Microsatellite-unstable cancers

Microsatellite instability is caused by dysfunction of the cellular DNA mismatch repair (MMR)-system, which detects and repairs DNA base mismatches during DNA replication. Deficiency of the MMR system can occur sporadically, or in the context of Lynch syndrome, in both cases leading to accumulation of insertion and deletion mutations at repetitive sequence stretches, called microsatellites.

The resulting genomic instability is characterized by altered length of these microsatellites and generation of frameshift proteins. Due to the unique mechanism of their generation, these proteins contain many highly immunogenic epitopes (amino acid stretches fitting into the pockets of antigen presenting molecules, HLA molecules) that can be recognized by the immune system. Therefore, MSI tumors are characterized by a pronounced immune response and favorable clinical outcome.  However, each person has a very individual set-up of HLA molecules. During tumor evolution tumors get to know the immune system of the host, including the HLA molecules and acquire tactics to avoid the immune attack. As our most recent research shows, this process is largely determined by the type of HLA molecules that a person possesses, his personal HLA type.