Article
Incidence and prognostic impact of genetic and epigenetic hTERT promoter alterations in atypical teratoid/rhaboid tumors in childhood
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Authors
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Benjamin Brokinkel
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Münster, Münster, Deutschland; Institut für Neuropathologie, Universitätsklinikum Münster, Münster, Deutschland
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Michael Frühwald
- I. Klinik für Kinder und Jugendliche, Klinikum Augsburg, Schwäbisches Kinderkrebszentrum, Augsburg, Deutschland
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Walter Stummer
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Münster, Münster, Deutschland
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Angela Brentrup
- Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Münster, Münster, Deutschland
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Björn Koos
- Institutionen för immunologi, genetik och patologi, BMC, Uppsala Universitet, Uppsala, Sverige
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Werner Paulus
- Institut für Neuropathologie, Universitätsklinikum Münster, Münster, Deutschland
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Martin Hasselblatt
- Institut für Neuropathologie, Universitätsklinikum Münster, Münster, Deutschland
| Published: | May 13, 2014 |
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Outline
Text
Objective: Atypical Teratoid/Rhabdoid Tumors (AT/RT) are highly malignant childhood brain tumors carrying a dismal prognosis. Alterations of the hTERT (human Telomerase Reverse Transcriptase) promoter are considered to increase telomerase activity and therefore to lengthen the telomeres and have been described in a variety of tumor entities. In AT/RT, two studies reported rare promoter hotspot (C228T and C250T) mutations but frequent promoter methylations. However, the relationship of both alterations as well as their meaning for the clinical outcome have not been investigated yet. We therefore analyzed hTERT promoter mutation and methylation status as well as clinical data in a large collective of AT/RT.
Method: DNA was isolated from formalin-fixed paraffin-embedded tumor samples of 52 cases of AT/RT diagnosed from 1992 to 2013. For methylation analyses, DANN from representative tumor material was subjected to methylation-specific PCR (MS-PCR). Promoter mutations were detected by Sanger sequencing. Clinical data was achieved with support of the European Rhabdoid Registry (EU-RHAB).
Results: The median age of the 24 girls and 28 boys was 19 months (range 0-215 months). Tumors were located supratentorially in 65%. Mortality and progression occurred in 23 of 39 (59%) and in 25 of 37 (68%) patients with available data on follow-up, with a median overall and progression free survival of 11 and 8 months, respectively. hTERT promoter methylation status was positive in 42/52 samples (81%). On sequencing of 18 tumors, no promoter mutations were encountered in both methylated and unmethylated samples. On univariate analyses, promoter methylation was not associated with sex, age, tumor location, metastases, progression or mortality. Lack of prognostic impact of promoter methylation remained unchanged after age- and sex-adjusting multivariate analyses. Kaplan Meier analyses revealed no correlation of promoter methylation to either overall or progression free survival.
Conclusions: In contrast to hTERT mutations, methylation of the hTERT promoter is frequent in AT/RTs, but not associated with clinical factors or outcome.
Note: This work was supported by the Interdisciplinary Centre for Clinical Research, University of Münster (Ha3/016/11).
