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ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis

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Abstract

Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients (n = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis.

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Acknowledgments

The authors (WW, MW) conducting this work represent the Neurooncology Working Group (NOA) of the German Cancer Society. BW is a scholar of the NCT Heidelberg School of Oncology Postdoc Program. We gratefully acknowledge the contributions of Ulrike Ernemann, MD and Christoph Meisner, PhD (Tübingen, Germany), Guido Reifenberger, MD and Michael C. Sabel, MD (Düsseldorf, Germany), Susanne Koeppen, MD (Essen, Germany), Otmar Wiestler, MD and Thorsten Pietsch, MD (Bonn, Germany) and Ralf Ketter, MD to the first publication of the study. We are indebted to Diana Rieker and Tanja Göck for excellent technical assistance with the ATRX immunohistochemistry. The Charitable Hertie Foundation and National Genome Network of the BMBF provided funding.

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Correspondence to Wolfgang Wick.

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401_2013_1156_MOESM1_ESM.jpg

Supplementary material 1 (JPG 798 kb) PFS of “molecular astrocytomas” by ATRX status. Tumors with ATRX loss had a significantly longer PFS than ATRX expressing tumors (median PFS 37.1 vs. 18.1 months, p = 0.038, log rank test)

Correlation coefficients of growth indices with precipitation and temperature data corresponding to August (Year prior to growth) to December (Year of growth) period, for Prades (a) and Arcalís (b). Climate and growth indices data are from the period 1952 to 2008. Asterisks indicate significant relationships (p < 0.05) (JPEG 1.15 MB)

401_2013_1156_MOESM2_ESM.jpg

Supplementary material 2 (JPG 1459 kb) PFS and TTF by treatment arm and molecular diagnosis. In “molecular astrocytomas”, initial radiotherapy was associated with a trend towards longer PFS (log rank p = 0.0944; a) and TTF (log rank p = 0.2784; b), while in “molecular oligodendrogliomas” and “molecular glioblastomas”, efficacy of both treatment arms was similar

Correlation coefficients of growth indices with precipitation and temperature data corresponding to August (Year prior to growth) to December (Year of growth) period, for Prades (a) and Arcalís (b). Climate and growth indices data are from the period 1952 to 2008. Asterisks indicate significant relationships (p < 0.05) (JPEG 1.15 MB)

401_2013_1156_MOESM3_ESM.jpg

Supplementary material 3 (JPG 813 kb) TTF by genetic signature. NOA-04 samples were grouped as described previously into tumors harboring ATRX loss (and IDH mutation), 1p/19q co-deletion (and IDH mutation), IDH mutation only or IDH wild type

Correlation coefficients of growth indices with precipitation and temperature data corresponding to August (Year prior to growth) to December (Year of growth) period, for Prades (a) and Arcalís (b). Climate and growth indices data are from the period 1952 to 2008. Asterisks indicate significant relationships (p < 0.05) (JPEG 1.15 MB)

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Wiestler, B., Capper, D., Holland-Letz, T. et al. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol 126, 443–451 (2013). https://doi.org/10.1007/s00401-013-1156-z

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