Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylationbased classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histological features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. (Word count: 131) SignificanceZFTA-RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histological characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion-positive tumors, such as GLI2. (Word count: 48)Research.

Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (Bcor ΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCOR ΔE9-10 ). While Bcor ΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, Bcor ΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1 +/− ;Bcor ΔE9-10 tumors, the growth factor gene Igf2 was aberrantly upregulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1 +/− GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1 +/− ;Bcor ΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

SummaryA retrospective cohort study was performed to investigate the effectiveness of preemptive postsurgical therapy with cetuximab for patients with a major risk of recurrence or metastasis after clinical complete resection of primary oral squamous cell carcinoma (OSCC). The study period was from 2007 to 2019 for patients treated at the Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine. OSCC patients with major risk (n = 88) in the follow-up period were divided into groups with no postsurgical treatment (NP group), with standard postsurgical treatment (SP group), and with postsurgical treatment including cetuximab (CP group), and prognosis were compared among those groups. The 5-year overall survival rate was significantly higher in patients who received postsurgical treatment with cetuximab (CP) compared to that in the other two groups ((CP vs. NP, p = 0.028; CP vs. SP, p = 0.042). Furthermore, we performed multivariate analysis to evaluate the effects of the main components of the treatment. Among CDDP, radiotherapy, and cetuximab, only cetuximab significantly contributed to improved survival by univariate analysis (crude HR:0.228, 95%CI:0.05–0.968, p = 0.045). cetuximab also showed the same tendency in multivariate analysis, although p value did not reach significant level (Adjusted HR: 0.233, 95%CI: 0.053–1.028, p = 0.054). The results suggest that the postsurgical treatment with cetuximab as a preemptive postsurgical therapy after complete surgical resection of a visible tumor is considerably effective for OSCC patients with major risk, in other words, invisible dormant metastasis.

The sonic hedgehog (SHH) pathway regulates the development of the central nervous system in vertebrates. Aberrant regulation of SHH signaling pathways often causes neurodevelopmental diseases and brain tumors. In the cerebellum, SHH secreted by Purkinje cells is a potent mitogen for granule cell progenitors, which are the most abundant cell type in the mature brain. While a reduction in SHH signaling induces cerebellar structural abnormalities, such as hypoplasia in various genetic disorders, the constitutive activation of SHH signaling often induces medulloblastoma (MB), one of the most common pediatric malignant brain tumors. Based on the existing literature on canonical and non-canonical SHH signaling pathways, emerging basic and clinical studies are exploring novel therapeutic approaches for MB by targeting SHH signaling at distinct molecular levels. In this review, we discuss the present consensus on SHH signaling mechanisms, their roles in cerebellar development and tumorigenesis, and the recent advances in clinical trials for MB.