MedWire News: Dutch scientists have discovered a chromosomal marker linked to the development of liver metastases in patients with colorectal cancer (CRC), and identified a candidate gene at this site.
"The possible role of this hepatic metastasis-associated gene in specific steps of the hepatic metastatic process needs to be functionally validated," say Iris Nagtegaal (Radboud University Nijmegen Medical Centre) and co-authors.
"Ultimately, this could result in… the identification of new prognostic markers that select patients with early-stage colorectal cancer who are most likely to develop liver metastases, and… the development of liver-specific antimetastatic therapies for the future," they suggest.
As reported in Gut, the researchers investigated whether chromosomal aberrations in primary tumors could help explain why CRC is associated with organ-specific metastases.
Specifically, they examined for clinicopathologic features in CRC patients with exclusively hepatic (n=182) or extrahepatic (n=139) metastases. In addition, chromosomal aberrations were examined for in tumors taken from 192 patients with hepatic and 54 patients with extrahepatic metastases.
Chromosomal aberrations correlated with gene and protein expression, and the results validated using data from an additional 80 primary tumors.
The researchers found that patients with hepatic metastases were significantly more likely than those with extrahepatic metastases to be male (71 vs 53%), to have abnormal lactate dehydrogenase activity (37 vs 14%), to have primary tumor localized in the colon (52 vs 40%), and to have synchronous metastases onset (70 vs 19%).
Primary tumors from patients with hepatic metastases were more likely than those from patients with extrahepatic metastases to be stage T3 (79 vs 63%), and less likely to be mucinous (5 vs 16%).
Furthermore, tumors from patients with hepatic metastases were more likely to have gain of chromosome 20p11, and this was confirmed in the independent data set.
Twelve genes were overexpressed due to a gain in 20p11 copy number, with C20orf3 showing the strongest correlation between RNA expression and DNA copy number.
Of note, C20orf3 protein expression was significantly more common in primary tumors from patients with hepatic metastases than those with extrahepatic metastases (59 vs 41%).
"C20orf3 is a member of the lactonohydrolase super family, and the potential involvement of this protein in enzymatic processes is suggested," write Nagtegaal et al.
They add: "In vitro assays should provide evidence for a causal role for this gene in metastasis formation."
However, the researchers caution: "We should keep in mind that primary tumours are highly heterogeneous in terms of both their cell populations and their ability to metastasise. Therefore it may be that the genes responsible for organ tropism are not detected in the bulk of the primary tumour."
They suggest: "A next step could be to search directly for genes involved in organ-specific metastases by profiling metastatic samples from different secondary sites in relation to their primary tumour."
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