Recurrent epimutation of SDHC in gastrointestinal stromal tumors

被引：151

作者：

Killian, J. Keith ^{[1
]}

Miettinen, Markku ^{[2
]}

Walker, Robert L. ^{[1
]}

Wang, Yonghong ^{[1
]}

Zhu, Yuelin Jack ^{[1
]}

Waterfall, Joshua J. ^{[1
]}

Noyes, Natalia ^{[1
]}

Retnakumar, Parvathy ^{[1
]}

Yang, Zhiming

Smith, William I., Jr. ^{[3
]}

Killian, M. Scott ^{[4
]}

Lau, C. Christopher ^{[1
]}

Pineda, Marbin ^{[1
]}

Walling, Jennifer ^{[1
]}

Stevenson, Holly ^{[1
]}

Smith, Carly ^{[5
]}

Wang, Zengfeng ^{[2
]}

Lasota, Jerzy ^{[2
]}

Kim, Su Young ^{[6
]}

Boikos, Sosipatros A. ^{[6
]}

Helman, Lee J. ^{[6
]}

Meltzer, Paul S. ^{[1
]}

机构：

[1] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA

[2] NIH, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA

[3] Suburban Hosp, Dept Pathol, Bethesda, MD 20814 USA

[4] Univ S Dakota, Vermillion, SD 57069 USA

[5] NHLBI, NIH, Bethesda, MD 20892 USA

[6] NIH, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2014年 / 6卷 / 268期

关键词：

CARNEY TRIAD; IDH2; MUTATIONS; SUCCINATE; HYPERMETHYLATION; PARAGANGLIOMA; RECEPTOR; INHIBITION; EXPRESSION; PHENOTYPE; HISTONE;

D O I：

10.1126/scitranslmed.3009961

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：9

共 30 条

[1] Molecular characterization of pediatric gastrointestinal stromal tumors [J].