Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, however, the mechanisms underlying tumorigenesis in different MB subgroups remain incompletely understood. Although previous studies of MB predisposition have been conducted in tertiary referral centers primarily in Caucasian cohorts, it is not unclear clear whether there exist population-specific genetic alterations in MBs. In this study, we investigated the contribution of genomic and transcriptomic alterations to the risk of malignant MB in the Chinese population (designated as the Asian cohort). We analyze the genomic and transcriptomic alterations of the Asian MB cohort by using a combination of whole-exome sequencing (WES) and RNA-deep-sequencing. In addition, we integrate publicly available data with the Asian MB cohort and identify a subset of potential MB-driving genes specifically enriched in each of the MB subgroups. We further characterize a newly identified group-3-enriched transcriptional regulator, ZNF124, and demonstrate that ZNF124 is critical for the growth of the most aggressive group-3 MB cells. Together, our analyses indicate conserved yet distinct genetic alterations and gene expression patterns of MBs between different ethnic groups. Our studies further provide an important resource for identifying potential tumor-driving factors in MBs, enhancing our understanding of the disease process for developing ethnically targeted therapies in patients with MB.

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

“…The fusion we report in this work has not been described in other works analyzing the transcriptional landscape of medulloblastoma so far [ 14 , 16 ]. The landscape of gene fusions in medulloblastoma is very heterogeneous with a low recurrence of the same fusion in different patients.…”

“…Although immunotherapeutic approaches for medulloblastoma patients such as cancer vaccines, natural killer cells and CAR T cells are promising [ 44 ], one of the major limitations in treating medulloblastoma with immunotherapy is the low immunogenicity and mutational load. It is interesting to note that few reported medulloblastoma-specific fusion peptides, such as MLLT6–MRPL45, LCLAT1–ERBB4, ASAP1–WD4HV1 and PTEN–THAP9 [ 2 , 14 , 15 ] have similar immunogenic potential to the EPC2–GULP1 fusion peptide SAEEITLTI. Therefore, future studies are needed to determine whether medulloblastoma patients with EPC2-GULP1 or other fusions have a higher response rate to immunotherapy.…”

“…Recently, Luo et al identified five different gene fusions affecting the WNT MB subgroup. Only two of them ( RAP1A–TMIGD3 and ZSWIM5P2–MEIS3 ) occurred in both the WNT and SHH subtype as well as in group 3 and group 4 medulloblastoma [ 14 ]. Based on these findings, it is worth exploring whether the EPC2–GULP1 fusion might also appear in group 3 and group 4 medulloblastoma.…”

“…Recently, a comparison of Asian and Caucasian medulloblastoma cohorts by Luo et al revealed 31 novel gene fusions among all medulloblastoma subgroups [ 14 ], including recurrent gene fusions such as RAP1A–TMIGD3 with identical breaking points in two WNT MBs and one group 3 MB, PVT1–CASC8 with different breaking points in two group 3 MBs and one group 4 MB, and three more gene fusions in at least two medulloblastoma patients affecting only the Asian cohort [ 14 ]. Furthermore, they confirmed already reported gene fusions involving GLI2 , DDX3X , SUFU in SHH, PVT1 , PTEN in group 3, and TP53 in Group 4 [ 2 , 14 ]. Additionally, Jones and colleagues detected a novel fusion transcript of DNAJB6 and SHH in one sample of SHH subgroup, and two further in-frame fusion transcripts in group 3 and group 4 medulloblastomas [ 15 ].…”

Loss of nuclear envelope phosphatase CTDNEP1 drives aggressive medulloblastoma by triggering MYC amplification and genomic instability

“…The regulatory mechanisms that control MYC activity and amplification for tumorigenesis in highly aggressive MYCdriven MB have remained incompletely understood. By integrating the transcriptomic and genomic profiles from our newly diagnosed and publicly available MB cohorts 5,6,25,33 , we found that CTDNEP1 mutations, which present predominantly in MYC-driven MBs, define a specific subset of aggressive MB tumors. In contrast to many mouse models of MYC-driven G3 MB, which require MYC overexpression and additional loss of p53 function 22,23 , here we demonstrate that ablation of a single gene, Ctdnep1, is sufficient to trigger MYC amplification and genomic instability, and promote malignant transformation of cerebellar NPCs into MYC-driven MB tumors.…”