Molecular Correlates of Outcomes in Clinical Trials of Colon Cancer

描述(申请人提供)：尽管在早期发现和治疗方面取得了进步，但结肠癌仍然是美国癌症死亡的主要原因。传统的结肠癌临床和病理特征不足以预测患者的生存。患者的特征，如生殖系遗传变异，可能提供额外的预后信息。到目前为止，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，还没有进行全面的全基因组研究来评估更广泛的基因变异与结肠癌诊断后预后的关系。随机临床试验(RCT)提供了一个强大的环境来解决这一知识差距，因为患者群体特征良好，治疗是标准化的，随访是统一的。这项拟议研究的首要目标是确定与结肠癌临床结果相关的遗传因素，并评估纳入基因变异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赞助的三项结肠癌III期随机对照试验的资源，以及最近批准的与遗传病研究中心的合作。我们建议使用基于发现的搜索宿主基因组范围的单核苷酸多态数据，在参与三项随机对照试验的6,500多名II-III期结肠癌患者中，所有这些患者都接受了5-氟尿嘧啶/亚叶酸钙/奥沙利铂(FOLFOX)化疗，并辅以或不辅助治疗，以检查与临床结果的相关性。具体地说，我们将评估常见基因变异与II-III期结肠癌患者的无病生存率和总生存率之间的关系(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(目标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，以确定是否可以结合患者特征和临床因素使用胚系遗传位点来更准确地预测结肠癌的结果(目标3)。这些预后模型将在来自三个随机对照试验的1000名II-III期结肠癌患者的独立样本中得到验证。这些研究产生的数据将是第一批描述与结肠癌预后相关的全基因组种系遗传因素的数据之一。这些结果在告知预后方面具有很高的翻译潜力，既加强了依赖传统临床因素的现有策略，也加强了纳入体细胞分子变化信息的新兴策略。此外，在结肠癌诊断后识别与临床结果相关的基因座可能提供对癌症进展和转移的机械性洞察，潜在地阐明可用于临床翻译的新的治疗靶点。

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.