Genetic and Epigenetic Alterations in Colorectal Cancer and Metastases

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Treatment of colorectal cancer is complicated by the potential difference in molecular profiles between the primary tumor and metastases. Miranda and colleagues from the Humanitas Clinical and Research Center in Milan, Italy, recently assessed the presence of molecular heterogeneity during metastatic progression of colorectal cancer.

In this study, the investigators analyzed KRAS codon 12, BRAF codon 1788, and p53 mutations and promoter methylation of Ras association domain family member 1 protein (RASSF1a), E-cadherin, and cyclin-dependent kinase inhibitor 2A (p16INK4a) genes in 101 primary colorectal cancer tumors (67 stage III and 34 stage IV) and their related lymph node and liver metastases. Lymph node metastases had fewer molecular alterations than did primary tumors and liver metastases, including significantly fewer KRAS and p16INK4a alterations.

Most genetic changes detectable in metastases were retained from the primary tumor, whereas epigenetic changes were newly acquired. Overall, 31 distinct colorectal cancer molecular profiles were detected in primary tumors, none of which characterized a particular tumor stage. When metastatic lesions were included in the analysis, 53 distinct profiles were found among the 67 patients with stage III disease and 34 distinct profiles were found among the 34 patients with stage IV disease.

The finding of such heterogeneity has implications for selection of targeted therapy in colorectal cancer. The investigators concluded, “Lymph node and liver metastases appear to originate in clonally different processes, with more molecular alterations occurring in distant metastases than in lymph node metastases and with elevated heterogeneity of the primary tumor. Thus, potential prognostic targets should be carefully evaluated for their heterogeneity in both primary tumors and distant metastases to avoid erroneous misclassification.” ■

Miranda E, et al: Cancer 119:266-276, 2013.




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