Circulating microRNAs as a biomarker of colorectal cancer recurrence

描述(申请人提供)：结肠癌是美国第三种最常见的癌症，也是导致男性和女性癌症死亡的第三大原因。大约30%的结直肠癌(CRC)患者有很高的复发风险，但决定复发的因素尚不完全清楚。肿瘤分期是目前判断CRC复发的最好的预后指标，但我们还不能自信地区分侵袭性癌症和不太可能复发的癌症。因此，需要建立预测标记物，以快速识别其原发肿瘤可能复发的患者，以便能够做出量身定制的治疗决定。利用一项对结直肠癌患者进行的前瞻性队列研究，使用重复的、广泛的随访数据，我们将检验循环水平的假设 结直肠癌患者中特定miRNAs的表达水平与肿瘤的病理生理相关，如肿瘤分期、复发和肿瘤miRNA表达水平。我们希望提供证据表明，循环中的miRNAs可以被用作结直肠癌复发的强有力的非侵入性生物标记物。我们建议通过qRT-PCR来测量miRNAs的表达，现有文献支持其在结直肠癌中的预后潜力。我们将评估这些miRNAs的血浆水平在手术前、术后6个月或两者之间的变化是否与肿瘤分期或复发相关。我们还将关联一部分患者的血浆和肿瘤miRNA表达。这项研究的基本原理是循环miRNAs与CRC患者的疾病有很强的相关性，因此我们建议确定手术前后循环miRNA测量作为CRC复发的生物标志物的有效性。这些新的生物标志物在多个独立研究人群中的验证是将这项研究转化为临床实践的必要步骤。此外，术前循环miRNA水平与肿瘤分期的相关性将为这些生物标记物作为早期检测标记物的用途提供证据。这项研究具有创新性，因为它将是第一次评估手术前和术后6个月循环中miRNA的水平。

DESCRIPTION (provided by applicant): Colon cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women in the United States. About 30 percent of colorectal cancer (CRC) patients are at a high risk of recurrence, yet factors that determine recurrence are not fully understood. Tumor stage is currently the best prognostic marker of CRC recurrence, but we are not yet able to confidently discriminate between aggressive cancers and those not likely to recur. A need therefore exists to establish predictive markers that rapidly identify patients whose primary tumor are likely to recur, to enable tailored treatment decisions. Using a prospective cohort study of colorectal cancer patients with repeat, extensive follow-up data, we will test the hypothesis that circulating levels of specific miRNAs in colorectal cancer patients correlate with the pathophysiology of the cancer, as indicated by tumor stage, recurrence, and tumor miRNA expression levels. We expect to provide evidence that circulating miRNAs can be used as a robust non-invasive biomarker of colorectal cancer recurrence. We propose to measure by qRT-PCR the expression of miRNAs for which literature exists supporting their prognostic potential in colorectal cancer. We will evaluate whether plasma levels of these miRNAs pre-surgery, 6 months post surgery, or the change between the two, correlates with tumor stage or recurrence. We will also correlate plasma and tumor miRNA expression for a subset of patients. The rationale for the proposed research is that circulating miRNAs have shown a strong correlation with disease in CRC patients, thus we propose to determine the utility of circulating miRNA measurements both before and after surgery as biomarkers for CRC recurrence. The validation of these new biomarkers in multiple, independent study populations is a necessary step towards translating this research into clinical practice. Furthermore, correlations between pre-surgical circulating miRNA levels and tumor stage will provide evidence on the utility of these biomarkers as early detection markers. This study is innovative because it will be the first to evaluate circulating levels of miRNA both prior to and 6 months post-surgery.