Summary Medulloblastoma, the most common malignant pediatric brain tumour, is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson’s disease gene SNCAIP, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGFβ signaling in Group 3, and NF-κB signaling in Group 4 suggest future avenues for rational, targeted therapy.

Ewing sarcoma is a primary bone tumor initiated by EWSR1–ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2 immuno-negative cells in relapsed tumors as compared with matched diagnostic samples.

The identification of subtype-specific translocations has revolutionized the diagnostics of sarcoma and has provided new insight into oncogenesis. We used RNA-seq to investigate samples from individuals diagnosed with small round cell tumors of bone, possibly Ewing sarcoma, but which lacked the canonical EWSR1-ETS translocation. A new fusion was observed between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR-CCNB3 or of truncated CCNB3 activates S phase in NIH3T3 cells. Thus, the intrachromosomal X-chromosome fusion described here represents a new subtype of bone sarcoma caused by a newly identified gene fusion mechanism.

We show here that CO2 partial pressure (pCO2) and temperature significantly interact on coral physiology. The effects of increased pCO2 and temperature on photosynthesis, respiration and calcification rates were investigated in the scleractinian coral Stylophora pistillata. Cuttings were exposed to temperatures of 25°C or 28°C and to pCO2 values of ca. 460 or 760 μatm for 5 weeks. The contents of chlorophyll c2 and protein remained constant throughout the experiment, while the chlorophyll a content was significantly affected by temperature, and was higher under the ‘high‐temperature–high‐pCO2’ condition. The cell‐specific density was higher at ‘high pCO2’ than at ‘normal pCO2’ (1.7 vs. 1.4). The net photosynthesis normalized per unit protein was affected by both temperature and pCO2, whereas respiration was not affected by the treatments. Calcification decreased by 50% when temperature and pCO2 were both elevated. Calcification under normal temperature did not change in response to an increased pCO2. This is not in agreement with numerous published papers that describe a negative relationship between marine calcification and CO2. The confounding effect of temperature has the potential to explain a large portion of the variability of the relationship between calcification and pCO2 reported in the literature, and warrants a re‐evaluation of the projected decrease of marine calcification by the year 2100.

Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Cladocora caespitosa seawater pH pCO 2 Mediterranean ocean acidificationBoron isotopic and elemental systematics are used to define the vital effects for the temperate shallow water Mediterranean coral Cladocora caespitosa. The corals are from a range of seawater pH conditions (pH T~7 .6 tõ 8.1) and environmental settings: (1) naturally living colonies harvested from normal pH waters offshore Levanto, (2) colonies transplanted nearby a subsea volcanic vent system, and (3) corals cultured in aquaria exposed to high (700 μatm) and near present day (400 μatm) pCO 2 levels. B/Ca compositions measured using laser ablation inductively coupled mass spectrometry (LA-ICPMS) show that boron uptake by C. caespitosa cultured at different pCO 2 levels is independent of ambient seawater pH being mainly controlled by temperature-dependent calcification. In contrast, the boron isotope compositions (δ 11 B carb ) of the full suite of corals determined by positive thermal ionisation mass spectrometry (PTIMS) shows a clear trend of decreasing δ 11 B carb (from 26.7 to 22.2‰) with decreasing seawater pH, reflecting the strong pH dependence of the boron isotope system. The δ 11 B carb compositions together with measurements of ambient seawater parameters enable calibration of the boron pH proxy for C. caespitosa, by using a new approach that defines the relationship between ambient seawater pH (pH sw ) and the internally controlled pH at the site of calcification (pH biol ). C. caespitosa exhibits a linear relationship between pH sw and the shift in pH due to physiological processes (ΔpH = pH biol − pH sw ) giving the regression ΔpH Clad = 4.80 − 0.52 × pH sw for this species. We further apply this method ("ΔpH-pH sw ") to calibrate tropical species of Porites, Acropora, and Stylophora reported in the literature. The temperate and tropical species calibrations are all linearly correlated (r 2 N 0.9) and the biological fractionation component (ΔpH) between species varies within~0.2 pH units. Our "ΔpH-pH sw " approach provides a robust and accurate tool to reconstruct palaeoseawater pH sw for both temperate and tropical corals, further validating the boron fractionation factor (α B3-B4 = 1.0272) determined experimentally by Klochko et al. (2006) and the boron isotope pH proxy, both of which have been the foci of considerable debate.