title: SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors.
abstract: Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-α. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C>T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands. l.oudijk@erasmusmc.nl
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.forename: José
authors.initials: J
authors.lastname: Gaal
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Lorna
authors.initials: L
authors.lastname: Kelly
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Michael A
authors.initials: MA
authors.lastname: den Bakker
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Oldenburg
authors.forename: Rosa L E
authors.initials: RL
authors.lastname: van Loon
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: O'Sullivan
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology; D002648:Child; D004252:DNA Mutational Analysis; D042963:Electron Transport Complex II / Q000235:genetics / Q000276:immunology; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D042963:Electron Transport Complex II; C511268:SDHA protein, human