In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 6, No. 268 ( 2014-12-24)
Abstract:
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 ( d SDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT / PDGFRA mutations. d SDH 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 d SDH 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 d SDH 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 d SDH GIST, whereby loss of SDH function stems from either SDHx mutation or SDHC epimutation.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.3009961
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2014
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