Distinct molecular profile of diffuse cerebellar gliomas.
Distinct molecular profile of diffuse cerebellar gliomas.
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DOI：
10.1007/s00401-017-1771-1
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发表时间：
2017-12
影响因子：
12.7
通讯作者：
Saito N
中科院分区：
文献类型：
--
作者：
Nomura M;Mukasa A;Nagae G;Yamamoto S;Tatsuno K;Ueda H;Fukuda S;Umeda T;Suzuki T;Otani R;Kobayashi K;Maruyama T;Tanaka S;Takayanagi S;Nejo T;Takahashi S;Ichimura K;Nakamura T;Muragaki Y;Narita Y;Nagane M;Ueki K;Nishikawa R;Shibahara J;Aburatani H;Saito N
最近的研究表明，肿瘤驱动的改变往往是不同的胶质瘤，起源于不同的脑区，并强调了分析的重要性，胶质瘤的分子特征分层的脑区。因此，为了阐明弥漫性小脑胶质瘤（DCG）的分子特征，分析了27例成人（主要是胶质母细胞瘤）病例。使用全外显子组测序、RNA测序和Infinium甲基化阵列（n = 17）的综合分析表明，与其他脑区的胶质瘤相比，它们具有独特的分子特征。染色质修饰基因的频繁突变被鉴定，包括，值得注意的是，在SETD 2中的截短突变（n = 4），其导致H3 K36三甲基化的丧失，并且与H3 F3 A K27 M突变（n = 3）互斥，这表明表观遗传失调可能导致DCG肿瘤发生。导致p53功能丧失的改变，包括TP 53突变（n = 9），PPM 1D突变（n = 2）和一种新型的PPM 1D融合（n = 1），也很常见。另一方面，在脑胶质瘤中常见的突变和拷贝数变化是罕见的。DNA甲基化谱分析表明，除了H3 F3 A突变的DCG外，所有DCG都被归类为“RTK I（PDGFRA）”组，并且这些DCG具有与PDGFRA高度相关的基因表达特征。此外，与来自不同脑区的315个胶质瘤的数据相比，与胶质细胞发育相关的转录因子基因的启动子甲基化显示出一种特征性模式，可能反映了它们的肿瘤起源。值得注意的是，SOX 10，一个关键的转录因子与少突胶质细胞分化和PDGFRA的调节，上调DCG和H3 K27 M突变型弥漫性中线胶质瘤，这表明他们的发展和生物学的共性。相反，在大多数脑胶质瘤中，SOX 10被启动子甲基化沉默。这些研究结果可能表明，潜在的定制的胶质瘤靶向治疗，根据他们的大脑区域，除了提供分子线索，以确定区域相关的细胞起源的DCG。本文的在线版本（doi：10.1007/s 00401 -017-1771-1）包含补充材料，可供授权用户使用。
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the “RTK I (PDGFRA)” group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs. The online version of this article (doi:10.1007/s00401-017-1771-1) contains supplementary material, which is available to authorized users.
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影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
7.1
作者：
Aihara K;Mukasa A;Nagae G;Nomura M;Yamamoto S;Ueda H;Tatsuno K;Shibahara J;Takahashi M;Momose T;Tanaka S;Takayanagi S;Yanagisawa S;Nejo T;Takahashi S;Omata M;Otani R;Saito K;Narita Y;Nagane M;Nishikawa R;Ueki K;Aburatani H;Saito N
通讯作者：
Saito N
影响因子：
5.7
作者：
Esfandiari A;Hawthorne TA;Nakjang S;Lunec J
通讯作者：
Lunec J
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1402121
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cancer Genome Atlas Research Network;Brat DJ;Verhaak RG;Aldape KD;Yung WK;Salama SR;Cooper LA;Rheinbay E;Miller CR;Vitucci M;Morozova O;Robertson AG;Noushmehr H;Laird PW;Cherniack AD;Akbani R;Huse JT;Ciriello G;Poisson LM;Barnholtz-Sloan JS;Berger MS;Brennan C;Colen RR;Colman H;Flanders AE;Giannini C;Grifford M;Iavarone A;Jain R;Joseph I;Kim J;Kasaian K;Mikkelsen T;Murray BA;O'Neill BP;Pachter L;Parsons DW;Sougnez C;Sulman EP;Vandenberg SR;Van Meir EG;von Deimling A;Zhang H;Crain D;Lau K;Mallery D;Morris S;Paulauskis J;Penny R;Shelton T;Sherman M;Yena P;Black A;Bowen J;Dicostanzo K;Gastier-Foster J;Leraas KM;Lichtenberg TM;Pierson CR;Ramirez NC;Taylor C;Weaver S;Wise L;Zmuda E;Davidsen T;Demchok JA;Eley G;Ferguson ML;Hutter CM;Mills Shaw KR;Ozenberger BA;Sheth M;Sofia HJ;Tarnuzzer R;Wang Z;Yang L;Zenklusen JC;Ayala B;Baboud J;Chudamani S;Jensen MA;Liu J;Pihl T;Raman R;Wan Y;Wu Y;Ally A;Auman JT;Balasundaram M;Balu S;Baylin SB;Beroukhim R;Bootwalla MS;Bowlby R;Bristow CA;Brooks D;Butterfield Y;Carlsen R;Carter S;Chin L;Chu A;Chuah E;Cibulskis K;Clarke A;Coetzee SG;Dhalla N;Fennell T;Fisher S;Gabriel S;Getz G;Gibbs R;Guin R;Hadjipanayis A;Hayes DN;Hinoue T;Hoadley K;Holt RA;Hoyle AP;Jefferys SR;Jones S;Jones CD;Kucherlapati R;Lai PH;Lander E;Lee S;Lichtenstein L;Ma Y;Maglinte DT;Mahadeshwar HS;Marra MA;Mayo M;Meng S;Meyerson ML;Mieczkowski PA;Moore RA;Mose LE;Mungall AJ;Pantazi A;Parfenov M;Park PJ;Parker JS;Perou CM;Protopopov A;Ren X;Roach J;Sabedot TS;Schein J;Schumacher SE;Seidman JG;Seth S;Shen H;Simons JV;Sipahimalani P;Soloway MG;Song X;Sun H;Tabak B;Tam A;Tan D;Tang J;Thiessen N;Triche T Jr;Van Den Berg DJ;Veluvolu U;Waring S;Weisenberger DJ;Wilkerson MD;Wong T;Wu J;Xi L;Xu AW;Yang L;Zack TI;Zhang J;Aksoy BA;Arachchi H;Benz C;Bernard B;Carlin D;Cho J;DiCara D;Frazer S;Fuller GN;Gao J;Gehlenborg N;Haussler D;Heiman DI;Iype L;Jacobsen A;Ju Z;Katzman S;Kim H;Knijnenburg T;Kreisberg RB;Lawrence MS;Lee W;Leinonen K;Lin P;Ling S;Liu W;Liu Y;Liu Y;Lu Y;Mills G;Ng S;Noble MS;Paull E;Rao A;Reynolds S;Saksena G;Sanborn Z;Sander C;Schultz N;Senbabaoglu Y;Shen R;Shmulevich I;Sinha R;Stuart J;Sumer SO;Sun Y;Tasman N;Taylor BS;Voet D;Weinhold N;Weinstein JN;Yang D;Yoshihara K;Zheng S;Zhang W;Zou L;Abel T;Sadeghi S;Cohen ML;Eschbacher J;Hattab EM;Raghunathan A;Schniederjan MJ;Aziz D;Barnett G;Barrett W;Bigner DD;Boice L;Brewer C;Calatozzolo C;Campos B;Carlotti CG Jr;Chan TA;Cuppini L;Curley E;Cuzzubbo S;Devine K;DiMeco F;Duell R;Elder JB;Fehrenbach A;Finocchiaro G;Friedman W;Fulop J;Gardner J;Hermes B;Herold-Mende C;Jungk C;Kendler A;Lehman NL;Lipp E;Liu O;Mandt R;McGraw M;Mclendon R;McPherson C;Neder L;Nguyen P;Noss A;Nunziata R;Ostrom QT;Palmer C;Perin A;Pollo B;Potapov A;Potapova O;Rathmell WK;Rotin D;Scarpace L;Schilero C;Senecal K;Shimmel K;Shurkhay V;Sifri S;Singh R;Sloan AE;Smolenski K;Staugaitis SM;Steele R;Thorne L;Tirapelli DP;Unterberg A;Vallurupalli M;Wang Y;Warnick R;Williams F;Wolinsky Y;Bell S;Rosenberg M;Stewart C;Huang F;Grimsby JL;Radenbaugh AJ;Zhang J
通讯作者：
Zhang J