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SDHA Mutations in Adult and Pediatric Wild-Type Gastrointestinal Stromal

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SDHA Mutations in Adult and Pediatric Wild-Type Gastrointestinal Stromal Modern Pathology (2013) 26, 456–463 456 & 2013 USCAP, Inc All rights reserved 0893-3952/13 $32.00 SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors Lindsey Oudijk1,5 , Jose´ Gaal1,5, Esther Korpershoek1,5, Francien H van Nederveen1, Lorna Kelly2, Gaia Schiavon3, Jaap Verweij3, Ron HJ Mathijssen3, Michael A den Bakker1, Rogier A Oldenburg4, Rosa LE van Loon4, Maureen J O’Sullivan2, Ronald R de Krijger1 and Winand NM Dinjens1 1Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands; 2Department of Pathology, Our Lady’s Children’s Hospital, Dublin, Ireland; 3Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands and 4Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-a. 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 immunohis- tochemistry. 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.91C4T 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. Modern Pathology (2013) 26, 456–463; doi:10.1038/modpathol.2012.186; published online 23 November 2012 Keywords: gastrointestinal stromal tumor; immunohistochemistry; succinate dehydrogenase Gastrointestinal stromal tumor (GIST) is the most and in the small intestine (30%), other tumor sites common mesenchymal tumor of the digestive tract, include the esophagus, large bowel and rectum but accounts for o1% of all gastrointestinal neo- (10%).1,2,4 plasms.1–4 GISTs are derived from the interstitial Most GISTs (75–80%) harbor oncogenic mutations cells of Cajal and up to 95% of these tumors express in KIT (receptor for stem cell factor) and an CD117 (KIT).1,4–6 Approximately one-third to half of additional 7% in platelet-derived growth factor KIT-negative GISTs stain for DOG-1.3,7,8 The receptor-a (PDGFRA).2,5,6,9–11 These GISTs respond majority of GISTs arise in the stomach (50–60%) to targeted imatinib mesylate therapy, which inhibits tyrosine kinase activity.12,13 A small subset (10%) of GISTs lacking KIT or PDGFRA mutations 9 Correspondence: L Oudijk, BSc, Department of Pathology, are defined as wild-type GISTs. In pediatric Erasmus MC, University Medical Center Rotterdam, Josephine patients, 85% of GISTs are KIT/PDGFRA wild-type. Nefkens Institute, room Be201, PO Box 2040, Rotterdam, CA 3000, These occur mainly in girls, and usually have a The Netherlands. clinically indolent course.4,9,14,15 Unfortunately, E-mail: [email protected] 16 5These authors contributed equally to this work. wild-type GISTs respond poorly to imatinib. The Received 30 May 2012; revised 6 September 2012; accepted 14 pathogenetic mechanism in wild-type GISTs is still September 2012; published online 23 November 2012 not clearly understood. www.modernpathology.org SDHA mutations in gastrointestinal stromal tumors L Oudijk et al 457 Succinate dehydrogenase (SDH), an enzyme that control (granular staining in endothelial cells) was is involved in the fundamental processes of energy positive. production, participates in both the citric acid cycle If a tumor was scored negative with SDHB and the electron transport chain.17 SDH functions immunohistochemistry, but stained positive with not only in mitochondrial energy generation, but the SDHA, the entire SDHB, SDHC and SDHD coding genes encoding this enzyme also act as tumor sequences, including intron-exon boundaries, were suppressors. SDH consists of the subunits SDHA, analyzed for mutations. If SDHA immunohistoche- SDHB, SDHC and SDHD. Germline mutation in any mistry was negative, sequencing analysis of SDHA subunit predisposes individuals to hereditary para- (NM_004168) was performed. The entire SDHA gangliomas and pheochromocytomas.18 In addition, coding sequence, including intron–exon bound- mutations in these genes can also cause GISTs.9,10,19 aries, was analyzed for mutations, taking into The familial dyad of paraganglioma and GIST is also account the SDHA pseudogenes (NCBI: known as Carney–Stratakis syndrome.10,15 Carney NR_003263, NR_003264, NR_003265). DNA was triad describes the association of paragangliomas isolated according to manufacturer’s instructions with GISTs and pulmonary chondromas.15 GISTs (Gentra Systems, Minneapolis, MN or AllPrep DNA/ arising in the setting of Carney triad or Carney– RNA Mini Kit, Qiagen). Stratakis syndrome are also ‘wild-type GISTs’.15 When a mutation was found in tumor DNA, the In previous reports, we showed that negative presence of the mutation was also investigated in SDHA and SDHB immunohistochemistry reliably corresponding germline DNA isolated from paraffin- identifies pheochromocytomas and paragangliomas embedded healthy tissue surrounding the tumor. caused by germline mutations in SDHA, SDHB, Sequence analysis is a semiquantitative procedure SDHC and SDHD.20,21 In addition, Carney–Stratakis and supplies some information on the relative and Carney triad associated and wild-type pediatric amount of the mutated—versus the non-mutated— GISTs can be recognized by SDHB immunohisto- SDHA allele. To substantiate the relative presence of chemistry.17,22 the mutated—and non-mutated—SDHA allele, loss In this work, we performed SDHA immunohisto- of heterozygosity (LOH) analysis was performed in chemistry on 33 wild-type GISTs, including nine SDHA-mutated tumors for a polymorphic microsa- pediatric/adolescent GISTs, in order to investigate tellite marker at the SDHA locus. For this, PCRs whether immunohistochemistry could identify were carried out with fluorescence-labeled primers SDHA-mutated GISTs. (Invitrogen, Paisley, UK) (primer sequences are available on request) for 35 cycles with an annealing temperature of 60 1C, and amplified products were Materials and methods analyzed, along with LIZ 500 size standard (Applied Biosystems, Foster City, CA, USA), using capillary Twenty-four adult wild-type GISTs diagnosed in, or electrophoresis on an ABI 3130-XL genetic analyzer referred to, the Erasmus University Medical Center (Applied Biosystems). Data were analyzed using (Rotterdam, The Netherlands) between 1999 and GeneMarker software (Soft-Genetics LLC, State 2011 were included in this study. In addition, seven College, PA, USA). pediatric and two adolescent wild-type cases from the files of Professor M O’Sullivan, Dublin, were included in this study. We considered a GIST as ‘pediatric’ if the tumor was diagnosed below the age of 18 years and ‘adolescent’ if the age at diagnosis Results was 19–25 years. All these GISTs previously Case series resulted negative for KIT and PDGFRA mutations (KIT: exon 8, 9, 11, 13 and 17; PDGFRA: exon 12, 14 Case 1. A 41-year-old woman was diagnosed with and 18). Clinicopathological features of all these a gastric GIST. Microscopy showed an epithelioid cases are shown in Table 1. The tissues were used in morphology and the tumor cells stained positive for accordance with the code of conduct Proper Sec- CD117 and DOG-1 during routine diagnostic work- ondary Use of Human Tissue established by the up. Sequencing analysis of exons 8, 9, 11, 13 and 17 Dutch Federation of Medical Scientific Societies of the KIT proto-oncogene and exons 12, 14 and 18 (http://www.federa.org). The Medical Ethical Com- of the PDGFRA gene did not reveal mutations. In mittee of the Erasmus MC approved the study (MEC- previous research, this GIST was tested by SDHB 2011-519). immunohistochemistry.17 The GIST was First, all GISTs were analyzed with SDHB im- immunonegative for SDHB and SDHA (Figure 1). munohistochemistry. If the tumors were SDHB Mutational analysis revealed a germline SDHA negative, SDHA immunohistochemistry was per- mutation c.91 C4T leading to p.Arg31X. This formed. Immunohistochemical analysis was per- patient was homozygous (not informative) for the formed on 4–5 mm sections of formalin-fixed para- microsatellite marker, so we could not show LOH, ffin-embedded tumor as previously described.20,21 though relative loss of the wild-type allele was seen Slides were considered suitable if the internal in the sequencing graph (Figure
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