The mutational landscape of MYCN, Lin28b and ALKF1174L driven murine neuroblastoma mimics human disease.

Bram De Wilde,Katleen De Preter,Elien Vandermarliere,Falk Hertwig,Sven Lindner,Anneleen Beckers,Frank Speleman,Tom Sante,Pieter Mestdagh,Pauline Depuydt,Jo Vandesompele,Althoff Kristina,Sangkyun Lee,Alexander Schramm,Zhiyu Peng,Björn Menten,Lennart Martens,Steve Lefever,Matthias Fischer,Leming Shi ,Johannes H Schulte

doi:10.18632/oncotarget.23614

Abstract

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.

Highlights

Mouse models are essential tools in the study of the molecular pathogenesis of cancer
We report on the further genomic characterization through exome sequencing and deoxyribonucleic acid (DNA) copy number analysis of four of the currently available murine neuroblastoma model systems (ALK, tyrosine hydroxylase (Th)-MYCN, DbhMYCN and Lin28b)
One outlier case was observed with 24 mutations, 21 of which were located in a 45 Mb stretch on chromosome 7, a region heavily affected by copy number changes in this tumor suggesting chromothripsis

Summary

Introduction

Mouse models are essential tools in the study of the molecular pathogenesis of cancer. TH-MYCN mice express the human MYCN gene under the control of the rat tyrosine hydroxylase (Th) promotor [2], which results in neuroblastic tumors in about 50% of transgenic animals. This model delivered many valuable insights into neuroblastomagenesis [3]. A novel MYCN Cre-inducible transgenic mouse model was established, driving MYCN expression from the Dbh promotor integrated into the murine ROSA26 locus (LSL-MYCN;Dbh-iCre) [4]. This model has a relatively high penetrance of tumor formation (> 75%). Two novel bona fide neuroblastoma oncogenes have been identified, ALK and LIN28B, that are sufficient to drive tumor formation when overexpressed in the neural crest or seem to increase the oncogenic potential of MYCN overexpression [5,6,7,8]

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Results

Conclusion