Lymph node evaluation is an important prognostic factor in colorectal cancer (CRC) because accurate identification of lymph node metastases significantly influences survival. However, a 30% recurrence rate in patients with node-negative CRC clearly indicates that current staging methods are inadequate. The primary form of treatment for all stages of colon cancer is surgical resection, but only patients with lymph node involvement or distant metastases receive adjuvant chemotherapy. Sentinel lymph node (SLN) mapping technique was developed to increase staging accuracy and has become the standard of care for melanoma. The SLN represents the first site of lymphatic drainage from the tumor. Therefore, SLN are at greatest risk for harboring metastases and should accurately predict the status of the regional node basin. SLN mapping has proven to be applicable to many types of cancers, in particular CRC. Ultrastaging methods, such as multilevel sectioning, immunohistochemistry (IHC), RT-PCR and, more recently, real-time quantitative qRT-PCR are currently being assessed for their ability to improve staging of colon cancer by allowing identification of lymph node micrometastic disease (MMD). However, although the clinical significance of MMD has not been resolved, its value is supported by a recent prospective, multi-center trial. Many biomarker candidates identified so far lack both specificity and sensitivity, therefore, new markers are needed to accurately identify lymph node MMD and prospective studies need to be performed to evaluate their prognostic value. MicroRNAs (miRNAs) are a class of recently identified small RNAs that play key regulatory roles in many cellular processes, such as development, differentiation, apoptosis and proliferation. Each tissue has a unique miRNA expression profile that allows identification of tissue type. miRNA profiles are significantly altered in cancers and there is mounting evidence suggesting that miRNAs play an active role in oncogenesis. The role of miRNAs as prognostic markers for cancer recurrence has not been determined. We propose to address this question using colorectal cancer as a model. We present preliminary data showing that miRNA expression profiles are substantially different in lymph nodes compared to other tissues, and that a subset of colon miRNAs can distinguish negative (normal) from positive lymph nodes in colon cancer patients. Our goal in phase I is to assess whether miRNAs can be used to accurately identify patients at risk of recurrence among the subset of patients scored node-negative by conventional histopathological examination, as they would benefit from more aggressive treatment and vigilant monitoring. Our long-term goal is to develop a miRNA- based prognostic assay for recurrence of colorectal cancer. Our phase I aims are 1) Identify and select colon and/or colon cancer miRNA marker candidates, and 2) Evaluate the prognostic value for recurrence of the miRNA marker candidates in FFPE sentinel lymph node samples using qRT-PCR method.
The long-term goal for this project is to develop a molecular diagnostic assay that can be used at the time of resection of a primary colon tumor to identify patients with a high risk of recurrence. This assay should reduce morbidity and mortality resulting from recurrent colon cancer as well as reduce health care costs. ? ? ?
