TY  - JOUR
A1  - Schwarz, Klaus
A1  - Hameister, Horst
A1  - Gessler, Manfred
A1  - Grzeschik, Karl-Heinz
A1  - Hansen-Hagge, Thomas E.
A1  - Bartram, Claus R.
T1  - Confirmation of the localization of the human recombination activating gene 1 (RAG1) to chromosome 11p13
N2  - The human recombination activating gene 1 (RAGl) has previously been mapped to chromosomes 14q and 11 p. Here we confirm the chromosome 11 assignment by two independent approaches: autoradiographic and fluorescence in situ hybridization to metaphase spreads and analysis of human-hamster somatic cell hybrid DNA by the polymerase chain reaction (PCR) and Southern blotting. Our results unequivocally localize RAG1 to llp13.
KW  - Biochemie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59136
ER  - 
TY  - JOUR
A1  - Engel, Christoph
A1  - Rhiem, Kerstin
A1  - Hahnen, Eric
A1  - Loibl, Sibylle
A1  - Weber, Karsten E.
A1  - Seiler, Sabine
A1  - Zachariae, Silke
A1  - Hauke, Jan
A1  - Wappenschmidt, Barbara
A1  - Waha, Anke
A1  - Blümcke, Britta
A1  - Kiechle, Marion
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Bartram, Claus R.
A1  - Speiser, Dorothee
A1  - Schlegelberger, Brigitte
A1  - Arnold, Norbert
A1  - Wieacker, Peter
A1  - Leinert, Elena
A1  - Gehrig, Andrea
A1  - Briest, Susanne
A1  - Kast, Karin
A1  - Riess, Olaf
A1  - Emons, Günter
A1  - Weber, Bernhard H. F.
A1  - Engel, Jutta
A1  - Schmutzler, Rita K.
T1  - Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history
JF  - BMC Cancer
N2  - Background 
There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. 

Methods
The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. 

Results
A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. 

Conclusions
Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
KW  - hereditary breast and ovarian cancer
KW  - BRCA1
KW  - BRCA2
KW  - triple-negative breast cancer
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226763
VL  - 18
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  -