Unfavorable pathological characteristics in familial colorectal cancer with low-level microsatellite instability

A high degree of microsatellite instability (MSI) in colorectal cancer (CRC) is a hallmark of hereditary non-polyposis colorectal cancer (HNPCC), caused by germline defects in the mismatch repair (MMR) genes. A low degree of instability (less than 30% of the microsatellites) is seen in a subset of tumors. To clarify the significance of this low degree of MSI phenotype, we studied the differences between patients with colorectal tumors with high-level, low-level and no MSI. Colorectal tumors with no (n = 68) and low-level (n = 18) MSI of patients clinically suspected of HNPCC were compared to colorectal tumors with high-level MSI (n = 12) of patients that carry a pathogenic germline mutation in a MMR gene. Compared to tumors with no MSI, tumors with low-level MSI were classified more frequently as stage T3 or T4 (100% vs 68% respectively), and showed less immune response (P = 0.02). No significant differences in familial CRC risk were found by comparing pedigrees of these two groups of tumors. Compared to the group of tumors with high-level MSI, the group of tumors with low-level MSI had a less suspicious family history, a higher percentage of lymph node metastasis (56 vs 17%), and less immune response. Thus, with respect to genetic risks, familial CRC can be divided into two groups: Tumors with high-level MSI and tumors with low-level or no MSI. However, tumors with low-level MSI show unfavorable pathological characteristics compared to tumors with no and tumors with high-level MSI. These differences suggest a distinct underlying biology of CRC with low-level MSI.