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Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas

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Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas. / Goschzik, Tobias; Mynarek, Martin; Doerner, Evelyn; Schenk, Alina; Spier, Isabel; Warmuth-Metz, Monika; Bison, Brigitte; Obrecht, Denise; Struve, Nina; Kortmann, Rolf-Dieter; Schmid, Matthias; Aretz, Stefan; Rutkowski, Stefan; Pietsch, Torsten.

In: ACTA NEUROPATHOL, Vol. 144, No. 6, 12.2022, p. 1143-1156.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Goschzik, T, Mynarek, M, Doerner, E, Schenk, A, Spier, I, Warmuth-Metz, M, Bison, B, Obrecht, D, Struve, N, Kortmann, R-D, Schmid, M, Aretz, S, Rutkowski, S & Pietsch, T 2022, 'Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas', ACTA NEUROPATHOL, vol. 144, no. 6, pp. 1143-1156. https://doi.org/10.1007/s00401-022-02505-5

APA

Goschzik, T., Mynarek, M., Doerner, E., Schenk, A., Spier, I., Warmuth-Metz, M., Bison, B., Obrecht, D., Struve, N., Kortmann, R-D., Schmid, M., Aretz, S., Rutkowski, S., & Pietsch, T. (2022). Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas. ACTA NEUROPATHOL, 144(6), 1143-1156. https://doi.org/10.1007/s00401-022-02505-5

Vancouver

Goschzik T, Mynarek M, Doerner E, Schenk A, Spier I, Warmuth-Metz M et al. Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas. ACTA NEUROPATHOL. 2022 Dec;144(6):1143-1156. https://doi.org/10.1007/s00401-022-02505-5

Bibtex

@article{a075947d242640aaa64bfd02fd38d0a4,
title = "Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas",
abstract = "This study aimed to re-evaluate the prognostic impact of TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers in WNT-activated medulloblastoma (WNT-MB). In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC, and TP53 were analyzed by DNA sequencing. Chromosomal copy-number aberrations were assessed by molecular inversion probe technology (MIP), SNP6, or 850k methylation array hybridization. Prognostic impact was evaluated in 120 patients with follow-up data from the HIT2000 medulloblastoma trial or HIT registries. CTNNB1 mutations were present in 92.2%, and APC mutations in 6.8% of samples. One CTNNB1 wild-type tumor gained WNT activation due to homozygous FBXW7 deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the TP53 locus (chromosome 17p13.1) was found in 40.7% (11/27) of TP53 mutant tumor samples and in 12.6% of TP53 wild-type cases (13/103). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, p = 0.001), and were enriched for chromosomes 17p (p = 0.001), 10, and 13 losses. Gains of OTX2 (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, p = 0.017 resp. 5-year-OS 83% versus 97%, p = 0.006). Multivariable Cox regression analysis for PFS/OS identified both genetic alterations as independent prognostic markers. Our data suggest that patients with WNT-MB carrying TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.",
author = "Tobias Goschzik and Martin Mynarek and Evelyn Doerner and Alina Schenk and Isabel Spier and Monika Warmuth-Metz and Brigitte Bison and Denise Obrecht and Nina Struve and Rolf-Dieter Kortmann and Matthias Schmid and Stefan Aretz and Stefan Rutkowski and Torsten Pietsch",
note = "{\textcopyright} 2022. The Author(s).",
year = "2022",
month = dec,
doi = "10.1007/s00401-022-02505-5",
language = "English",
volume = "144",
pages = "1143--1156",
journal = "ACTA NEUROPATHOL",
issn = "0001-6322",
publisher = "Springer",
number = "6",

}

RIS

TY - JOUR

T1 - Genetic alterations of TP53 and OTX2 indicate increased risk of relapse in WNT medulloblastomas

AU - Goschzik, Tobias

AU - Mynarek, Martin

AU - Doerner, Evelyn

AU - Schenk, Alina

AU - Spier, Isabel

AU - Warmuth-Metz, Monika

AU - Bison, Brigitte

AU - Obrecht, Denise

AU - Struve, Nina

AU - Kortmann, Rolf-Dieter

AU - Schmid, Matthias

AU - Aretz, Stefan

AU - Rutkowski, Stefan

AU - Pietsch, Torsten

N1 - © 2022. The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - This study aimed to re-evaluate the prognostic impact of TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers in WNT-activated medulloblastoma (WNT-MB). In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC, and TP53 were analyzed by DNA sequencing. Chromosomal copy-number aberrations were assessed by molecular inversion probe technology (MIP), SNP6, or 850k methylation array hybridization. Prognostic impact was evaluated in 120 patients with follow-up data from the HIT2000 medulloblastoma trial or HIT registries. CTNNB1 mutations were present in 92.2%, and APC mutations in 6.8% of samples. One CTNNB1 wild-type tumor gained WNT activation due to homozygous FBXW7 deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the TP53 locus (chromosome 17p13.1) was found in 40.7% (11/27) of TP53 mutant tumor samples and in 12.6% of TP53 wild-type cases (13/103). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, p = 0.001), and were enriched for chromosomes 17p (p = 0.001), 10, and 13 losses. Gains of OTX2 (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, p = 0.017 resp. 5-year-OS 83% versus 97%, p = 0.006). Multivariable Cox regression analysis for PFS/OS identified both genetic alterations as independent prognostic markers. Our data suggest that patients with WNT-MB carrying TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.

AB - This study aimed to re-evaluate the prognostic impact of TP53 mutations and to identify specific chromosomal aberrations as possible prognostic markers in WNT-activated medulloblastoma (WNT-MB). In a cohort of 191 patients with WNT-MBs, mutations in CTNNB1, APC, and TP53 were analyzed by DNA sequencing. Chromosomal copy-number aberrations were assessed by molecular inversion probe technology (MIP), SNP6, or 850k methylation array hybridization. Prognostic impact was evaluated in 120 patients with follow-up data from the HIT2000 medulloblastoma trial or HIT registries. CTNNB1 mutations were present in 92.2%, and APC mutations in 6.8% of samples. One CTNNB1 wild-type tumor gained WNT activation due to homozygous FBXW7 deletion. Monosomy 6 was present in 78.6%, and more frequent in children than adults. 16.1% of tumor samples showed TP53 mutations, of those 60% with nuclear positivity for the p53 protein. Loss of heterozygosity at the TP53 locus (chromosome 17p13.1) was found in 40.7% (11/27) of TP53 mutant tumor samples and in 12.6% of TP53 wild-type cases (13/103). Patients with tumors harboring TP53 mutations showed significant worse progression-free survival (PFS; 5-year-PFS 68% versus 93%, p = 0.001), and were enriched for chromosomes 17p (p = 0.001), 10, and 13 losses. Gains of OTX2 (14q22.3) occurred in 38.9% of samples and were associated with poor PFS and OS (5-year-PFS 72% versus 93%, p = 0.017 resp. 5-year-OS 83% versus 97%, p = 0.006). Multivariable Cox regression analysis for PFS/OS identified both genetic alterations as independent prognostic markers. Our data suggest that patients with WNT-MB carrying TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.

U2 - 10.1007/s00401-022-02505-5

DO - 10.1007/s00401-022-02505-5

M3 - SCORING: Journal article

C2 - 36181537

VL - 144

SP - 1143

EP - 1156

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 6

ER -