Characterization of the genetic alterations in RTEL1 deficient mouse medulloblastoma model
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Date
2019-08-28
Authors
Hizon, Nikho
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Abstract
Regulator of Telomere Length-1 (RTEL1) is a novel DNA-helicase found to be expressed in cerebellar stem cells. Conditional knockout of RTEL1 in these stem cells could induce medulloblastoma (MB) formation. MB is a common, highly heterogenetic, pediatric brain tumour originating in the cerebellum. Omics-studies have divided MB into four molecular subgroups which differ in genomics and prognostics: WNT, SHH, Group 3, and Group 4.
RTEL1-deficient mice developing MB could be used as a model to better understand the pathogenesis of MB, identify potential therapeutic targets, and for preclinical studies. Since MB subgroups vary in prognostics, it is crucial to determine the MB subgroup which RTEL1-deficent mice MB best recapitulates. Here bioinformatics approaches are applied on omics-based data to accurately subgroup RTEL1-deficient mouse MB and identify recurrent genetic alterations.
To determine subgroup affiliation of our mouse model, machine learning algorithms, such as t-SNE and SVM, were used to compare the transcriptomes of RTEL1-deficient mouse MB and human MB subgroups. These analyses reveal that RTEL1-deficient mouse MB may closely resemble human SHH MB. This is further supported by analysis of array comparative genomic hybridization (aCGH) which characterizes RTEL1-deficient mouse MBs as having highly unstable genomes, with massive genetic alterations including rearrangements, amplifications, and deletions. All of which are traits commonly found in human SHH MB.
To search for putative driver mutations in RTEL1-deficient mouse MB model, recurrent genetic alterations are identified from aCGH, whole exome and RNA sequencing. MycN, an oncogene that is associated with SHH MBs, was amplified and upregulated in 65% and 100% of RTEL1-deficient mice, respectively, indicating a possible driving role for MycN.
To better understand how RTEL1-deficiency can lead to these alterations, copy number profiles of RTEL1-deficient mouse MBs were investigated. 13/21 tumours presented with a chromothripsis-like pattern, here described as a clustering of breakpoints in one chromosome with an oscillating copy number state of no more than three states. Chromothripsis is a catastrophic event that can induce massive genomic rearrangement. This finding indicates chromothripsis could be the main mechanism resulting in genomic instability and MycN amplification in RTEL1-deficient mouse MB model.
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Keywords
Medulloblastoma, chromothripsis, bioinformatics, Telomere maintenance, RTEL1