Microsatellite high colorectal cancer: Does the underlying mechanism for instability matter?

575 Background: Microsatellite instability (MSI) testing in colorectal cancer (CRC) provides prognosis, predicts chemotherapy response, and guides diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MSI can be sporadic or hereditary, arising from somatic or germline mutations in DNA mismatch repair (MMR) genes respectively. The clinical implications of these distinct mechanisms are uncertain. Methods: Patients who underwent MSI testing for CRC between 2000 and 2011 were identified. MSI-high (MSH) CRCs were defined by: pathogenic mutation in MMR genes; >30% of markers with allelic shift in PCR-based MSI testing; or loss of expression in at least 1 MMR protein on immunohistochemistry. The subset with MLH1 gene promoter methylation, BRAF mutation, or EPCAM mutation was considered sporadic. Clinicopathologic features and disease-free survival (DFS) were examined in reference to microsatellite stable (MSS) CRCs. Results: MSH CRC’s, 92 germline and 49 sporadic, were compared with 105 MSS CRCs. Compared to MSS CRCs, both germline and sporadic MSH CRCs more commonly arose in the proximal colon (63% and 92%, vs. 30%; p Conclusions: Patients with sporadic MSH CRCs exhibit distinct clinicopathologic features compared to those with germline MSH tumors. Despite poor prognostic features, no apparent survival difference was observed. Further characterization of these distinct groups is warranted to explain the discordance between risk factors and outcomes.