7月25日，Nature雜志以開放論文的形式在線報道了,，科學(xué)家對成神經(jīng)管細(xì)胞瘤四個不同亞型的基因組特性的深入解析結(jié)果。
成神經(jīng)管細(xì)胞瘤是一種侵襲性生長的腫瘤,，起源于小腦和延髓/腦干中,。它是兒童最常見的惡性腦腫瘤，并顯示出顯著的生物學(xué)和臨床表現(xiàn)的異質(zhì)性,。盡管最近在治療上獲得進(jìn)展,，仍有約40％兒童患者的腫瘤復(fù)發(fā)，30％將死于該疾病,。
即使是那些生存下來的患者,，生活質(zhì)量也顯著降低。目前發(fā)現(xiàn)成神經(jīng)管細(xì)胞瘤具有四個在臨床癥狀,，生物學(xué)特性和遺傳背景上獨特的亞型,。帶有激活的wingless信號通路的WNT亞型腫瘤，在目前治療手段下具有良好的預(yù)后,。SHH亞型腫瘤帶有Hedgehog信號通路的激活,，其預(yù)后比WNT亞型稍差。 人們對于第3和第4組腫瘤其分子特點還了解不多,，也最缺少有效的治療方法,。人們目前仍不清楚，是什么遺傳突變造成了這些亞型之間的獨特差異,。
作為國際癌癥基因組協(xié)會（ICGC）PedBrain腫瘤項目的一部分,，本研究對125例成神經(jīng)管細(xì)胞瘤患者與正常人配對樣本進(jìn)行了綜合性深入測序分析。在第3組和4組腫瘤亞型中,，形成四倍體被認(rèn)定為頻繁的早期事件,。而且，研究者觀察到,，病人的年齡和突變率之間呈正相關(guān),。
此外，研究者還發(fā)現(xiàn),，幾個常見突變經(jīng)常以亞類型特異性的模式出現(xiàn),，其中有些是已知的成神經(jīng)管細(xì)胞瘤相關(guān)基因（CTNNB1，PTCH1,，MLL2,，SMARCA4），而有些基因（DDX3X,，CTDNEP1,，KDM6A TBR1）的突變以前沒有發(fā)現(xiàn)與此類腫瘤的關(guān)聯(lián),。
RNA測序證實了這些改變，并發(fā)現(xiàn)了,，就目前所知,，第一個成神經(jīng)管細(xì)胞瘤融合基因的表達(dá)。在不同腫瘤亞型間,，染色質(zhì)修飾常常發(fā)生變異,。這些結(jié)果增進(jìn)了人類對成神經(jīng)管細(xì)胞瘤的基因組復(fù)雜性和異質(zhì)性的了解，并為研發(fā)成神經(jīng)管細(xì)胞瘤（特別是第3,，4亞型）新療法,，提供了一些潛在的靶點。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
Dissecting the genomic complexity underlying medulloblastoma
David T. W. Jones,Natalie J?ger,Marcel Kool,Thomas Zichner,Barbara Hutter,Marc Sultan,Yoon-Jae Cho,Trevor J. Pugh,Volker Hovestadt,Adrian M. Stütz,Tobias Rausch,Hans-J?rg Warnatz,Marina Ryzhova,Sebastian Bender,Dominik Sturm,Sabrina Pleier,Huriye Cin,Elke Pfaff,Laura Sieber,Andrea Wittmann,Marc Remke,Hendrik Witt,Sonja Hutter,Theophilos Tzaridis,Joachim Weischenfeld et al.
Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified2, 3. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges2, 3, 5. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour–normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
