Identification of microRNAs as blood-based markers for colorectal cancer

描述(申请人提供)：结直肠癌(CRC)是美国癌症相关死亡的第二大常见原因，根据NCI的数据，2010年估计有51,370人死亡。尽管过去三十年来，结直肠癌的5年死亡率有所下降，但由于对预防和发现结直肠癌早期阶段、监测疾病进展和预测治疗结果的策略的遵从性不佳，阻碍了进一步的进展。因此，开发非侵入性、简单但准确的检测方法是必要的。MicroRNAs(MiRNAs)是一种小的、非编码的RNA，通过不完美的碱基配对来调节基因的表达。近年来，越来越多的证据表明miRNAs的异常表达与肿瘤的发生发展密切相关。使用循环miRNAs作为生物标记物的研究已经开始，并在一些研究中发表。成功的血液测试将对决定新辅助或辅助化疗有很大帮助，也将用于跟踪患者根治性切除后的复发和化疗后的反应。在一项先导性研究中，我们使用基于TaqMan qRT-PCR的miRNA分析方法，比较了5个选定的miRNAs在85个来自健康捐赠者、有局部疾病的结直肠癌患者和有远处转移疾病的结直肠癌患者的血浆样本中的表达。我们的初步数据显示，所有这些miRNAs都可以在血浆中检测到。此外，远处转移性结直肠癌患者的血浆样本中miR-141水平显著升高，miR-141是miR-200家族的成员之一。我们的初步数据支持我们的假设，即特定的miRNAs可以作为无创性的、基于血液的标志物，用于结直肠癌的早期检测、分期和预后预测。我们的总体目标是找到一套强大的血浆miRNA标志物并将其用于结直肠癌的早期检测、早期转移监测和预后评估。 公共卫生相关性：尽管寻找癌症的血浆标记物是一个公认的概念，但发现临床上有用的标记物的情况非常罕见。任何具有良好性能特征的标记物都将有利地影响癌症筛查和监测，并有助于提高患者的存活率。因此，在这项建议中寻找结肠癌的血浆标志物是至关重要的。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States, with estimated 51,370 deaths in 2010 according to NCI. Even though the 5-year death rate of CRC has declined over the past three decades, further progress has been hindered by suboptimal compliance with strategies that can prevent and detect CRC in its early stages, monitor disease progression and predict therapy outcome. Thus, development of non- invasive, simple but accurate tests is needed. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression through non-perfect base-pairing. Recently, accumulating evidence has indicated that aberrant expression of miRNAs is associated with cancer development and progression. The use of circulating miRNAs as biomarkers has begun to be investigated and published in a few studies. A successful blood test would be a major help in deciding on neoadjuvant or adjuvant chemotherapy, and would also be used to follow patients for recurrence after curative resection and after chemotherapy for response. In a pilot study, using TaqMan qRT-PCR based miRNA assays we compared expression of 5 selected miRNAs in a cohort of 85 plasma samples from healthy donors, CRC patients with localized disease, and CRC patients with distant metastatic disease. Our preliminary data showed that all of these miRNAs can be detected in the plasma. Further, the levels of miR-141, a member of the miR-200 family, were significantly elevated in plasma samples from patients with distant metastatic colorectal cancer. Our preliminary data support our hypothesis that specific miRNAs can be used as non-invasive, blood-based markers for early detection, stage stratification and prediction of prognosis in CRC. Our overall objective is to identify and put into routine usage a set of robust plasma miRNA markers for CRC early detection, monitoring early metastasis and evaluating prognosis. PUBLIC HEALTH RELEVANCE: Although the search for plasma markers for cancer is a well-established concept, the finding of markers that are clinically useful is very infrequent. Any marker with favorable performance characteristics would favorably impact cancer screening and monitoring and contribute to improved survival of patients. Therefore, the search for plasma markers for colon cancer in this proposal is critically important.