Recurrent epimutation of SDHC in gastrointestinal stromal tumors

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 (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.

Classification of gastrointestinal stromal tumor syndromes

“…Killian et al then confirmed these results, performing genomewide DNA methylation profiling and demonstrating that six of the 15 Carney triad patients had SDHC epimutation (Haller et al 2014, Killian et al 2014. Finally, very recently, SDHx mutations were found in patients with Carney triad, suggesting that the various SDH-deficient syndromes overlap significantly (Boikos et al 2016b).…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…Alternatively, targeted NGS panels can be designed to optimize detection of larger deletions, insertions or rearrangements, as reported in hereditary breast cancer diagnostic panels 45 . Finally, the existence of epimutations, such as those detected in the promoter of the SDHC gene should also be considered in cases where no mutations are detected 46,47 . Specific attention to the mode of inheritance and the existence of mosaicism are briefly discussed in BOX 1.…”

Carney triad can be (rarely) associated with germline succinate dehydrogenase defects

“…13 Recently, SDHC locus-specific methylation was found to be present in CTr tumors, 14 a defect that was also later described in GISTs that lack SDHB immunoreactivity but have no variations in the SDHx genes. 15 This was a distinct defect, separate from the overall increased methylation of the genome seen in lesions that bear SDHx defects. 16 and SDHC gene-specific methylation provide the most recent means of identification of a CTr-associated tumor, in the absence of a known causative genetic defect.…”