Oncotarget

Priority Research Papers:

Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors

Lei Wei, Brian L. Murphy, Gang Wu, Matthew Parker, John Easton, Richard J. Gilbertson, Jinghui Zhang, _ Martine F. Roussel

Metrics: PDF 135 views  |   HTML 150 views  |   ?  


Abstract

Lei Wei1,5,*, Brian L. Murphy2,6,*, Gang Wu1,*, Matthew Parker1,7, John Easton3, Richard J. Gilbertson4, Jinghui Zhang1 and Martine F. Roussel2

1 Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

2 Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

3 Pediatric Cancer Genome Project, St. Jude Children’s Research Hospital, Memphis, TN, USA

4 Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

5 Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA

6 Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA

7 Genomics England, Queen Mary University of London, London, UK

* Co-first authors

Correspondence to:

Jinghui Zhang, email:

Martine F. Roussel, email:

Keywords: medulloblastoma, whole-exome sequencing, WDR11, somatic mutations, mouse models

Received: May 17, 2017 Accepted: July 09, 2017 Published: July 27, 2017

Abstract

Mouse models of human cancers are widely used in cancer research, yet questions frequently arise regarding their faithfulness in recapitulating their human counterparts. To compare the somatic mutations of murine models with human medulloblastoma (MB), we performed whole-exome sequencing on 12 tumors representing three distinct medulloblastoma subgroups: Wnt, Sonic Hedgehog (Shh) and Group 3 (G3). In total, 64 somatic mutations were identified and validated, including 40 predicted to cause amino acid changes. After filtering and cross-species analysis with 366 human MBs from four independent studies, human orthologs for 16 of the 40 mouse genes were found to harbor non-silent mutations in human MB. Loss-of-function Kmt2d mutations detected in one mouse tumor was previously reported in 30 of 366 human MBs. In mice bearing G3 MB, one mouse succumbed to tumor burden at least 15 days earlier than other mice, raising the possibility that somatic mutations may have accelerated the tumorigenesis process. In this mouse tumor, four novel candidate genes harbored non-silent somatic mutations, Lrfn2, Smyd1, Ubn2 and Wdr11. Extended survival was found in mice harboring mouse G3 overexpressing WDR11 but not the other three genes. Genes in the KEGG WNT signaling pathway, including Ccnd1/2/3, Myc and Tcf7l1, were down-regulated in the transcriptome of G3 MB tumorspheres overexpressing WDR11, consistent with reduced tumor progression. In conclusion, we demonstrated that common spontaneous mutations were shared between human and murine models of MB suggesting similar molecular mechanisms of tumorigenesis, and identified WDR11 as a protein with tumor suppressive activity in G3 MB.

Author Information

Lei Wei

Brian L. Murphy

Gang Wu

Matthew Parker

John Easton

Richard J. Gilbertson

Jinghui Zhang
Primary Contact  _

Martine F. Roussel


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 19642