The Use of Molecular Profiling of Early Colorectal Cancer to Predict Micrometastases

Abstract

Background: Approximately one third of nodenegative colorectal cancers (CRCs) recur, suggesting the failure to detect occult disease. Lymphatic mapping followed by focused analysis of the sentinel node is highly accurate in identifying micrometastases. Hypothesis: Because aberrant genetic changes occur early in tumor progression and are associated with lymphatic metastases, we hypothesized that the molecular profiling of specific tumor markers in the primary tumor might predict that tumor's metastatic potential. Design: A prospective patient series. Patients and Interventions: Forty consecutive patients with early CRC underwent lymphatic mapping after subserosal injection of 1 mL of isosulfan blue dye. All lymph nodes were examined by hematoxylin-eosin (HE) staining, and multiple sections of each sentinel node were examined by HE and cytokeratin immunohistochemistry (CK-IHC) staining. Primary tumors were analyzed for p53 expression using IHC staining and for ␤-human chorionic gonadotropin (␤-hCG), hepatocyte growth factor receptor (c-Met), and universal melanoma antigen (uMAGE) messenger RNA expression using reversetranscriptase polymerase chain reaction and electrochemiluminescence. Results: Nine patients (23%) had positive nodes by routine HE staining. Of the remaining 31 patients with negative nodes on HE staining, 8 tumors (26%) were upstaged by CK-IHC identification of occult micrometastases. There was a direct correlation between the number of markers and the T stage (P=.001). The expression of p53, ␤-hCG, c-Met, and uMAGE in primary tumors was significantly higher in the presence of nodal micrometastases vs no metastases (P=.03). Conclusions: Sentinel lymphatic mapping is an accurate method of detecting micrometastases in CRC. Molecular profiling of primary CRC tumors, similar to that used for breast cancer, may be important in predicting metastatic potential and determining which patients may benefit from adjuvant therapy.

High Ki67 expression is an independent good prognostic marker in colorectal cancer

“…Patients with nodal negative disease generally show a favourable clinical course. However, approximately one-third of node-negative CRCs recurs or shows progressive disease, suggesting failure to detect occult disease 2. Because aberrant genetic changes occur early in tumour progression, molecular profiling of specific tumour markers in the primary tumour might predict the tumour’s metastatic potential.…”

Molecular Profiles of Sentinel and Non-Sentinel Lymph Nodes in Breast Cancer Progression and Prognosis

“…They also state that all the patients who were HGF and MUC1 negative were free of metastatic disease in the lymph nodes. Similarly HGF/c-met expression was higher in SLN of early colorectal cancer patients with micrometastases in the nodes as compared with those with no metastases [83] ( Table 1).…”

“…The expression of p53 and Rb, and the cell proliferation indicator gene Ki67 has been the subject of many investigations. Primary early colonic tumours have been analysed for p53 expression by IHC and expression levels in SLN have correlated with the presence of micrometastases [83]. Malmstrom et al [88] investigated the expression of these as well that of E-cadherin, microvessel density and apoptosis in bladder carcinoma.…”

Lymphatic Staging in Colorectal Cancer: Pathologic, Molecular, and Sentinel Node Techniques

“…We found only one report by Bilchik et al 108 in which he described a molecular profiling technique for colorectal cancer. Molecular profiling of the primary tumor was performed using a combination of RT-PCR on three tumor markers (␤-HCG, c-Met, and uMAGE) and immunohistochemical staining against p53.…”