Italiano et al. BMC Cancer 2012, 12:408 http://www.biomedcentral.com/1471-2407/12/408 R E S E A R C H A R T I C L E Open Access SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors Antoine Italiano1,2,6, Chun-Liang Chen1, Yun-Shao Sung1, Samuel Singer3, Ronald P DeMatteo3, Michael P LaQuaglia3, Peter Besmer4, Nicholas Socci5 and Cristina R Antonescu1* Abstract Background: A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II. Methods: Next generation sequencing was applied on five pediatric and one young adult WT GIST, by whole exome capture and SOLiD 3-plus system sequencing. The putative mutations were first confirmed by Sanger sequencing and then screened on a larger panel of 11 pediatric and young adult WT GIST, including 5 in the context of Carney triad. Results: A germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform. An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort. Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors. Results were further confirmed by immunohistochemistry for both SDHA and SDHB, which showed a concurrent loss of expression of both proteins in SDHA-mutant lesions, while the remaining WT tumors showed only loss of SDHB expression. Conclusions: Germline and/or somatic aberrations of SDHA occur in a small subset of KIT/PDGFRA WT GISTs, outside the Carney’s triad and are associated with loss of both SDHA and SDHB protein expression. Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults. Although pediatric GIST consistently display alterations of SDHB protein expression, further molecular studies are needed to identify the crucial genes involved in their tumorigenesis. Keywords: GIST, Pediatric, Wild-type, SDHA, SDHB, Succinate dehydrogenase complex II Background The majority of gastrointestinal stromal tumors (GIST) harbor gain-of-function mutations in KIT or PDGFRA, resulting in the activation of the down- stream pathways PI3K/AKT, Ras/MAPK, and JAK/ STAT3, and playing a crucial role in tumorigenesis [1,2]. A subset of GIST lack specific KIT or PDGFRA mutations and form a heterogeneous group, including * Correspondence: antonesc@mskcc.org 1Departments of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA Full list of author information is available at the end of the article NF1, Carney Triad (CT), Carney-Stratakis Syndrome (CSS), pediatric and young adult GIST, and a small proportion (<10%) of sporadic adult GIST [3-8]. The mechanisms involved in the tumorigenesis of GIST lacking KIT or PDGFRA mutations are still poorly understood. A subgroup of these GISTs forms a unique clinicopathological entity, defined by nega- tive staining for SDHB in addition to exhibiting dis- tinct morphologic and clinical features [9,10]. Indeed, such SDH-deficient GISTs account for 5–7.5% of all gastric GISTs in unselected populations and include the great majority of pediatric GISTs. They are © 2012 Italiano et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.