BACKGORUND: Synchronous and metachronous colorectal cancer(CRC) are considered clinical features of Hereditary Non-Polyposis Colorectal Cancer(HNPCC)syndrome, and molecular screening for microsatellite instability(MSI) is recommended for patients with multiple colorectal cancers. However, most MSI tumors are not due to germline mutation of the mismatch repair genes, but rather to inactivation of the MLH1 gene by promoter methylation(PM). The aim of this study was to compare the molecular mechanisms responsible for the MSI tumors in patients with metachronous and synchronous CRC.
METHODS: MSI was determined by PCR using a set of five markers. The presence of new alleles at two or more markers was scored as MSI. MLH1 and MSH2 expression was determined by immunohistochemistry. PM of MLH1 gene was determined by methylation-specific PCR assay.
RESULTS: We identified one hundred and nine patients (76 with synchronous tumors and 33 with metachronous tumors) with a total of 211 invasive CRC (166 synchronous and 45 metachronous CRC)from a database of 2884 CRC patients. Patients with metachronous cancers were significantly younger than those with synchronous cancer(65 vs.72 years, p=0.046). Thirty percent of patients with metachronous CRC and 24% of those with synchronous CRC had at least one first-degree relative with CRC. However, only one patient with metachronous CRC met the Amsterdam criteria. The proportion of MSI tumor in patients with metachronous and synchronous CRC were 38% and 32%, respectively. The mechanisms of MSI are presented in table I.
CONCLUSION: The proportion of MSI tumors is similar in patients with synchronous and metachronous CRC. Epigenetic inactivation of the MLH1 gene is responsible for most synchronous CRC, but less than half of metachronous CRC. This data suggests that patients with synchronous and metachronous CRC have a different probability of having HNPCC.
Table I. The mechanism of MSI in multiple CRC
MLH1(-) PM* MSH2(-) MLH1(+), MSH2(+)
Sync. 81% 81% 17% 2%
Meta. 53% 41% 30% 18%
Sync.: synchronous CRC, Meta.: metachronous CRC
MSI: microsatellite instability, PM: promoter methylation of MLH1 gene
*p<0.05(chi square test)