Document Detail

Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation.
MedLine Citation:
PMID:  23282968     Owner:  NLM     Status:  MEDLINE    
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.
Markku Miettinen; Jonathan Keith Killian; Zeng-Feng Wang; Jerzy Lasota; Christopher Lau; Laura Jones; Robert Walker; Marbin Pineda; Yuelin Jack Zhu; Su Y Kim; Lee Helman; Paul Meltzer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The American journal of surgical pathology     Volume:  37     ISSN:  1532-0979     ISO Abbreviation:  Am. J. Surg. Pathol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-14     Completed Date:  2013-03-05     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  7707904     Medline TA:  Am J Surg Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  234-40     Citation Subset:  IM    
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MeSH Terms
Aged, 80 and over
DNA Mutational Analysis
DNA, Neoplasm / analysis
Electron Transport Complex II / genetics*
Gastrointestinal Neoplasms / enzymology,  genetics*
Gastrointestinal Stromal Tumors / enzymology,  genetics*
Germ-Line Mutation*
Immunohistochemistry / methods
Middle Aged
Succinate Dehydrogenase / deficiency*
Young Adult
Grant Support
Reg. No./Substance:
0/DNA, Neoplasm; EC Transport Complex II; EC protein, human; EC Dehydrogenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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