title: [Pathogenesis of microsatellite-unstable colorectal cancer. Evaluation of new diagnostic and therapeutic options].
abstract: The molecular pathogenesis of colorectal cancer is heterogeneous. Whereas the majority of colorectal cancers follow the classical adenoma-carcinoma sequence and display chromosomal instability, a subset of approximately 15 % of colorectal cancers show a deficiency of the DNA mismatch repair system. These carcinomas present with numerous mutations at repetitive DNA stretches, a phenotype termed high-level microsatellite instability (MSI-H). The pathogenesis of MSI-H cancers is driven by mismatch repair deficiency-induced insertion/deletion mutations affecting microsatellites located in the coding region of tumor suppressor genes, such as TGFBR2. The MSI-induced mutations of tumor suppressor genes not only lead to functional inactivation but also to shifts of the translational reading frame and consequently to the generation of frameshift peptides (FSPs). These FSPs can be recognized as foreign by the host immune system. It could be shown that in the majority of MSI-H colorectal cancer patients, FSP-specific T cell-mediated immune responses can be detected. These tumor antigen-specific immune responses are regarded as a major reason for the dense local lymphocyte infiltration which is typical of MSI-H colorectal cancer. A further characteristic feature of MSI-H cancers is the occurrence of alterations affecting the cellular antigen presentation mechanism where beta2-microglobulin (B2M) mutations that directly result from DNA mismatch repair deficiency represent the most common mechanism. It could be demonstrated that B2M mutations are associated with M0 stage and a very favorable prognosis. The characterization of the particular immunological properties of MSI-H tumors have paved the way for the initiation of a clinical trial in which FSP vaccination is currently being clinically evaluated in patients with MSI-H colorectal cancer.
authors.affiliation: Abteilung für Angewandte Tumorbiologie, Institut für Pathologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Deutschland, matthias.kloor@med.uni-heidelberg.de.
authors.forename: M
authors.initials: M
authors.lastname: Kloor
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D053843:DNA Mismatch Repair; D006801:Humans; D053842:Microsatellite Instability; D009367:Neoplasm Staging; D011379:Prognosis; D012007:Rectum / Q000473:pathology