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Open AccessArticle

Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

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Institute for Biostatistics and Informatics in Medicine and Ageing Research (IBIMA), Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany
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Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
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Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany
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Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1485; https://doi.org/10.3390/cancers11101485
Received: 6 August 2019 / Revised: 18 September 2019 / Accepted: 26 September 2019 / Published: 2 October 2019
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. View Full-Text
Keywords: tumor mutational burden; exclusive/shared mutations; predicted tumor antigens tumor mutational burden; exclusive/shared mutations; predicted tumor antigens
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Gladbach, Y.S.; Wiegele, L.; Hamed, M.; Merkenschläger, A.-M.; Fuellen, G.; Junghanss, C.; Maletzki, C. Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice. Cancers 2019, 11, 1485.

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