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@ARTICLE{Waszak:135972,
author = {S. M. Waszak and P. A. Northcott$^*$ and I. Buchhalter$^*$
and G. W. Robinson and C. Sutter and S. Groebner$^*$ and K.
B. Grund and L. Brugières and D. Jones$^*$ and K.
Pajtler$^*$ and A. S. Morrissy and M. Kool$^*$ and D.
Sturm$^*$ and L. Chavez$^*$ and A. Ernst$^*$ and S.
Brabetz$^*$ and M. Hain$^*$ and T. Zichner and M.
Segura-Wang and J. Weischenfeldt and T. Rausch and B. R.
Mardin and X. Zhou and C. Baciu and C. Lawerenz$^*$ and J.
A. Chan and P. Varlet and L. Guerrini-Rousseau and D. W.
Fults and W. Grajkowska and P. Hauser and N. Jabado and
Y.-S. Ra and K. Zitterbart and S. S. Shringarpure and F. M.
De La Vega and C. D. Bustamante and H.-K. Ng and A. Perry
and T. J. MacDonald and P. Hernáiz Driever and A. E. Bendel
and D. C. Bowers and G. McCowage and M. M. Chintagumpala and
R. Cohn and T. Hassall and G. Fleischhack and T. Eggen and
F. Wesenberg and M. Feychting and B. Lannering and J. Schüz
and C. Johansen and T. V. Andersen and M. Röösli and C. E.
Kuehni and M. Grotzer and K. Kjaerheim and C. M. Monoranu
and T. C. Archer and E. Duke and S. L. Pomeroy and R.
Shelagh and S. Frank and D. Sumerauer and W. Scheurlen and
M. V. Ryzhova and T. Milde$^*$ and C. P. Kratz and D. Samuel
and J. Zhang and D. A. Solomon and M. Marra and R. Eils$^*$
and C. R. Bartram and K. von Hoff and S. Rutkowski and V.
Ramaswamy and R. J. Gilbertson and A. Korshunov$^*$ and M.
D. Taylor and P. Lichter$^*$ and D. Malkin and A. Gajjar and
J. O. Korbel and S. Pfister$^*$},
title = {{S}pectrum and prevalence of genetic predisposition in
medulloblastoma: a retrospective genetic study and
prospective validation in a clinical trial cohort.},
journal = {The lancet / Oncology},
volume = {19},
number = {6},
issn = {1470-2045},
address = {London},
publisher = {The Lancet Publ. Group},
reportid = {DKFZ-2018-00708},
pages = {785 - 798},
year = {2018},
abstract = {<?xml version='1.0' encoding='UTF-8'?><html
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xmlns:mml='http://www.w3.org/1998/Math/MathML'
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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.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.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.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.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 Childrens Hospital Foundation},
cin = {B062 / L101 / B080 / G200 / B060 / W610 / G340 / G380},
ddc = {610},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)L101-20160331 /
I:(DE-He78)B080-20160331 / I:(DE-He78)G200-20160331 /
I:(DE-He78)B060-20160331 / I:(DE-He78)W610-20160331 /
I:(DE-He78)G340-20160331 / I:(DE-He78)G380-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29753700},
pmc = {pmc:PMC5984248},
doi = {10.1016/S1470-2045(18)30242-0},
url = {https://inrepo02.dkfz.de/record/135972},
}
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