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

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.