Genetic and epigenetic alterations in primary colorectal cancers and related lymph node and liver metastases

BACKGROUND: Colorectal cancer (CRC) prognosis and survival are strictly related to the development of distant metastases. New targeted therapies have increased patient survival, but the objective response rate is still very limited, partially because of a traditional focus on designing treatment acc...

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Bibliographic Details
Published in:Cancer 2013-01, Vol.119 (2), p.266-276
Main Authors: Miranda, Elena, Bianchi, Paolo, Destro, Annarita, Morenghi, Emanuela, Malesci, Alberto, Santoro, Armando, Laghi, Luigi, Roncalli, Massimo
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cadherins - genetics
Codons
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Cyclin-Dependent Kinase Inhibitor p16 - genetics
DNA Methylation
DNA Mutational Analysis
Epigenesis, Genetic
Gastroenterology. Liver. Pancreas. Abdomen
genetic and epigenetic alterations
Humans
liver metastases
Liver Neoplasms - genetics
Liver Neoplasms - secondary
lymph node metastases
Lymphatic Metastasis
Medical sciences
molecular heterogeneity
Mutation
Neoplasm Staging
Oncogene Proteins v-raf - genetics
primary colorectal cancer
Promoter Regions, Genetic
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins p21(ras)
ras Proteins - genetics
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Proteins - genetics
Tumors
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Summary:BACKGROUND: Colorectal cancer (CRC) prognosis and survival are strictly related to the development of distant metastases. New targeted therapies have increased patient survival, but the objective response rate is still very limited, partially because of a traditional focus on designing treatment according to the molecular profile of the primary tumor regardless the diversity between the primary tumor and metastases. The objective of this study was to evaluate the presence of molecular heterogeneity during metastatic progression and its potential impact on clinical treatment. METHODS: The authors analyzed v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) codon 12 mutations, the v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF) thymine to adenine substitution at codon 1788, and tumor protein 53 (p53) mutations and investigated promoter methylation of Ras association (RalGDS/AF‐6) domain family member 1 protein (RASSF1a), E‐cadherin, and cyclin‐dependent kinase inhibitor 2A (p16INK4a) in 101 primary CRCs (67 stage III and 34 stage IV) and related lymph node and liver metastases. RESULTS: Lymph node metastases were characterized by fewer alterations compared with primary tumors and liver metastases, especially KRAS (P = .03) and p16INK4a (P = .05). Genetic changes, when detectable in metastases, mostly were retained from the primary tumor, whereas epigenetic changes more frequently were acquired de novo. Overall, 31 distinct CRC molecular profiles were detected, none of which characterized a particular tumor stage. When the metastatic lesions also were included in the profiles, there were 53 distinct molecular profiles in 67 patients with stage III disease and 34 distinct molecular profiles in 34 patients with stage IV disease. CONCLUSIONS: 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. Cancer 2013. © 2012 American Cancer Society. Prognosis and survival in colorectal cancer are mainly associated with the development of distant metastases rather than the primary tumor itself. A comparison of these alterations between primary tumors and distant metastases demonstrates the amount of molecular hete
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.27722