Medulloblastomlardaki Epigenetik Değişikliklerin Moleküler Alt Grupları ile İlişkisi

Year 2022, Volume: 1 Issue: 1, 35 - 46, 01.01.2022

Naz Kanıt , Erdener Özer

Abstract

Medulloblastom (MB) çocukluk çağının malign beyin tümörü olmakla beraber klinik heterojenitesi oldukça yüksektir. Histolojik alt sınıflandırma yanısıra; moleküler olarak WNT-aktive, SHH-aktive ve WNT/SHH-aktive-olmayan üzere üç temel alt grubu tanımlanmıştır. Son grup, Grup 3 ve Grup 4 medulloblastomları içermektedir. Tüm gruplar, farklı histolojik tiplerin yanı sıra, farklı genetik ve epigenetik özellikler gösterebilmektedir. Geçtiğimiz on yılda hastalığın genetik yapısı detaylı bir şekilde incelenmiştir, ancak epigenetik temelleri son zamanlarda araştırma odağı olmuştur. Epigenetik araştırmalar KDM6A ve EZH2 gibi genler üzerinden histon modifikasyon mekanizmaları, PRC2 kompleksi ve başta SWI/SNF kompleksi olmak üzere ATP-bağımlı kromatin yeniden-düzenleyici kompleksleri üzerine yoğunlaşmıştır. EZH2 geninin baskılayıcıları günümüzde klinik denemelerde MB hastaları üzerinde test edilmekte olup bu gen aday hedef genlerden biridir. Son olarak, kodlamayan RNA’lardan lncRNA’ların alt gruplara özgü belirteçler arasında en umut verici belirteçler olacağı tahmin edilmektedir. Medulloblastomlardaki genetik ve epigenetik farklılıkları anlamak, alt gruplara özgü değişiklikleri tanımlamak ve bu değişiklikleri hedefleyen terapötiklerin ortaya çıkarılması, bu kanserin tedavisinde oldukça önemli olacaktır. Bu derlemede amacımız, medulloblastomlardaki epigenetik değişiklikleri güncel literatür ile irdelemek ve konuyla ilişkili yürüttüğümüz çalışmadaki ön verilerimizi ortaya koymaktır.

Keywords

medulloblastom, DNA metilasyonu, histon modifikasyonları, kromatin yeniden düzenlenmesi, lncRNA

Epigenetic Changes in Medulloblastoma: Correlation with Molecular Subclassification

Abstract

Medulloblastoma is a malignant childhood brain tumor and shows high clinical heterogeneity among patients. Three major molecular categories of MB have been established; WNT activated group, SHH activated group, and non-WNT/non-SHH-activated group. The latter includes Group 3 and Group 4. All groups show different histological features as well as different genetic and epigenetic backgrounds. Genetic basis of the disease has been widely studied in the last decade, however epigenetic basis of the disease has become a trend research area. The epigenetic researches focus on histone modification mechanisms involving some genes such as KDM6A and EZH2, and also PRC2 complex, in addition to variations in ATP-dependent chromatin remodeling complexes, mainly on SWI/SNF complexes. EZH2 is a candidate target gene as its repressors are currently on trial for MB patients. Finally lncRNA, a noncoding RNA is likely to be the most promising subgroup specific marker. Understanding both genetic and epigenetic differences in medulloblastomas, determining subtype-specific alterations and discovering therapeutics that specifically targets those alterations might be valuable for management of this cancer. In this review, we aimed to address the epigenetic mechanisms in medulloblastomas in the light of the current literature and emphasize the relevant unpublished data in our preliminary study.

Keywords

medulloblastoma, DNA methylation, histone modifications, chromatin remodeling, lncRNA

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