Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario

Development of specially shaped laser beams for the optimized acceleration of particles

The laser-driven acceleration of protons from thin foils irradiated by hollow high-intensity laser beams in the regime of target normal sheath acceleration is reported for the first time. The use of hollow beams aims at reducing the initial emission solid angle of the TNSA source, due to a flattening of the electron sheath at the target rear side. The experiments were conducted at the PHELIX laser facility at the GSI Helmholtzzentrum für Schwerionenforschung GmbH with laser intensities in the range from 10^18 to 10^20 W/cm^2. We observed an average reduction of the half opening angle by (3.07±0.42)° or (13.2±2)% when the targets have a thickness between 12 to 14 μm. In addition, the highest proton energies were achieved with the hollow laser beam in comparison to the typical Gaussian focal spot

WOMBAT: A modular software for wavefront sensing and optimization at PHELIX

Many experiments at large-scale laser systems require the highest on-target intensities. This is achieved only for beams with minimal aberration, which becomes more and more difficult to realize for large-aperture laser systems where the beam dimension nowadays exceeds 10 cm. Therefore, wavefront sensing and correction is crucial to suit the needs of current applications [1]. Commercial solutions in software and hardware have been available for the last two decades. However, these solutions often are specialized for a certain setup that might not fit the particular needs of the facility. Adaptions of existing systems are possible, but rather cost-intensive and do often require third-party-maintenance over the lifetime of the system.Therefore, a more flexible software for wavefront sensing and correction is currently being developed at the PHELIX facility at GSI, Darmstadt. The “Wavefront Optics Measurement and Beam Analysis Tool” (WOMBAT) is a modular LabVIEW-software that offers great flexibility while working with custom and commercial hardware. The software contains a camera-module that acquires images from arbitrary camera model, including commercial Shack-Hartmann sensors (SHS). Further modules are available to perform and analysis of its data, wavefront reconstruction as well as a modal analysis in terms of the Zernike-polynomials. The measurement quality is comparable to commercial solutions and even supersedes them in some fields. Wavefront correction can be conducted with different adaptive optics systems, including motorized mirrors, movable lenses and deformable mirrors. For this purpose, modules for response recording and wavefront control are implemented, using a driver interface that can easily be adapted for new hardware.The performance of the current state of WOMBAT has been quantitatively verified and proven in various experiments, compensating static aberrations and enabling manual optimization of the focus. Further functionality is being investigated, including continuous recording and compensation of on-shot-aberrations and an algorithm to retrieve the wavefront from far-field-images