Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study

\ua9 The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.Background.MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients’ MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management. Methods. We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases. Results. Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a “canonical” very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS).MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline.MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS. Conclusions.MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR “canonical” MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB

Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples

The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials

Two c's in a pod: Cosmology independent measurement of the Type Ia supernova colour-luminosity relation with a sibling pair

Using Zwicky Transient Facility (ZTF) observations, we identify a pair of "sibling" Type Ia supernovae (SNe Ia), i.e., hosted by the same galaxy at z = 0.0541. They exploded within 200 days from each other at a separation of $0.6^{"}$ corresponding to a projected distance of only 0.6 kpc. Performing SALT2 light curve fits to the gri ZTF photometry, we show that for these equally distant "standardizable candles", there is a difference of 2 magnitudes in their rest frame B-band peaks, and the fainter SN has a significantly red SALT2 colour $c = 0.57 \pm$ 0.04, while the stretch values $x_1$ of the two SNe are similar, suggesting that the fainter SN is attenuated by dust in the interstellar medium of the host galaxy. We use these measurements to infer the SALT2 colour standardization parameter, $\beta$ = 3.5 $\pm$ 0.3, independent of the underlying cosmology and Malmquist bias. Assuming the colour excess is entirely due to dust, the result differs by $2\sigma$ from the average Milky-Way total-to-selective extinction ratio, but is in good agreement with the colour-brightness corrections empirically derived from the most recent SN Ia Hubble-Lemaitre diagram fits. Thus we suggest that SN "siblings", which will increasingly be discovered in the coming years, can be used to probe the validity of the colour and lightcurve shape corrections using in SN Ia cosmology while avoiding important systematic effects in their inference from global multi-parameter fits to inhomogeneous data-sets, and also help constrain the role of interstellar dust in SN Ia cosmology

Is supernova SN 2020faa an iPTF14hls look-alike?

Context. We present observations of ZTF20aatqesi (SN 2020faa). This Type II supernova (SN) displays a luminous light curve (LC) that started to rebrighten from an initial decline. We investigate this in relation to the famous SN iPTF14hls, which received a great deal of attention and multiple interpretations in the literature, but whose nature and source of energy still remain unknown. Aims. We demonstrate the great similarity between SN 2020faa and iPTF14hls during the first 6 months, and use this comparison to forecast the evolution of SN 2020faa and to reflect on the less well observed early evolution of iPTF14hls. Methods. We present and analyse our observational data, consisting mainly of optical LCs from the Zwicky Transient Facility in the gri bands and of a sequence of optical spectra. We construct colour curves and a bolometric lc, and we compare ejecta-velocity and black-body radius evolutions for the two supernovae (SNe) and for more typical Type II SNe. Results. The LCs show a great similarity with those of iPTF14hls over the first 6 months in luminosity, timescale, and colour. In addition, the spectral evolution of SN 2020faa is that of a Type II SN, although it probes earlier epochs than those available for iPTF14hls. Conclusions. The similar LC behaviour is suggestive of SN 2020faa being a new iPTF14hls. We present these observations now to advocate follow-up observations, since most of the more striking evolution of SN iPTF14hls came later, with LC undulations and a spectacular longevity. On the other hand, for SN 2020faa we have better constraints on the explosion epoch than we had for iPTF14hls, and we have been able to spectroscopically monitor it from earlier phases than was done for the more famous sibling

First results from GeMS/GSAOI for project SUNBIRD: Supernovae UNmasked By Infra-Red Detection

Core collapse supernova (CCSN) rates suffer from large uncertainties as many CCSNe exploding in regions of bright background emission and significant dust extinction remain unobserved. Such a shortfall is particularly prominent in luminous infrared galaxies (LIRGs), which have high star formation (and thus CCSN) rates and host bright and crowded nuclear regions, where large extinctions and reduced search detection efficiency likely lead to a significant fraction of CCSNe remaining undiscovered. We present the first results of project SUNBIRD (Supernovae UNmasked By Infra-Red Detection), where we aim to uncover CCSNe that otherwise would remain hidden in the complex nuclear regions of LIRGs, and in this way improve the constraints on the fraction that is missed by optical seeing-limited surveys. We observe in the near-infrared 2.15 mu m Ks-band, which is less affected by dust extinction compared to the optical, using the multiconjugate adaptive optics imager GeMS/GSAOI on Gemini South, allowing us to achieve a spatial resolution that lets us probe close in to the nuclear regions. During our pilot program and subsequent first full year we have discovered three CCSNe and one candidate with projected nuclear offsets as small as 200 pc. When compared to the total sample of LIRG CCSNe discovered in the near-IR and optical, we show that our method is singularly effective in uncovering CCSNe in nuclear regions and we conclude that the majority of CCSNe exploding in LIRGs are not detected as a result of dust obscuration and poor spatial resolution

Molecular subgroups of medulloblastoma: the current consensus

Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups

Real-time discovery of AT2020xnd: a fast, luminous ultraviolet transient with minimal radioactive ejecta

The many unusual properties of the enigmatic AT2018cow suggested that at least some subset of the empirical class of fast blue optical transients (FBOTs) represents a genuinely new astrophysical phenomenon. Unfortunately, the intrinsic rarity and fleeting nature of these events have made it difficult to identify additional examples early enough to acquire the observations necessary to constrain theoretical models. We present here the Zwicky Transient Facility discovery of AT2020xnd (ZTF20acigmel, the 'Camel') at z = 0.243, the first unambiguous AT2018cow analogue to be found and confirmed in real time. AT2018cow and AT2020xnd share all key observational properties: a fast optical rise, sustained high photospheric temperature, absence of a second peak attributable to ejection of a radioactively heated stellar envelope, extremely luminous radio, millimetre, and X-ray emission, and a dwarf-galaxy host. This supports the argument that AT2018cow-like events represent a distinct phenomenon from slower-evolving radio-quiet supernovae, likely requiring a different progenitor or a different central engine. The sample properties of the four known members of this class to date disfavour tidal disruption models but are consistent with the alternative model of an accretion powered jet following the direct collapse of a massive star to a black hole. Contextual filtering of alert streams combined with rapid photometric verification using multiband imaging provides an efficient way to identify future members of this class, even at high redshift

Real-time Discovery of AT2020xnd: A Fast, Luminous Ultraviolet Transient with Minimal Radioactive Ejecta

The many unusual properties of the enigmatic AT2018cow suggested that at least some subset of the empirical class of fast blue optical transients (FBOTs) represents a genuinely new astrophysical phenomenon. Unfortunately, the intrinsic rarity and fleeting nature of these events have made it difficult to identify additional examples early enough to acquire the observations necessary to constrain theoretical models. We present here the Zwicky Transient Facility discovery of AT2020xnd (ZTF20acigmel, the "Camel") at z=0.243, the first unambiguous AT2018cow analog to be found and confirmed in real time. AT2018cow and AT2020xnd share all key observational properties: a fast optical rise, sustained high photospheric temperature, absence of a second peak attributable to ejection of a radioactively-heated stellar envelope, extremely luminous radio, millimetre, and X-ray emission, and a dwarf-galaxy host. This supports the argument that AT2018cow-like events represent a distinct phenomenon from slower-evolving radio-quiet supernovae, likely requiring a different progenitor or a different central engine. The sample properties of the four known members of this class to date disfavour tidal disruption models but are consistent with the alternative model of an accretion powered jet following the direct collapse of a massive star to a black hole. Contextual filtering of alert streams combined with rapid photometric verification using multi-band imaging provides an efficient way to identify future members of this class, even at high redshift