TY  - JOUR
A1  - Waszak, Sebastian M
A1  - Northcott, Paul A
A1  - Buchhalter, Ivo
A1  - Robinson, Giles W
A1  - Sutter, Christian
A1  - Groebner, Susanne
A1  - Grund, Kerstin B
A1  - Brugières, Laurence
A1  - Jones, David T W
A1  - Pajtler, Kristian W
A1  - Morrissy, A Sorana
A1  - Kool, Marcel
A1  - Sturm, Dominik
A1  - Chavez, Lukas
A1  - Ernst, Aurelie
A1  - Brabetz, Sebastian
A1  - Hain, Michael
A1  - Zichner, Thomas
A1  - Segura-Wang, Maia
A1  - Weischenfeldt, Joachim
A1  - Rausch, Tobias
A1  - Mardin, Balca R
A1  - Zhou, Xin
A1  - Baciu, Cristina
A1  - Lawerenz, Christian
A1  - Chan, Jennifer A
A1  - Varlet, Pascale
A1  - Guerrini-Rousseau, Lea
A1  - Fults, Daniel W
A1  - Grajkowska, Wiesława
A1  - Hauser, Peter
A1  - Jabado, Nada
A1  - Ra, Young-Shin
A1  - Zitterbart, Karel
A1  - Shringarpure, Suyash S
A1  - De La Vega, Francisco M
A1  - Bustamante, Carlos D
A1  - Ng, Ho-Keung
A1  - Perry, Arie
A1  - MacDonald, Tobey J
A1  - Driever, Pablo Hernáiz
A1  - Bendel, Anne E
A1  - Bowers, Daniel C
A1  - McCowage, Geoffrey
A1  - Chintagumpala, Murali M
A1  - Cohn, Richard
A1  - Hassall, Timothy
A1  - Fleischhack, Gudrun
A1  - Eggen, Tone
A1  - Wesenberg, Finn
A1  - Feychting, Maria
A1  - Lannering, Birgitta
A1  - Schüz, Joachim
A1  - Johansen, Christoffer
A1  - Andersen, Tina V
A1  - Röösli, Martin
A1  - Kuehni, Claudia E
A1  - Grotzer, Michael
A1  - Kjaerheim, Kristina
A1  - Monoranu, Camelia M
A1  - Archer, Tenley C
A1  - Duke, Elizabeth
A1  - Pomeroy, Scott L
A1  - Shelagh, Redmond
A1  - Frank, Stephan
A1  - Sumerauer, David
A1  - Scheurlen, Wolfram
A1  - Ryzhova, Marina V
A1  - Milde, Till
A1  - Kratz, Christian P
A1  - Samuel, David
A1  - Zhang, Jinghui
A1  - Solomon, David A
A1  - Marra, Marco
A1  - Eils, Roland
A1  - Bartram, Claus R
A1  - von Hoff, Katja
A1  - Rutkowksi, Stefan
A1  - Ramaswamy, Vijay
A1  - Gilbertson, Richard J
A1  - Korshunov, Andrey
A1  - Taylor, Michael D
A1  - Lichter, Peter
A1  - Malkin, David
A1  - Gajjar, Amar
A1  - Korbel, Jan O
A1  - Pfister, Stefan M
T1  - Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
JF  - The Lancet Oncology
N2  - 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.
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233425
VL  - 19
ER  - 
TY  - JOUR
A1  - Sommerfeld, Andreas
A1  - Senf, Cornelius
A1  - Buma, Brian
A1  - D'Amato, Anthony W.
A1  - Després, Tiphaine
A1  - Díaz-Hormazábal, Ignacio
A1  - Fraver, Shawn
A1  - Frelich, Lee E.
A1  - Gutiérrez, Álvaro G.
A1  - Hart, Sarah J.
A1  - Harvey, Brian J.
A1  - He, Hong S.
A1  - Hlásny, Tomáš
A1  - Holz, Andrés
A1  - Kitzberger, Thomas
A1  - Kulakowski, Dominik
A1  - Lindenmayer, David
A1  - Mori, Akira S.
A1  - Müller, Jörg
A1  - Paritsis, Juan
A1  - Perry, George L. W.
A1  - Stephens, Scott L.
A1  - Svoboda, Miroslav
A1  - Turner, Monica G.
A1  - Veblen, Thomas T.
A1  - Seidl, Rupert
T1  - Patterns and drivers of recent disturbances across the temperate forest biome
JF  - Nature Communications
N2  - Increasing evidence indicates that forest disturbances are changing in response to global change, yet local variability in disturbance remains high. We quantified this considerable variability and analyzed whether recent disturbance episodes around the globe were consistently driven by climate, and if human influence modulates patterns of forest disturbance. We combined remote sensing data on recent (2001–2014) disturbances with in-depth local information for 50 protected landscapes and their surroundings across the temperate biome. Disturbance patterns are highly variable, and shaped by variation in disturbance agents and traits of prevailing tree species. However, high disturbance activity is consistently linked to warmer and drier than average conditions across the globe. Disturbances in protected areas are smaller and more complex in shape compared to their surroundings affected by human land use. This signal disappears in areas with high recent natural disturbance activity, underlining the potential of climate-mediated disturbance to transform forest landscapes.
KW  - forest ecology
KW  - forestry
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239157
VL  - 9
ER  - 
TY  - JOUR
A1  - Westbury, Sarah K
A1  - Turro, Ernest
A1  - Greene, Daniel
A1  - Lentaigne, Claire
A1  - Kelly, Anne M
A1  - Bariana, Tadbir K
A1  - Simeoni, Ilenia
A1  - Pillois, Xavier
A1  - Attwood, Antony
A1  - Austin, Steve
A1  - Jansen, Sjoert BG
A1  - Bakchoul, Tamam
A1  - Crisp-Hihn, Abi
A1  - Erber, Wendy N
A1  - Favier, Rémi
A1  - Foad, Nicola
A1  - Gattens, Michael
A1  - Jolley, Jennifer D
A1  - Liesner, Ri
A1  - Meacham, Stuart
A1  - Millar, Carolyn M
A1  - Nurden, Alan T
A1  - Peerlinck, Kathelijne
A1  - Perry, David J
A1  - Poudel, Pawan
A1  - Schulman, Sol
A1  - Schulze, Harald
A1  - Stephens, Jonathan C
A1  - Furie, Bruce
A1  - Robinson, Peter N
A1  - van Geet, Chris
A1  - Rendon, Augusto
A1  - Gomez, Keith
A1  - Laffan, Michael A
A1  - Lambert, Michele P
A1  - Nurden, Paquita
A1  - Ouwehand, Willem H
A1  - Richardson, Sylvia
A1  - Mumford, Andrew D
A1  - Freson, Kathleen
T1  - Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders
JF  - Genome Medicine
N2  - Background: 
Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases. 
Methods: 
We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes. Results: 
We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician. 
Conclusions: 
These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.
KW  - disease
KW  - thrombocytopenia
KW  - guidelines
KW  - complex
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143329
VL  - 7
IS  - 36
ER  -