预测生存率。患者特征，如生殖系遗传变异，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结局相关的生殖系遗传因素，并且没有进行全面的全基因组研究来评估与结肠癌诊断后结局相关的更广泛的遗传变异。随机临床试验（RCT）为解决这一知识缺口提供了强有力的环境，因为患者人群特征良好，治疗标准化，随访一致。这项研究的总体目标是确定与结肠癌临床结局相关的遗传因素，并评估遗传变异的结合是否改善了现有的预后模型。为了实现这一目标，我们将利用三个NCI赞助的结肠癌III期RCT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搜索宿主全基因组单核苷酸多态性数据，在超过6,500例II-III期结肠癌患者中参与三项随机对照试验，所有患者均接受5-氟尿嘧啶/亚叶酸/奥沙利铂（FOLFOX）化疗伴或不伴辅助治疗，以检查与临床结局的相关性。具体来说，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（目标1）。我们还将评估生殖系遗传变异与治疗相关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，以确定生殖系遗传基因座是否可以与患者特征和临床因素相结合，更准确地预测结肠癌结局（目标3）。这些预后模型将在来自三项RCT的1，000例II-III期结肠癌患者的独立样本中进行验证。这些研究获得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。这些结果具有很高的翻译潜力，为告知预后，增强目前的战略，依赖于传统的临床因素和新兴的战略，纳入信息的体细胞分子改变。此外，在结肠癌诊断后鉴定与临床结果相关的基因座可以提供对癌症进展和转移的机制性见解，潜在地阐明可用于临床转化的新的治疗靶点。

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.