MLH1 knock out mice represent a preclinical model that resembles features of the human counterpart. As these mice develop mismatch repair deficient (MMR-D) neoplasias in a sequential twin-peaked manner (first lymphomas, then gastrointestinal tumors) we aimed at identification of the underlying molecular mechanisms. Using whole-exome sequencing, we focused on (I) shared and (II) mutually exclusive mutations and described the processes of ongoing mutational events in tumor-derived cultures. A

more »

... rogeneous genetic landscape was found, with few mutations shared among different neoplasias (ARID1A and IDH2). Mutations in tumor suppressor genes SMAD4 and POLE were mutually exclusive in lymphomas, most likely contributing to a more aggressive in vivo phenotype. Comparing the mutational profile of selected primary tumors and their corresponding cell line upon in vitro culture revealed continuous increased numbers of somatic gene mutations. The same was true for coding microsatellite mutations in selected MMR-D target genes, showing a gradual increase during in vitro passage. With respect to this latter type of mutations, partial overlap was detectable, yet recognizing shared vaccination antigens. The two most promising candidates are AKT3, a RAC-gamma serine/threonine-protein kinase with relevance in maintenance of cellular homeostasis and the endonuclease ERCC5 (Excision Repair 5), involved in DNA excision repair. Novel results of a comparison between spontaneously developing lymphomas and gastrointestinal tumors as models for MMR-D driven tumorigenesis are reported. In addition to identification of ARID1A as a potentially causative mutation hotspot, our comprehensive characterization of the mutational signature is a starting point for immune-based approaches to therapy.