Medulloblastomlardaki Epigenetik Değişikliklerin Moleküler Alt Grupları ile İlişkisi

Yıl 2022, Cilt: 1 Sayı: 1, 35 - 46, 01.01.2022

Naz Kanıt Erdener Özer

Öz

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.

Anahtar Kelimeler

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

Epigenetic Changes in Medulloblastoma: Correlation with Molecular Subclassification

Öz

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.

Anahtar Kelimeler

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

Kaynakça

• Crawford JR, MacDonald TJ, Packer RJ. Medulloblastoma in childhood: new biological advances. Lancet Neurol. 2007 Dec;6(12):1073–85.
• Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Webster, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.
• Northcott PA, Korshunov A, Pfister SM, Taylor MD. The clinical implications of medulloblastoma subgroups. Nat Publ Gr. 2012;8:340–51.
• Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: The current consensus. Acta Neuropathol. 2012;123(4):465–72.
• Liang L, Aiken C, Felton K, Hogg A, van Landeghem F, Klonisch T, et al. Primary Pediatric Brain Tumors of the Posterior Fossa Part II: A Comprehensive Overview of Medulloblastoma. In: Development of the Cerebellum from Molecular Aspects to Diseases. Springer International Publishing; 2017. p. 327–51.
• Zurawel RH, Chiappa SA, Allen C, Raffel C. Sporadic medulloblastomas contain oncogenic β-catenin mutations. Cancer Res. 1998;58(5):896–9.
• Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al. Medulloblastoma Comprises Four Distinct Molecular Variants. J Clin Oncol. 2010;29:1408–14.
• Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJH, Martin DC, et al. Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma. J Clin Oncol. 2013;31(23):2927–35.
• Taylor MD, Mainprize TG, Rutka JT. Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: A review. Neurosurgery. 2000;47(4):888–901.
• Sadakierska-Chudy A, Kostrzewa RM, Filip M. A Comprehensive View of the Epigenetic Landscape Part I: DNA Methylation, Passive and Active DNA Demethylation Pathways and Histone Variants. Neurotox Res. 2015; 27(1): 84–97
• Frühwald MC, O’Dorisio MS, Dai Z, Tanner SM, Balster DA, Gao X, et al. Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas–Implications for tumor biology and potential clinical utility. Oncogene. 2001;20(36):5033–42.
• Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol. 2013;3:913–6.
• Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68.
• Lusher ME, Lindsey JC, Latif F, Pearson ADJ, Ellison DW, Clifford SC. Biallelic epigenetic inactivation of the RASSF1A tumor suppressor gene in medulloblastoma development. Cancer Res. 2002;62(20):5906–11.
• Rood BR, Zhang H, Weitman DM, Cogen PH. Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res. 2002;62(13):3794–7.
• Zuzak TJ, Steinhoff DF, Sutton LN, Phillips PC, Eggert A, Grotzer MA. Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur J Cancer. 2002;38(1):83–91.
• Pfister S, Schlaeger C, Mendrzyk F, Wittmann A, Benner A, Kulozik A, et al. Array-based profiling of reference-independent methylation status (aPRIMES) identifies frequent promoter methylation and consecutive downregulation of ZIC2 in pediatric medulloblastoma. Nucleic Acids Res. 2007;35(7).
• Nakahara Y, Northcott PA, Li M, Kongkham PN, Smith C, Yan H, et al. Genetic and epigenetic inactivation of Kruppel-like Factor 4 in medulloblastoma. Neoplasia. 2010;12(1):20–7.
• Diede SJ, Guenthoer J, Geng LN, Mahoney SE, Marotta M, Olson JM, et al. DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences. Proc Natl Acad Sci U S A. 2010;107(1):234–9.
• Kongkham PN, Northcott PA, Ra YS, Nakahara Y, Mainprize TG, Croul SE, et al. An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma. Cancer Res. 2008;68(23):9945–53.
• Lindsey JC, Kawauchi D, Schwalbe EC, Solecki DJ, Selby MP, Mckinnon PJ, et al. Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance. Oncogene. 2015;34:4746–57.
• Hovestadt V, Jones DTW, Picelli S, Wang W, Kool M, Northcott PA, et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature. 2014 Jun 18;510(7506):537–41.
• Sadakierska-Chudy A, Filip M. A Comprehensive View of the Epigenetic Landscape. Part II: Histone Post-translational Modification, Nucleosome Level, and Chromatin Regulation by ncRNAs. Neurotox Res. 2015; 27(2): 172–197
• Yi J, Wu J. Epigenetic regulation in medulloblastoma. Mol Cell Neurosci. 2018 Mar; 87: 65–76.
• Roussel MF, Stripay JL. Epigenetic Drivers in Pediatric Medulloblastoma. Cerebellum. 2018; 17(1): 28–36.
• Pfister S, Rea S, Taipale M, Mendrzyk F, Straub B, Ittrich C, et al. The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int J Cancer. 2008;122(6):1207–13.
• Milde T, Oehme I, Korshunov A, Kopp-Schneider A, Remke M, Northcott P, et al. HDAC5 and HDAC9 in medulloblastoma: Novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res. 2010;16(12):3240–52.
• Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488(7409):43–8.
• Shi J, Vakoc CR. The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition. Mol Cell. 2014;54(5):728–36.
• Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science. 2002;298(5595):1039–43.
• Dubuc AM, Remke M, Korshunov A, Northcott PA, Zhan SH, Mendez-Lago M, et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 2013;125(3):373–84.
• Clapier CR, Iwasa J, Cairns BR, Peterson CL. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol. 2017 Jul; 18(7): 407–422.
• Shi X, Wang Q, Gu J, Xuan Z, Wu JI. SMARCA4/Brg1 coordinates genetic and epigenetic networks underlying Shh-type medulloblastoma development. Nat Publ Gr. 2016;35:5746–58.
• Leung JWC, Makharashvili N, Agarwal P, Chiu LY, Pourpre R, Cammarata MB, et al. ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair. Genes Dev. 2017;31(3):260–74.
• Motameny S, Wolters S, Nürnberg P, Schumacher B. Next Generation Sequencing of miRNAs – Strategies, Resources and Methods. Genes. 2010;1:70–84.
• Gokhale A, Kunder R, Goel A, Sarin R, Moiyadi A, Shenoy A, et al. Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway. J Cancer Res Ther. 2010;6(4):521–9.
• Northcott PA, Fernandez-L A, Hagan JP, Ellison DW, Grajkowska W, Gillespie Y, et al. The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. Cancer Res. 2009;69(8):3249–55.
• Weeraratne SD, Amani V, Teider N, Pierre-Francois J, Winter D, Kye MJ, et al. Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma. Acta Neuropathol. 2012;123(4):539–52.
• Grunder E, D’ambrosio R, Fiaschetti G, Abela L, Arcaro A, Zuzak T, et al. MicroRNA-21 suppression impedes medulloblastoma cell migration. Eur J Cancer. 2011;47(16):2479-90.
• Pal R, Greene S. microRNA-10b Is Overexpressed and Critical for Cell Survival and Proliferation in Medulloblastoma. PLoS One. 2015;10(9):e0137845.
• Li KK-W, Xia T, Ma FMT, Zhang R, Mao Y, Wang Y, et al. miR-106b is overexpressed in medulloblastomas and interacts directly with PTEN. Neuropathol Appl Neurobiol. 2015;41(2):145–64.
• Pierson J, Hostager B, Fan R, Vibhakar R. Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma. J Neurooncol. 2008;90(1):1–7.
• Ferretti E, De Smaele E, Miele E, Laneve P, Po A, Pelloni M, et al. Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells. EMBO J. 2008;27(19):2616–27.
• Joshi P, Katsushima K, Zhou R, Meoded A, Stapleton S, Jallo G, et al. The therapeutic and diagnostic potential of regulatory noncoding RNAs in medulloblastoma. Neuro-Oncology Adv. 2019;1(1):1–14.
• Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47(3):199–208.
• Laneve P, Po A, Favia A, Legnini I, Alfano V, Rea J, et al. The long noncoding RNA linc-NeD125 controls the expression of medulloblastoma driver genes by microRNA sponge activity. Oncotarget. 2017;8(19):31003-31015.
• Zhang Y, Wang T, Wang S, Xiong Y, Zhang R, Zhang X, et al. Nkx2-2as suppression contributes to the pathogenesis of sonic hedgehog medulloblastoma. Cancer Res. 2018;78(4):962–73.
• Kesherwani V, Shukla M, Coulter DW, Sharp JG, Joshi SS, Chaturvedi NK, et al. Long non-coding RNA profiling of pediatric Medulloblastoma. BMC Med Genomics. 2020;13(1):1–14.