Molecular stratification of medulloblastoma: Comparison of histological and genetic methods to detect Wnt activated tumors
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Molecular stratification of medulloblastoma: Comparison of histological and genetic methods to detect Wnt activated tumors. / Goschzik, Tobias; Zur Mühlen, Anja; Kristiansen, Glen; Haberler, Christine; Stefanits, Harald; Friedrich, Carsten; von Hoff, Katja; Rutkowski, Stefan; Pfister, Stefan M; Pietsch, Torsten.
In: NEUROPATH APPL NEURO, Vol. 41, No. 2, 02.2015, p. 135-144.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Molecular stratification of medulloblastoma: Comparison of histological and genetic methods to detect Wnt activated tumors
AU - Goschzik, Tobias
AU - Zur Mühlen, Anja
AU - Kristiansen, Glen
AU - Haberler, Christine
AU - Stefanits, Harald
AU - Friedrich, Carsten
AU - von Hoff, Katja
AU - Rutkowski, Stefan
AU - Pfister, Stefan M
AU - Pietsch, Torsten
N1 - This article is protected by copyright. All rights reserved.
PY - 2015/2
Y1 - 2015/2
N2 - AIMS: Wnt activation in medulloblastomas is associated with good outcome. Upfront testing and risk-adapted stratification of patients will be done in future clinical studies. In a cohort of 186 pediatric medulloblastomas our aim was to identify the optimal methods in standard clinical practice to detect this subgroup.METHODS: Nuclear accumulation of ß-catenin was analyzed by immunohistochemistry (IHC). DNA of FFPE tissue was amplified by PCR for single-strand conformation polymorphism analysis and direct sequencing of CTNNB1 exon 3. Copy number of chromosome 6 was analyzed by multiplex ligation-dependent probe amplification and molecular inversion profiling.RESULTS: Different automated immunostaining systems showed similar results. 21 of 186 samples had nuclear accumulation in ≥5% of cells, 17 samples showed <5% ß-catenin positive nuclei. None of these 17 cases had CTNNB1 mutations, but 18 of 21 cases with ≥5% accumulation did, identifying these 18 cases as Wnt-subgroup medulloblastomas. 15 of 18 mutated cases showed monosomy 6, 3 had balanced chromosome 6. On the contrary, none of the CTNNB1 wildtype tumors had monosomy 6.CONCLUSIONS: Standard neuropathological evaluation of medulloblastoma samples should include IHC of ß-catenin because tumors with high nuclear accumulation of ß-catenin most probably belong to the Wnt subgroup of medulloblastomas. Still, IHC alone may be insufficient to detect all Wnt cases. Similarly, chromosome 6 aberrations were not present in all CTNNB1-mutated cases. Therefore, we conclude that sequencing analysis of CTNNB1 exon 3 in combination with ß-catenin IHC (possibly as pre-screening method) is a feasible and cost-efficient way for the determination of Wnt medulloblastomas.
AB - AIMS: Wnt activation in medulloblastomas is associated with good outcome. Upfront testing and risk-adapted stratification of patients will be done in future clinical studies. In a cohort of 186 pediatric medulloblastomas our aim was to identify the optimal methods in standard clinical practice to detect this subgroup.METHODS: Nuclear accumulation of ß-catenin was analyzed by immunohistochemistry (IHC). DNA of FFPE tissue was amplified by PCR for single-strand conformation polymorphism analysis and direct sequencing of CTNNB1 exon 3. Copy number of chromosome 6 was analyzed by multiplex ligation-dependent probe amplification and molecular inversion profiling.RESULTS: Different automated immunostaining systems showed similar results. 21 of 186 samples had nuclear accumulation in ≥5% of cells, 17 samples showed <5% ß-catenin positive nuclei. None of these 17 cases had CTNNB1 mutations, but 18 of 21 cases with ≥5% accumulation did, identifying these 18 cases as Wnt-subgroup medulloblastomas. 15 of 18 mutated cases showed monosomy 6, 3 had balanced chromosome 6. On the contrary, none of the CTNNB1 wildtype tumors had monosomy 6.CONCLUSIONS: Standard neuropathological evaluation of medulloblastoma samples should include IHC of ß-catenin because tumors with high nuclear accumulation of ß-catenin most probably belong to the Wnt subgroup of medulloblastomas. Still, IHC alone may be insufficient to detect all Wnt cases. Similarly, chromosome 6 aberrations were not present in all CTNNB1-mutated cases. Therefore, we conclude that sequencing analysis of CTNNB1 exon 3 in combination with ß-catenin IHC (possibly as pre-screening method) is a feasible and cost-efficient way for the determination of Wnt medulloblastomas.
U2 - 10.1111/nan.12161
DO - 10.1111/nan.12161
M3 - SCORING: Journal article
C2 - 24894640
VL - 41
SP - 135
EP - 144
JO - NEUROPATH APPL NEURO
JF - NEUROPATH APPL NEURO
SN - 0305-1846
IS - 2
ER -