title: Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation.
abstract: A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA. miettinenmm@mail.nih.gov
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.forename: Jonathan Keith
authors.initials: JK
authors.lastname: Killian
authors.forename: Zeng-Feng
authors.initials: ZF
authors.lastname: Wang
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.forename: Laura
authors.initials: L
authors.lastname: Jones
authors.forename: Robert
authors.initials: R
authors.lastname: Walker
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.forename: Yuelin Jack
authors.initials: YJ
authors.lastname: Zhu
authors.forename: Su Y
authors.initials: SY
authors.lastname: Kim
authors.forename: Lee
authors.initials: L
authors.lastname: Helman
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D042963:Electron Transport Complex II / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D013385:Succinate Dehydrogenase / Q000172:deficiency*; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D042963:Electron Transport Complex II; C511268:SDHA protein, human; D013385:Succinate Dehydrogenase