PO-005 Prevention strategies for intestinal cancer development in lynch syndrome

Abstract

IntroductionLynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome which is mostly caused by defects in DNA mismatch repair (MMR) genes MLH1 and MSH2. LS patients have an increased lifetime risk of developing a range of neoplasms including a non-polyposis form of colorectal cancer (HNPCC) which typically manifests at a young age. In this project, we focus on distinct factors that may influence the pathogenesis of CRC in LS.Material and methodsThe mouse models that have been used in the past to study LS do not correspond well to the human pathology. Therefore, our research group has recently developed an inducible mouse model that closely mimics the clinical situation in MSH2-deficient LS patients.Wojciechowicz et al., 2014 After administration of tamoxifen, Lgr5-CreERT2;Msh2flox/- (Msh2-Lynch) mice have been shown to carry about 5% MSH2-deficient intestinal crypts that remained present over time. Since the cells of these crypts lack functional MMR, they have a high mutational burden and may develop into intestinal tumours.Results and discussionsExposure of Msh2-Lynch mice to the methylating agent temozolomide (TMZ) led to expansion of the MSH2-deficient cell compartment and accelerated tumour development.Wojciechowicz et al., 2014 All intestinal tumours were shown to be MSH2 deficient and especially the tumours from TMZ treated mice showed a high mutational burden. Strikingly, a change in the housing conditions (conventional housing to SPF) almost fully ablated intestinal tumour development in our mouse model. We hypothesise that a change in the microbiome underlies this phenotype. Therefore, we are currently dissecting the role of the microbiome, the immune system and inflammation in intestinal tumour development in Msh2-Lynch mice.ConclusionThe strong effect of housing conditions on tumour development in Msh2-Lynch mice may help us to divulge distinct factors that modulate cancer risk in LS. The results of this study may ultimately contribute to a reduction of tumour incidence among LS patients and improve treatment options.