title: 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.
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Yuelin Jack
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Waterfall
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Noyes
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Parvathy
authors.initials: P
authors.lastname: Retnakumar
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pathology, Suburban Hospital, Bethesda, MD 20814, USA.
authors.forename: William I
authors.initials: WI
authors.lastname: Smith
authors.affiliation: University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Killian
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: C Christopher
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Walling
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Stevenson
authors.affiliation: National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Carly
authors.initials: C
authors.lastname: Smith
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Zengfeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Sosipatros A
authors.initials: SA
authors.lastname: Boikos
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. pmeltzer@mail.nih.gov.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019175:DNA Methylation / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human