Abstract
Mismatch repair deficient (MMR-D) tumors exemplify the prototypic hypermutator phenotype. Owing to the high mutation rates, plenty of neo-antigens are present on the tumor cells’ surface, ideally shared among different cancer types. The MLH1 knock out mouse represents a preclinical model that resembles features of the human MMR-D counterpart. While these mice develop neoplasias in a sequential twin-peaked manner (lymphomas > gastrointestinal tumors (GIT)) we aimed at identification of underlying molecular mechanisms. Using whole-genome sequencing, we focused on (I) shared and (II) mutually exclusive mutations and describe the process of ongoing mutational events in tumor-derived cell cultures. The landscape of MLH1−/− tumors is heterogeneous with only a few shared mutations being detectable among different tumor entities (ARID1A and IDH2). With respect to coding microsatellite analysis of MMR-D-related target genes, partial overlap was detectable, yet recognizing shared antigens. The present study is the first reporting results of a comparison between spontaneously developing tumors in MMR-D driven tumorigenesis. Additionally to identifying ARID1A as potential causative mutation hotspot, this comprehensive characterization of the mutational landscape may be a good starting point to refine therapeutic concepts.
Highlights
Comprehensive genomic sequencing is an increasingly common practice in oncological precision medicine
Gender-specific differences are apparent with female mice developing lymphomas more frequently than gastrointestinal tract (GIT) and vice versa in males (Figure 1A)
We included a set of four tumor samples, mainly covering the spectrum observed in MLH1−/− mice (Table 1)
Summary
Comprehensive genomic sequencing is an increasingly common practice in oncological precision medicine. To detect disease-causing variants (so-called driver mutations) and discover therapeutic target genes, whole-exome sequencing (WES) is a highly meaningful sequencing method [1]. By applying this technique, the coding region of the genome is captured and sequenced at high depth. The hallmarks of the resulting tumors are mismatch-repair deficiency (MMR-D) and an exceedingly high tumor mutational burden (TMB) [4]. The latter is characterized by frameshift mutations and, in consequence, by functionally impaired proteins as well as elevated frequencies of non-synonymous mutations. Immune evasion, such as loss of the MHC class I subunit, beta-2-microglobulin as well as upregulation of immune-checkpoint molecules (PD-1/PD-L1) is quite common and most tumor-infiltrating T cells show signs of exhaustion [5]
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