Abstract | 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: 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.
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Authors | Elena Miranda, Paolo Bianchi, Annarita Destro, Emanuela Morenghi, Alberto Malesci, Armando Santoro, Luigi Laghi, Massimo Roncalli |
Journal | Cancer
(Cancer)
Vol. 119
Issue 2
Pg. 266-76
(Jan 15 2013)
ISSN: 1097-0142 [Electronic] United States |
PMID | 22786759
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 American Cancer Society. |
Chemical References |
- Antigens, CD
- CDH1 protein, human
- Cadherins
- Cyclin-Dependent Kinase Inhibitor p16
- KRAS protein, human
- Proto-Oncogene Proteins
- RASSF1 protein, human
- TP53 protein, human
- Tumor Suppressor Protein p53
- Tumor Suppressor Proteins
- BRAF protein, human
- Oncogene Proteins v-raf
- Proto-Oncogene Proteins B-raf
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
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Topics |
- Antigens, CD
- Cadherins
(genetics)
- Colorectal Neoplasms
(genetics, pathology)
- Cyclin-Dependent Kinase Inhibitor p16
(genetics)
- DNA Methylation
- DNA Mutational Analysis
- Epigenesis, Genetic
- Humans
- Liver Neoplasms
(genetics, secondary)
- Lymphatic Metastasis
- Mutation
- Neoplasm Staging
- Oncogene Proteins v-raf
(genetics)
- Promoter Regions, Genetic
- Proto-Oncogene Proteins
(genetics)
- Proto-Oncogene Proteins B-raf
(genetics)
- Proto-Oncogene Proteins p21(ras)
- Tumor Suppressor Protein p53
(genetics)
- Tumor Suppressor Proteins
(genetics)
- ras Proteins
(genetics)
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