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.
Lynch syndrome is the most common inherited cancer syndrome affecting 1:280 individuals. Lynch syndrome carriers have 30-80% lifetime risk of developing malignancies, most commonly affecting patients’ bowel (colorectal cancer, CRC) and in female patients the uterus (endometrial cancer, EC).
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.
Our antigen repertoire determines the recognition of our own cells by the immune system as “self”. As soon as the antigen repertoire of a cell changes, be it due to viral infection or tumor development, the immune system can recognize those novel antigens as “foreign” and eliminate the affected cell.
Human leukocyte antigens (HLA) serve as recognition molecules, which allow our immune system to identify cells as part of the body. Our immune system is educated from childhood to tolerate cells as „self“ that present, like an identity card, the right HLA molecules on their surface. Cells that fail to present the right HLA molecules will be normally attacked by the immune system.
