The Epigenetics of Cancer in Children

Abstract

Malignant tumors of childhood represent a rather heterogeneous group of neoplasms originating from virtually any anatomical structure. Despite major improvements in the clinical management including timely diagnosis, advanced supportive care and refined multimodality treatment, prognosis remains grim for certain risk groups. Aberrant epigenetic regulation, i.e. changes in gene transcription not due to DNA sequence alterations, is now increasingly recognized as a fundamental process in malignant transformation, tumor progression and drug resistance. The molecular mechanisms involve aberrant activity of enzymes controlling the packaging and transcriptional regulation of the genome. Two major protein families are involved in this process, DNA methyltransferases and histone deacetylases. With the availability of small molecule inhibitors targeting the aberrant epigenetic machinery in cancer cells, these compounds are evaluated in several clinical trials.

Zusammenfassung

Trotz großer Fortschritte in der Diagnostik und Therapie von Krebserkrankungen im Kindes- und Jugendalter ist die Prognose insbesondere von fortgeschrittenen Tumoren weiterhin ungünstig. In den letzten Jahren hat sich gezeigt, dass fehlgesteuerte epigenetische Regulationsmechanismen eine fundamentale Rolle in der malignen Transformation, Progression und Therapieresistenz von Tumoren spielen. Unter „Epigenetik” versteht man den erblichen Aktivitätszustand von Genen, dessen Information unabhängig von der Basensequenz der DNA ist. Hierbei spielen die DNA-Methyltransferasen und die Histon-Deacetylasen eine zentrale Rolle. Sie regulieren den „Verpackungszustand” des menschlichen Genoms und sind an der Kontrolle des Expressionsprofils von Genen in einer Zelle beteiligt. In malignen Geweben sind diese Enzymfamilien pathologisch aktiv. Durch kleinmolekulare Inhibitoren können DNA-Methyltransferasen und Histon-Deacetylasen gehemmt werden und dadurch anti-tumorale Wirkungen entfalten.

Key words

epigenetics - DNMT - HDAC - inhibitors - pediatric oncology

Schlüsselwörter

Epigenetik - DNMT - HDAC - Inhibitoren - pädiatrische Onkologie

Literatur

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