Scientific background
Lynch syndrome is inherited via a pathogenic germline variant in one of the Mismatch Repair (MMR) genes. Therefore, MMR deficiency as a mutational process strongly shapes the molecular phenotype and immunological characteristics of tumors developing in frame of Lynch syndrome. However, tumor development, particularly in the scenario of MMR deficiency, is a result of a complex interplay between cancer precursors and the host’s immune system. We study both, tumor and host factors influencing tumorigenesis in order to identify markers capable of predicting the outcome of this interplay and generate a new “molecular” level of cancer risk assessment for Lynch syndrome carriers.
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.
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