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 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.
Molecular Genetics Laboratory, Humanitas Clinical and Research Center, Milan, Italy.
Elena
E
Miranda
Paolo
P
Bianchi
Annarita
A
Destro
Emanuela
E
Morenghi
Alberto
A
Malesci
Armando
A
Santoro
Luigi
L
Laghi
Massimo
M
Roncalli
D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008207:Lymphatic Metastasis; D009154:Mutation; D009367:Neoplasm Staging; D027384:Oncogene Proteins v-raf / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; D027384:Oncogene Proteins v-raf; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins