Recurrent epimutation of SDHC in gastrointestinal stromal tumors.
Recurrent epimutation of SDHC in gastrointestinal stromal tumors.
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DOI：
10.1126/scitranslmed.3009961
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发表时间：
2014-12-24
影响因子：
17.1
通讯作者：
Meltzer PS
中科院分区：
文献类型：
--
作者：
Killian JK;Miettinen M;Walker RL;Wang Y;Zhu YJ;Waterfall JJ;Noyes N;Retnakumar P;Yang Z;Smith WI Jr;Killian MS;Lau CC;Pineda M;Walling J;Stevenson H;Smith C;Wang Z;Lasota J;Kim SY;Boikos SA;Helman LJ;Meltzer PS
Succinate dehydrogenase (SDH) is a conserved effector of cellular metabolism and energy production, and loss of SDH function is a driver mechanism in several cancers. SDH-deficient gastrointestinal stromal tumors (dSDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT/PDGFRA mutations. dSDH GISTs often harbor deleterious mutations in SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx), but some are SDHx wild type (WT). To further elucidate mechanisms of SDH deactivation in SDHx-WT GIST, we performed targeted exome sequencing on 59 dSDH GISTs to identify 43 SDHx-mutant and 16 SDHx-WT cases. Genome-wide DNA methylation and expression profiling exposed SDHC promoter–specific CpG island hypermethylation and gene silencing in SDHx-WT dSDH GISTs [15 of 16 cases (94%)]. Six of 15 SDHC-epimutant GISTs occurred in the setting of the multitumor syndrome Carney triad. We observed neither SDHB promoter hypermethylation nor large deletions on chromosome 1q in any SDHx-WT cases. Deep genome sequencing of a 130-kbp (kilo–base pair) window around SDHC revealed no recognizable sequence anomalies in SDHC-epimutant tumors. More than 2000 benign and tumor reference tissues, including stem cells and malignancies with a hypermethylator epigenotype, exhibit solely a non-epimutant SDHC promoter. Mosaic constitutional SDHC promoter hypermethylation in blood and saliva from patients with SDHC-epimutant GIST implicates a postzygotic mechanism in the establishment and maintenance of SDHC epimutation. The discovery of SDHC epimutation provides a unifying explanation for the pathogenesis of dSDH GIST, whereby loss of SDH function stems from either SDHx mutation or SDHC epimutation.
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影响因子：
6
作者：
Killian, J. Keith;Bilke, Sven;Meltzer, Paul S.
通讯作者：
Meltzer, Paul S.
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
4
作者：
Baysal, BE;Willett-Brozick, JE;Ferrell, RE
通讯作者：
Ferrell, RE
影响因子：
5.6
作者：
Lasota, Jerzy;Wang, Zengfeng;Miettinen, Markku
通讯作者：
Miettinen, Markku
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y