The mutational landscape of MYCN, Lin28b and ALKF1174L driven murine neuroblastoma mimics human disease
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Bram De Wilde1,2 , Anneleen Beckers1, Sven Lindner3, Althoff Kristina3, Katleen De Preter1,2, Pauline Depuydt1,2, Pieter Mestdagh1,2, Tom Sante1, Steve Lefever1,2, Falk Hertwig4,5, Zhiyu Peng6, Le-Ming Shi7, Sangkyun Lee8, Elien Vandermarliere9,10, Lennart Martens9,10, Björn Menten1, Alexander Schramm3, Matthias Fischer4,5, Johannes Schulte11, Jo Vandesompele1,2 and Frank Speleman1,2
1Center for Medical Genetics, Ghent University, Ghent, Belgium
2Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
3Department of Pediatric Oncology and Hematology, University Children’s Hospital, Essen, Germany
4Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany
5Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
6BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, China
7Center for Pharmacogenomics and Fudan-Zhangjiang Center for Clinical Genomics, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
8Department of Computer Science, Artificial Intelligence Group, TU Dortmund, Dortmund, Germany
9Medical Biotechnology Center, VIB, Ghent, Belgium
10Department of Biochemistry, Ghent University, Ghent, Belgium
11Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany
Frank Speleman, email: Franki.Speleman@UGent.be
Keywords: neuroblastoma; mouse model; exome sequencing; array CGH
Received: March 01, 2017 Accepted: October 28, 2017 Published: December 22, 2017
Genetically engineered mouse models have proven to be essential tools for unraveling fundamental aspects of cancer biology and for testing novel therapeutic strategies. To optimally serve these goals, it is essential that the mouse model faithfully recapitulates the human disease. Recently, novel mouse models for neuroblastoma have been developed. Here, we report on the further genomic characterization through exome sequencing and DNA copy number analysis of four of the currently available murine neuroblastoma model systems (ALK, Th-MYCN, Dbh-MYCN and Lin28b). The murine tumors revealed a low number of genomic alterations – in keeping with human neuroblastoma - and a positive correlation of the number of genetic lesions with the time to onset of tumor formation was observed. Gene copy number alterations are the hallmark of both murine and human disease and frequently affect syntenic genomic regions. Despite low mutational load, the genes mutated in murine disease were found to be enriched for genes mutated in human disease. Taken together, our study further supports the validity of the tested mouse models for mechanistic and preclinical studies of human neuroblastoma.
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