TY  - JOUR
A1  - Kohl, S.
A1  - Gruendler, T. O. J.
A1  - Huys, D.
A1  - Sildatke, E.
A1  - Dembek, T. A.
A1  - Hellmich, M.
A1  - Vorderwulbecke, M.
A1  - Timmermann, L.
A1  - Ahmari, S. E.
A1  - Klosterkoetter, J.
A1  - Jessen, F.
A1  - Sturm, V.
A1  - Visser-Vandewalle, V.
A1  - Kuhn, J.
T1  - Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder
JF  - Translational Psychiatry
N2  - Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation.
KW  - nucleus
KW  - serotonin
KW  - schizophrenia
KW  - dopamine
KW  - double-blind
KW  - psychiatric disorders
KW  - in vivo
KW  - acoustic startle
KW  - reflex
KW  - modulation
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138300
VL  - 5
IS  - e675
ER  - 
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  -