Identification of microRNAs as blood-based markers for colorectal cancer

描述（由申请人提供）：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。尽管在过去的三十年中，结直肠癌的5年死亡率有所下降，但由于在早期阶段预防和发现结直肠癌、监测疾病进展和预测治疗结果的策略依从性欠佳，进一步的进展受到阻碍。因此，需要开发一种无创、简单而准确的检测方法。MicroRNAs （miRNAs）是一种小的非编码rna，通过非完美碱基配对调节基因表达。近年来，越来越多的证据表明，mirna的异常表达与癌症的发生和进展有关。循环mirna作为生物标志物的使用已经开始被研究并发表在一些研究中。成功的血检是决定新辅助化疗或辅助化疗的重要帮助，也可用于随访患者治愈性切除后的复发情况和化疗后的反应情况。在一项初步研究中，我们使用基于TaqMan qRT-PCR的miRNA检测方法，比较了来自健康供体、局部结直肠癌患者和远处转移性结直肠癌患者的85个血浆样本中5种选定的miRNA的表达。我们的初步数据显示，所有这些mirna都可以在血浆中检测到。此外，miR-141 （miR-200家族的一员）的水平在远处转移性结直肠癌患者的血浆样本中显著升高。我们的初步数据支持我们的假设，即特异性mirna可以作为CRC早期检测、分期分层和预测预后的非侵入性、基于血液的标志物。我们的总体目标是确定一套强大的血浆miRNA标志物，用于CRC的早期发现、早期转移监测和预后评估。

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.