Project Details
Projekt
The clinical impact of microsatellite instability in colorectal cancer
Applicant
Privatdozent Dr. Matthias Kloor
Subject Area
General and Visceral Surgery
Term
from 2009 to 2015
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 101804013
The present project aims to investigate the clinical impact of mismatch repair deficiency and microsatellite instability on colorectal cancer. Mismatch repair deficiency causes mutations of repetitive microsatellite sequences in about 15% of colorectal cancers. Mismatch repair deficiency-induced mutations can inactivate genes that carry microsatellites in their coding regions. The distribution of coding microsatellites in the genome hence contributes significantly to the phenotype of mismatch repair-deficient cells. The present project has been initiated on the basis of a systematic database of coding microsatellites in the genome and led to the identification of key mechanisms of microsatellite instability-associated tumorigenesis: (1) Mismatch repair deficiency leads to the generation of frameshift-derived neo-antigens that may activate effector, but only rarely suppressor T cells. (2) Mismatch repair deficiency-induced mutations of the Beta2-microglobulin gene are the major mechanism of immune evasion in microsatellite-unstable cancer, contributing to a low frequency of distant metastasis typical of this tumor type and representing a favorable prognostic marker. Functional studies have been performed and established the basis for further examination of the underlying mechanisms in vitro and in vivo. (3) Pathogenesis of mismatch repair deficiency-induced cancers follows a process of continuous clonal selection, starting in very early stages of mismatch repair deficiency to late stages of invasive cancer and lymph node metastases. Within the project, novel potential precursor lesions, mismatch repair-deficient crypt foci, have been identified, and key steps of tumor progression have been defined, which shall be further explored by using novel exome sequencing technologies. As a first step into this direction, extensive regional mutation analyses have been performed and led to the identification of potential candidate genes relevant for cancer progression and metastasis formation.
DFG Programme
Clinical Research Units
Participating Person
Professor Dr. Magnus von Knebel Doeberitz
