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Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications

Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic... The discovery of underlying molecular genetic abnormalities in gastrointestinal stromal tumors (GISTs) such as activating mutations in the tyrosine kinase genes, KIT and platelet derived growth factor receptor-alpha (PDGFRA), has led to remarkable clinical advances in treatment. Small molecule inhibitors such as imatinib and sunitinib are known to inhibit the aberrantly activated KIT and PDGFRA receptor signaling and can lead to excellent clinical outcomes for patients with GIST. Though the majority of GISTs appear to arise sporadically, a number of families with high frequencies of GISTs have been reported and germline mutations have been identified. This review will highlight the various inherited mutations associated with familial GIST syndromes and describe how an improved understanding of these genetic syndromes has important clinical implications for future understanding of this heterogeneous disease. Keywords: Gastrointestinal stromal tumor, c-KIT, Platelet-derived growth factor-alpha, Neurofibromatosis, Carney triad, Carney-stratakis syndrome, Succinate dehydrogenase Introduction over the time period of data collection may have Gastrointestinal stromal tumors (GISTs) are the most accounted for some of the variation. No specific epi- common mesenchymal tumors arising in the gastro- demiological risk factors for GIST have been described. intestinal tract [1,2]. Though the majority of GISTs ap- The majority of GISTs appear to be sporadic, but a pear to arise sporadically, a number of families with high number of families with inherited predisposition to frequencies of GISTs have been reported and germline GISTs have been identified. The first family with features mutations have been identified [3]. The true frequency consistent with inherited GIST was reported in 1990, of all GIST diagnoses has been difficult to determine be- but it was not until 1998 that Nishida and colleagues cause the definition of GIST was derived in 1990 before identified the first germline mutation associated with fa- it was molecularly characterized. One United States re- milial predisposition to GIST [8,9]. In this Japanese fam- port from the Surveillance, Epidemiology, and End ily, three individuals in two generations were diagnosed Results (SEER) database indicated that, from 1992 to with multiple GISTs. The germline DNA of the available 2000, the yearly incidence rate in the United States was affected family members contained a mutation in exon 6.8 cases per million [4]. The reported US annual inci- 11 of c-KIT, which resulted in deletion of a valine resi- dence rate is slightly lower than incidence rates reported due at codon 559_560 in the juxta-membrane domain of in several international epidemiological studies with the KIT protein. This same mutation was observed in highest described incidence of 14.5 cases per million in the subjects’ GIST tumors and resulted in constitutive Sweden [5-7]. Discrepancies between diagnostic criteria activation of KIT. Since this first description of a family with an exon 11 * Correspondence: robsonm@mskcc.org KIT mutation, multiple other families with inherited Department of Medicine, Memorial Sloan-Kettering Cancer Center, New GIST syndromes have been described. Though many York, NY, USA have been found to have exon 11 KIT mutations, others Clinical Genetics and Breast Cancer Medicine Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA have alternative KIT mutations or mutations involving Full list of author information is available at the end of the article © 2012 Postow and Robson; 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. Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 2 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 PDGFRA, neurofibromatosis- 1 (NF1), and succinate de- the KIT juxta-membrane domain [31]. Another exon 11 hydrogenase (SDH) genes [10-29]. Similarities exist KIT juxta-membrane missense mutation (W557R) was among the clinical features of these various germline fa- described in a family consisting of 19 individuals of Ital- milial GIST mutations, but each germline mutation can ian ancestry who had variable expression of clinical manifest differently (Table 1). phenotype involving hyperpigmentation and dysphagia [26]. Although the development of GIST was nearly uni- C-kit mutations form in this kindred, not all family members harboring Paralleling the high frequency of KIT mutations in spor- this specific germline mutation had hyperpigmentation adic GIST, most reported inherited GISTs have involved or dysphagia, suggesting a degree of variability of expres- families with germline mutations in the KIT gene, com- sion, even within a family with a specific KIT germline monly in exon 11, which encodes the juxta-membrane mutation. domain. In addition to the development of GISTs, these KIT exon 11 mutations are not the only KIT mutations families manifest variable clinical phenotypes that typic- implicated in familial GIST syndromes. Hirota et al. ally also include hyperpigmentation, urticaria pigment- (2002) reported the first identified family with a germline osa, and dysphagia. The specific KIT exon 11 deletion mutation in exon 17, encoding the KIT tyrosine kinase II mutation described in the first family with an identified domain [32]. Though the precise clinical phenotype of germline mutation in familial GIST, does not seem to be KIT mutations may be influenced by reporting, none of required for the familial GIST syndrome as a similar the members of this family with KIT tyrosine kinase II clinical phenotype involving hyperpigmentation and domain mutations had hyperpigmentation, differing from GIST predisposition was seen in a Spanish family with some families with KIT exon 11 mutations. Dysphagia, an alternative exon 11 KIT mutation consisting of a du- however, was a common similar complaint and suggests plication of the sequence CAACTT [30]. dysphagia may be a feature more characteristic of germ- Missense mutations involving exon 11 have been line KIT mutations in general, rather than associated implicated in similar familial GIST syndromes. Several with a specific mutation. families have to found with germline point mutations A third KIT mutation in exon 13 encoding the tyro- leading to the substitution of alanine for valine (559) in sine kinase I domain, has also been implicated in familial Table 1 Germline Mutations Associated with GIST Predisposition and Associated Clinical Features Gene (Exon) Mutation General Clinical Features Reference C-KIT (11) V559del Hyperpigmentation, urticaria pigmentosa, dysphagia Nishida 1998 [9] CAACTTdup Carballo 2005 [11] V559A Beghini 2001 [30] W557R Maeyama 2001 [31] Robson 2004 [26] C-KIT (17) D820Y Dysphagia but no hyperpigmentation Hirota 2002 [32] C-KIT (13) K642E No hyperpigmentation and no urticaria pigmentosa Isozaki 2000 [33] Graham 2007 [34] PDGFRA* D846Y Large hands Chompret 2004 [35] Y555C Lipomas and small intestine fibrous tumors de Raedt 2006 [36] V561D Pasini 2007 [37] NF1** Many various mutations in Café au lait spots, dermal neurofibromas, Relles 2010 [38] NF1 gene (>300 identified) axillary/inguinal freckling, ocular hamartomas SDHB, SDHC, and SDHD*** SDHB IVS1 + 1 G! T Paraganglioma and pheochromocytoma Carney 2002 [39] SDHB c.423 + 1 G! C (Carney-Stratakis Syndrome) McWhinney 2007 [40] SDHB c.45_46insCC SDHC c.43 + 1 C! T SDHC IVS5 + 1 G! A SDHD c.57delG *Platelet derived growth factor receptor-alpha. **Neurofibromin 1. ***Succinate dehydrogenase (B, C, and D). Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 3 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 GIST syndrome. Families have been described that have neurofibromatosis is a specific subtype of KIT negative, single base mutations in the tyrosine kinase I domain familial GIST, associated with PDGFRA mutations and resulting in a substitution of Glu for Lys (642) [33,34]. A not a completely distinct disease. Affected individuals predisposition to GIST was present in these families but had large hands, a finding similar to other families not hyperpigmentation or urticaria pigmentosa, provid- described with inherited GIST and PDGFRA mutations, ing further support to the fact that specific KIT germline though not described in familial GIST associated with mutations may lead to variable clinical phenotypes. KIT germline mutations. None of the other related clin- Mouse models with “knock-in” mutations, represent- ical manifestations of inherited GIST (dysphagia, hyper- ing inherited GIST syndromes, additionally support the pigmentation, urticaria pigmentosa) associated with slightly different clinical phenotypes associated with spe- germline KIT mutations was seen in patients with cific KIT mutations. Mice with the V558del mutation PDGFRA mutations. (corresponding to the human exon 11 deletion muta- A third PDGFRA germline missense mutation (V561D) tion) as well as the D818Y mutation (corresponding to involving exon 12 was identified in a young female pa- human exon 17 missense mutation) had interstitial cell tient with several gastric GISTs [37]. This patient’s alter- of Cajal hyperplasia and GISTs [41,42]. Only mice with native germline PDGFRA mutation may have resulted in V558del had increased dermal mast cells, a finding not her slightly different phenotype as she was noted to have, seen in mice with the D818Y mutation. This suggests in addition to gastric GISTs, multiple lipomas and fibrous the specific KIT exon 11 mutation may be required for tumors of her small intestine. Lipomas and fibrous the feature of urticaria pigmentosa whereas development tumors of the small intestine were not previously part of of GIST may be a more generalized phenomenon, asso- other families described [35,36] with PDGFRA mutations ciated with a broad spectrum of KIT activating germline and predisposition to GIST nor where they a feature of mutations. Despite the suggestion of genotype specific families with KIT germline mutations. clinical features, variability in patient reporting of add- itional components of the inherited GIST syndrome may Neurofibromatosis type 1; von Recklinghausen’s complicate precise genotype-phenotype correlations as disease (NF1) suggested in one report [26]. NF1 is a common genetic disorder occurring in approxi- mately 1 in every 3,000 live births. The disease is classic- PDGFRA mutations ally associated with café au lait spots, multiple dermal Though the majority of described inherited GIST syn- neurofibromas, axillary and inguinal freckling, and ocu- dromes have been associated with germline KIT muta- lar hamartomas [43]. NF1 is inherited in an autosomal tions, several families with inherited predisposition to dominant manner, and the mutated NF1 protein encodes GISTs have been described with germline PDGFRA the GTPase activating protein neurofibromin. mutations. One French family with five affected indivi- Patients with NF1 have been felt to be at increased risk duals was found to have a germline PDGFRA missense of a variety of GI tumors. A previous report reviewing mutation (2675 G > T), resulting in a tyrosine substitu- the literature found that 34% of GI tract malignancies in tion for the highly conserved aspartic amino acid at patients with NF1 were GISTs [38]. NF1 associated codon 846 which showed perfect cosegregation with the GISTs are somewhat different than typical sporadic GIST phenotype in the tested family members [35]. GISTs as NF1 associated GISTs typically have neither Affected individuals also had large hands whereas those mutated KIT nor PDGFRA genes [44,45]. One series, without the mutation, did not. Interestingly, the nevertheless, reported that a small number of NF1 PDGFRA Asp846Tyr mutation identified in this family is patients did have KIT and PDGFRA mutations [46]. homologous to codon 820, located on the KIT tyrosine Since the majority of GISTs associated with NF1 muta- kinase II domain, the site of inherited GIST involving a tions do not have c-KIT or PDGFRA mutations, NF1 Japanese kindred of six affected family members [32]. associated GISTs may have alternative pathogenesis Other PDGFRA mutations, in addition to Asp846Tyr, which may result in different clinical outcomes. The have been associated with inherited GIST. Three sisters majority of the tumors from patients in the series by who were affected with intestinal neurofibromatosis in Miettinen et al. 2006 had small, mitotically inactive an autosomal dominant pattern of inheritance, without tumors, and the majority of patients in this series with other manifestations of neurofibromatosis 1 (NF1) or long-term follow-up had good prognosis [44]. Whether neurofibromatosis 2 (NF2), underwent genetic screening, NF1 associated GISTs arise from a completely KIT inde- and a PDGFRA Y555C mutation, located in the juxta- pendent process or whether the mutated neurofibromin membrane domain, was identified [36]. The similarity of protein indirectly activates KIT pathways carries signifi- these tumors’ genetic composition and clinical phenotype cant clinical implications. Therapies that directly target to GIST led the authors to conclude that intestinal KIT such as imatinib may not be effective in patients Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 4 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 with NF1 associated GIST. Despite the lack of KIT contrasted starkly with KIT and PDGFRA mutant GIST mutations in most cases of NF1 GIST, one case report samples which all stained strongly for SDHB [12]. indicated disease stabilization with sunitinib [47]. Though mutations in SDHB, SDHC, and SDHD, have been described most thoroughly, recently two young Succinate dehydrogenase mutations patients with GIST were found to have detectable muta- Succinate dehydrogenase (SDH) is an enzyme localized tions in SDHA, representing the first described cases of to the inner mitochondrial membrane and is integral to SDHA inactivation in GIST [51]. cellular respiration by participating in both the citric acid cycle and the electron transport chain. SDH is com- Deletions in chromosome 1 involving succinate posed of four subunits (A-D), and mutations in the SDH dehydrogenase C genes encoding each subunit have been associated with Due to associations between SDH mutations and various human diseases [48]. Not surprisingly, a number patients with paraganglioma and GIST syndromes, the of these diseases involve disordered mitochondrial res- presence of SDH mutations was evaluated in patients piration, resulting in severe metabolic and neurologic with Carney Triad (CT), a similar, though distinct, syn- dysfunction. drome from CSS [52]. CT is felt to be non-hereditary In addition to SDH’s critical role in cellular respiration, and consists of having at least two of the triad of para- SDH is believed to function as a tumor suppressor. ganglioma, GIST, and pulmonary chordoma. CT was Mutations in SDH subunits B (SDHB), C (SDHC), and first described in 1977 when Carney and colleagues D (SDHD), in particular, have been associated with fa- reported seven unrelated women with the triad [14]. In milial cancer predisposition syndromes with affected 2007, comparative genomic hybridization studies were individuals at increased risk for the development of performed on 41 tumor samples from 37 patients with paragangliomas and pheochromocytomas [10]. In 2002, CT, and though no tumors had coding sequence muta- 12 individuals from five unrelated families were found to tions of the investigated SDH genes, a number of DNA have developed paragangliomas and GISTs, and the copy changes were seen [52]. Particularly, deletions of Carney-Stratakis Syndrome (CSS) was described [39]. chromosome 1p and 1q12-q21, the site of the SDHC CSS appears to be an autosomal dominant syndrome gene, were found. Interestingly, other classic mutations with incomplete penetrance characterized by the devel- associated with GIST such as KIT and PDGFRA were opment of paraganglioma, GIST, or both. CSS has a vari- not found in these tumor specimens from patients with able phenotypic expression as demonstrated by a report CT. This finding is consistent with results from other of monozygotic twins with CSS where one developed a studies [15,53], raising the possibility that GISTs in CT paraganglioma and the other GIST [49]. To better arise from alternative pathologic mechanisms from most characterize the germline mutations present in patients sporadic GISTs. with CSS, genetic sequencing was performed for six Consistent with an alternative genetic and possible individuals in six unrelated families, and mutations in pathologic mechanism of tumorigenesis, GISTs in CT SDHB, SDHC, and SDHD, were identified [40]. Differing behave differently clinically from most sporadic GISTs as from most sporadic GISTs, no mutations in KIT or they affect young women and have been associated with PDGFRA were seen. frequent lymph node metastasis, multifocality, and un- Additional recent work has confirmed the important predictable behavior [20]. In a review published in 1999, role SDH plays in the pathogenesis of GISTs. A study of Carney described a higher rate of gastric GIST and 34 GIST patients without KIT or PDGFRA mutations metastatic disease at presentation [29]. How deletions of (WT GIST) revealed that four patients (12%) had SDH chromosome 1p and 1q (in the region of the SDHC germline mutations, even in the absence of a family or gene) contribute to the alternative clinical behavior of personal history of paragangliomas. Further, even in GISTs associated with CT remains to be explained. patients without germline SDH mutations, patients with WT GISTs had complete loss or markedly reduced Treatment of patients with inherited GIST SDHB protein expression compared to patients with Although various germline mutations have been asso- KIT mutant GIST. This further suggests the important ciated with heterogeneous clinical syndromes, no data role of SDH in the pathogenesis of GIST, in addition to currently exist that inherited GIST should be treated dif- cases where a germline mutation in SDH is found [50]. ferently from its sporadic counterpart. Nevertheless, on a The finding of absent or low levels of SDH protein in theoretical basis, increasing knowledge of the various patients with CSS was confirmed by a study showing germline mutations associated with hereditary GIST sug- that none of the four patients with CSS had positive gests that different clinical approaches may ultimately immunohistochemical staining for SDHB, even though show increased benefit. For example, when GIST is only one was found to have a germline mutation. This present in patients with paragangliomas (Carney-Stratakis Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 5 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 Syndrome), due to the lack of mutations in KIT and GIST, particularly wild-type inherited GIST, may lead to PDGFRA (WT GIST), these tumors theoretically may be improved understanding of perturbed molecular path- less sensitive to imatinib. This may also be true for inher- ways in sporadic GIST as well. For instance, the recogni- ited GIST associated with NF1 mutations as KIT muta- tion of genetic abnormalities in SDH in GISTs that are tions are only found in small proportions of NF1 GIST. not associated with KIT and PDGFRA mutations intro- Clinical data are not yet available to address these theoret- duces a new avenue of research that may have relevance ical speculations. for sporadic disease. Inherited GIST associated with CSS has been shown to Abbreviations be related to deficits in SDH, and improved understand- CSS: Carney-Stratakis syndrome; CT: Carney triad; GIST: Gastrointestinal ing of the mechanisms surrounding SDH regulation may stromal tumor; NF1: Neurofibromatosis-1; NF2: Neurofibromatosis-2; PDGFRA: Platelet derived growth factor receptor-alpha; SEER: Surveillance lead to future therapeutic approaches. Unfortunately, epidemiology and end results; SDH: Succinate dehydrogenase; WT: Wild patients with advanced WT GIST when treated with type. imatinib had decreased objective response, time to Competing interests tumor progression, and overall survival compared to The authors declare that they have no competing interests. patients with KIT exon 11 mutations [54]. Mutations in SDH and NF1 may explain the non-KIT mediated Authors’ contributions pathogenesis in patients with WT GIST, and patients MP collected the references and wrote the first draft of the manuscript. MR revised the manuscript and provided intellectual guidance in support of the with inherited SDH mutations, and possibly NF1 muta- content of this project. Both authors read and approved the final manuscript. tions, may ultimately benefit from alternative targeted treatment. The relationship between SDH and NF1 to Authors’ information MP is a medical oncology fellow in the Melanoma/Sarcoma Oncology GIST pathogenesis will first need to be further clarified. Service at Memorial Sloan-Kettering Cancer Center. MR is the clinic director Patients whose GISTs are characterized by a deficiency of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in SDHB by immunohistochemistry have been described and a member of the Breast Cancer Medicine Service. to have a somewhat different clinical course from the Acknowledgements majority of GIST patients. Specifically, one study found None. that deficiency of SDHB was associated with a female Author details predominance, gastric primary location, lymph node in- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New volvement, and similar morphology to GIST arising in York, NY, USA. Clinical Genetics and Breast Cancer Medicine Services, pediatric patients [55]. Since these patients’ GISTs fol- Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Weill Cornell Medical College of Cornell University, New York, NY, USA. lowed a more indolent course, SDHB deficient tumors may ultimately need to be managed differently. Received: 12 August 2011 Accepted: 19 December 2011 Sunitinib may be particularly helpful for patients with Published: 4 October 2012 GIST who develop resistance or intolerance to imatinib. References A study involving 97 patients with metastatic, imatinib- 1. Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, Corless CL, resistant/intolerant GIST, demonstrated the particular Debiec-Rychter M, DeMatteo RP, Ettinger DS, Fisher GA, Fletcher CD, efficacy of sunitinib in patients with primary exon 9 and Gronchi A, Hohenberger P, Hughes M, Joensuu H, Judson I, Le Cesne A, Maki RG, Morse M, Pappo AS, Pisters PW, Raut CP, Reichardt P, Tyler DS, WT GIST [56,57]. 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QJM 2009, 102:649–653. multiple GIST family with KIT-Asp820Tyr mutation generated by a 24. Qiao GB, Zeng WS, Peng LJ, Zhong WZ, Fang Y, Huang WJ, Wu YL: Multiple knock-in strategy. J Pathol 2008, 214:302–311. pulmonary chondromas in a young female patient: a component of Carney triad. J Thorac Oncol 2009, 4:751–752. 43. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, 25. Alberto VO, Kelleher D, Denholm RB, Nutt M, Carney JA: A calcified lung Rubenstein A, Viskochil D: The diagnostic evaluation and multidisciplinary tumour and microcytic anaemia in a young woman: partial expression of management of neurofibromatosis 1 and neurofibromatosis 2. the Carney triad. Surgeon 2008, 6:249–251. JAMA 1997, 278:51–57. Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 7 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 44. 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Wozniak A, Floris G, Debiec-Rychter M, Sciot R, Schöffski P: Implications of • Thorough peer review mutational analysis for the management of patients with • No space constraints or color figure charges gastrointestinal stromal tumors and the application of targeted therapies. Cancer Invest 2010, 28:839–848. • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar doi:10.1186/2045-3329-2-16 Cite this article as: Postow and Robson: Inherited gastrointestinal • Research which is freely available for redistribution stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clinical Sarcoma Research 2012 2:16. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications

Postow, Michael; Robson, Mark
Clinical Sarcoma Research , Volume 2 (1) – Oct 4, 2012
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Springer Journals
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Copyright © 2012 by Postow and Robson; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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2045-3329
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10.1186/2045-3329-2-16
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23036227
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Abstract

The discovery of underlying molecular genetic abnormalities in gastrointestinal stromal tumors (GISTs) such as activating mutations in the tyrosine kinase genes, KIT and platelet derived growth factor receptor-alpha (PDGFRA), has led to remarkable clinical advances in treatment. Small molecule inhibitors such as imatinib and sunitinib are known to inhibit the aberrantly activated KIT and PDGFRA receptor signaling and can lead to excellent clinical outcomes for patients with GIST. Though the majority of GISTs appear to arise sporadically, a number of families with high frequencies of GISTs have been reported and germline mutations have been identified. This review will highlight the various inherited mutations associated with familial GIST syndromes and describe how an improved understanding of these genetic syndromes has important clinical implications for future understanding of this heterogeneous disease. Keywords: Gastrointestinal stromal tumor, c-KIT, Platelet-derived growth factor-alpha, Neurofibromatosis, Carney triad, Carney-stratakis syndrome, Succinate dehydrogenase Introduction over the time period of data collection may have Gastrointestinal stromal tumors (GISTs) are the most accounted for some of the variation. No specific epi- common mesenchymal tumors arising in the gastro- demiological risk factors for GIST have been described. intestinal tract [1,2]. Though the majority of GISTs ap- The majority of GISTs appear to be sporadic, but a pear to arise sporadically, a number of families with high number of families with inherited predisposition to frequencies of GISTs have been reported and germline GISTs have been identified. The first family with features mutations have been identified [3]. The true frequency consistent with inherited GIST was reported in 1990, of all GIST diagnoses has been difficult to determine be- but it was not until 1998 that Nishida and colleagues cause the definition of GIST was derived in 1990 before identified the first germline mutation associated with fa- it was molecularly characterized. One United States re- milial predisposition to GIST [8,9]. In this Japanese fam- port from the Surveillance, Epidemiology, and End ily, three individuals in two generations were diagnosed Results (SEER) database indicated that, from 1992 to with multiple GISTs. The germline DNA of the available 2000, the yearly incidence rate in the United States was affected family members contained a mutation in exon 6.8 cases per million [4]. The reported US annual inci- 11 of c-KIT, which resulted in deletion of a valine resi- dence rate is slightly lower than incidence rates reported due at codon 559_560 in the juxta-membrane domain of in several international epidemiological studies with the KIT protein. This same mutation was observed in highest described incidence of 14.5 cases per million in the subjects’ GIST tumors and resulted in constitutive Sweden [5-7]. Discrepancies between diagnostic criteria activation of KIT. Since this first description of a family with an exon 11 * Correspondence: robsonm@mskcc.org KIT mutation, multiple other families with inherited Department of Medicine, Memorial Sloan-Kettering Cancer Center, New GIST syndromes have been described. Though many York, NY, USA have been found to have exon 11 KIT mutations, others Clinical Genetics and Breast Cancer Medicine Services, Memorial Sloan-Kettering Cancer Center, New York, NY, USA have alternative KIT mutations or mutations involving Full list of author information is available at the end of the article © 2012 Postow and Robson; 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. Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 2 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 PDGFRA, neurofibromatosis- 1 (NF1), and succinate de- the KIT juxta-membrane domain [31]. Another exon 11 hydrogenase (SDH) genes [10-29]. Similarities exist KIT juxta-membrane missense mutation (W557R) was among the clinical features of these various germline fa- described in a family consisting of 19 individuals of Ital- milial GIST mutations, but each germline mutation can ian ancestry who had variable expression of clinical manifest differently (Table 1). phenotype involving hyperpigmentation and dysphagia [26]. Although the development of GIST was nearly uni- C-kit mutations form in this kindred, not all family members harboring Paralleling the high frequency of KIT mutations in spor- this specific germline mutation had hyperpigmentation adic GIST, most reported inherited GISTs have involved or dysphagia, suggesting a degree of variability of expres- families with germline mutations in the KIT gene, com- sion, even within a family with a specific KIT germline monly in exon 11, which encodes the juxta-membrane mutation. domain. In addition to the development of GISTs, these KIT exon 11 mutations are not the only KIT mutations families manifest variable clinical phenotypes that typic- implicated in familial GIST syndromes. Hirota et al. ally also include hyperpigmentation, urticaria pigment- (2002) reported the first identified family with a germline osa, and dysphagia. The specific KIT exon 11 deletion mutation in exon 17, encoding the KIT tyrosine kinase II mutation described in the first family with an identified domain [32]. Though the precise clinical phenotype of germline mutation in familial GIST, does not seem to be KIT mutations may be influenced by reporting, none of required for the familial GIST syndrome as a similar the members of this family with KIT tyrosine kinase II clinical phenotype involving hyperpigmentation and domain mutations had hyperpigmentation, differing from GIST predisposition was seen in a Spanish family with some families with KIT exon 11 mutations. Dysphagia, an alternative exon 11 KIT mutation consisting of a du- however, was a common similar complaint and suggests plication of the sequence CAACTT [30]. dysphagia may be a feature more characteristic of germ- Missense mutations involving exon 11 have been line KIT mutations in general, rather than associated implicated in similar familial GIST syndromes. Several with a specific mutation. families have to found with germline point mutations A third KIT mutation in exon 13 encoding the tyro- leading to the substitution of alanine for valine (559) in sine kinase I domain, has also been implicated in familial Table 1 Germline Mutations Associated with GIST Predisposition and Associated Clinical Features Gene (Exon) Mutation General Clinical Features Reference C-KIT (11) V559del Hyperpigmentation, urticaria pigmentosa, dysphagia Nishida 1998 [9] CAACTTdup Carballo 2005 [11] V559A Beghini 2001 [30] W557R Maeyama 2001 [31] Robson 2004 [26] C-KIT (17) D820Y Dysphagia but no hyperpigmentation Hirota 2002 [32] C-KIT (13) K642E No hyperpigmentation and no urticaria pigmentosa Isozaki 2000 [33] Graham 2007 [34] PDGFRA* D846Y Large hands Chompret 2004 [35] Y555C Lipomas and small intestine fibrous tumors de Raedt 2006 [36] V561D Pasini 2007 [37] NF1** Many various mutations in Café au lait spots, dermal neurofibromas, Relles 2010 [38] NF1 gene (>300 identified) axillary/inguinal freckling, ocular hamartomas SDHB, SDHC, and SDHD*** SDHB IVS1 + 1 G! T Paraganglioma and pheochromocytoma Carney 2002 [39] SDHB c.423 + 1 G! C (Carney-Stratakis Syndrome) McWhinney 2007 [40] SDHB c.45_46insCC SDHC c.43 + 1 C! T SDHC IVS5 + 1 G! A SDHD c.57delG *Platelet derived growth factor receptor-alpha. **Neurofibromin 1. ***Succinate dehydrogenase (B, C, and D). Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 3 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 GIST syndrome. Families have been described that have neurofibromatosis is a specific subtype of KIT negative, single base mutations in the tyrosine kinase I domain familial GIST, associated with PDGFRA mutations and resulting in a substitution of Glu for Lys (642) [33,34]. A not a completely distinct disease. Affected individuals predisposition to GIST was present in these families but had large hands, a finding similar to other families not hyperpigmentation or urticaria pigmentosa, provid- described with inherited GIST and PDGFRA mutations, ing further support to the fact that specific KIT germline though not described in familial GIST associated with mutations may lead to variable clinical phenotypes. KIT germline mutations. None of the other related clin- Mouse models with “knock-in” mutations, represent- ical manifestations of inherited GIST (dysphagia, hyper- ing inherited GIST syndromes, additionally support the pigmentation, urticaria pigmentosa) associated with slightly different clinical phenotypes associated with spe- germline KIT mutations was seen in patients with cific KIT mutations. Mice with the V558del mutation PDGFRA mutations. (corresponding to the human exon 11 deletion muta- A third PDGFRA germline missense mutation (V561D) tion) as well as the D818Y mutation (corresponding to involving exon 12 was identified in a young female pa- human exon 17 missense mutation) had interstitial cell tient with several gastric GISTs [37]. This patient’s alter- of Cajal hyperplasia and GISTs [41,42]. Only mice with native germline PDGFRA mutation may have resulted in V558del had increased dermal mast cells, a finding not her slightly different phenotype as she was noted to have, seen in mice with the D818Y mutation. This suggests in addition to gastric GISTs, multiple lipomas and fibrous the specific KIT exon 11 mutation may be required for tumors of her small intestine. Lipomas and fibrous the feature of urticaria pigmentosa whereas development tumors of the small intestine were not previously part of of GIST may be a more generalized phenomenon, asso- other families described [35,36] with PDGFRA mutations ciated with a broad spectrum of KIT activating germline and predisposition to GIST nor where they a feature of mutations. Despite the suggestion of genotype specific families with KIT germline mutations. clinical features, variability in patient reporting of add- itional components of the inherited GIST syndrome may Neurofibromatosis type 1; von Recklinghausen’s complicate precise genotype-phenotype correlations as disease (NF1) suggested in one report [26]. NF1 is a common genetic disorder occurring in approxi- mately 1 in every 3,000 live births. The disease is classic- PDGFRA mutations ally associated with café au lait spots, multiple dermal Though the majority of described inherited GIST syn- neurofibromas, axillary and inguinal freckling, and ocu- dromes have been associated with germline KIT muta- lar hamartomas [43]. NF1 is inherited in an autosomal tions, several families with inherited predisposition to dominant manner, and the mutated NF1 protein encodes GISTs have been described with germline PDGFRA the GTPase activating protein neurofibromin. mutations. One French family with five affected indivi- Patients with NF1 have been felt to be at increased risk duals was found to have a germline PDGFRA missense of a variety of GI tumors. A previous report reviewing mutation (2675 G > T), resulting in a tyrosine substitu- the literature found that 34% of GI tract malignancies in tion for the highly conserved aspartic amino acid at patients with NF1 were GISTs [38]. NF1 associated codon 846 which showed perfect cosegregation with the GISTs are somewhat different than typical sporadic GIST phenotype in the tested family members [35]. GISTs as NF1 associated GISTs typically have neither Affected individuals also had large hands whereas those mutated KIT nor PDGFRA genes [44,45]. One series, without the mutation, did not. Interestingly, the nevertheless, reported that a small number of NF1 PDGFRA Asp846Tyr mutation identified in this family is patients did have KIT and PDGFRA mutations [46]. homologous to codon 820, located on the KIT tyrosine Since the majority of GISTs associated with NF1 muta- kinase II domain, the site of inherited GIST involving a tions do not have c-KIT or PDGFRA mutations, NF1 Japanese kindred of six affected family members [32]. associated GISTs may have alternative pathogenesis Other PDGFRA mutations, in addition to Asp846Tyr, which may result in different clinical outcomes. The have been associated with inherited GIST. Three sisters majority of the tumors from patients in the series by who were affected with intestinal neurofibromatosis in Miettinen et al. 2006 had small, mitotically inactive an autosomal dominant pattern of inheritance, without tumors, and the majority of patients in this series with other manifestations of neurofibromatosis 1 (NF1) or long-term follow-up had good prognosis [44]. Whether neurofibromatosis 2 (NF2), underwent genetic screening, NF1 associated GISTs arise from a completely KIT inde- and a PDGFRA Y555C mutation, located in the juxta- pendent process or whether the mutated neurofibromin membrane domain, was identified [36]. The similarity of protein indirectly activates KIT pathways carries signifi- these tumors’ genetic composition and clinical phenotype cant clinical implications. Therapies that directly target to GIST led the authors to conclude that intestinal KIT such as imatinib may not be effective in patients Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 4 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 with NF1 associated GIST. Despite the lack of KIT contrasted starkly with KIT and PDGFRA mutant GIST mutations in most cases of NF1 GIST, one case report samples which all stained strongly for SDHB [12]. indicated disease stabilization with sunitinib [47]. Though mutations in SDHB, SDHC, and SDHD, have been described most thoroughly, recently two young Succinate dehydrogenase mutations patients with GIST were found to have detectable muta- Succinate dehydrogenase (SDH) is an enzyme localized tions in SDHA, representing the first described cases of to the inner mitochondrial membrane and is integral to SDHA inactivation in GIST [51]. cellular respiration by participating in both the citric acid cycle and the electron transport chain. SDH is com- Deletions in chromosome 1 involving succinate posed of four subunits (A-D), and mutations in the SDH dehydrogenase C genes encoding each subunit have been associated with Due to associations between SDH mutations and various human diseases [48]. Not surprisingly, a number patients with paraganglioma and GIST syndromes, the of these diseases involve disordered mitochondrial res- presence of SDH mutations was evaluated in patients piration, resulting in severe metabolic and neurologic with Carney Triad (CT), a similar, though distinct, syn- dysfunction. drome from CSS [52]. CT is felt to be non-hereditary In addition to SDH’s critical role in cellular respiration, and consists of having at least two of the triad of para- SDH is believed to function as a tumor suppressor. ganglioma, GIST, and pulmonary chordoma. CT was Mutations in SDH subunits B (SDHB), C (SDHC), and first described in 1977 when Carney and colleagues D (SDHD), in particular, have been associated with fa- reported seven unrelated women with the triad [14]. In milial cancer predisposition syndromes with affected 2007, comparative genomic hybridization studies were individuals at increased risk for the development of performed on 41 tumor samples from 37 patients with paragangliomas and pheochromocytomas [10]. In 2002, CT, and though no tumors had coding sequence muta- 12 individuals from five unrelated families were found to tions of the investigated SDH genes, a number of DNA have developed paragangliomas and GISTs, and the copy changes were seen [52]. Particularly, deletions of Carney-Stratakis Syndrome (CSS) was described [39]. chromosome 1p and 1q12-q21, the site of the SDHC CSS appears to be an autosomal dominant syndrome gene, were found. Interestingly, other classic mutations with incomplete penetrance characterized by the devel- associated with GIST such as KIT and PDGFRA were opment of paraganglioma, GIST, or both. CSS has a vari- not found in these tumor specimens from patients with able phenotypic expression as demonstrated by a report CT. This finding is consistent with results from other of monozygotic twins with CSS where one developed a studies [15,53], raising the possibility that GISTs in CT paraganglioma and the other GIST [49]. To better arise from alternative pathologic mechanisms from most characterize the germline mutations present in patients sporadic GISTs. with CSS, genetic sequencing was performed for six Consistent with an alternative genetic and possible individuals in six unrelated families, and mutations in pathologic mechanism of tumorigenesis, GISTs in CT SDHB, SDHC, and SDHD, were identified [40]. Differing behave differently clinically from most sporadic GISTs as from most sporadic GISTs, no mutations in KIT or they affect young women and have been associated with PDGFRA were seen. frequent lymph node metastasis, multifocality, and un- Additional recent work has confirmed the important predictable behavior [20]. In a review published in 1999, role SDH plays in the pathogenesis of GISTs. A study of Carney described a higher rate of gastric GIST and 34 GIST patients without KIT or PDGFRA mutations metastatic disease at presentation [29]. How deletions of (WT GIST) revealed that four patients (12%) had SDH chromosome 1p and 1q (in the region of the SDHC germline mutations, even in the absence of a family or gene) contribute to the alternative clinical behavior of personal history of paragangliomas. Further, even in GISTs associated with CT remains to be explained. patients without germline SDH mutations, patients with WT GISTs had complete loss or markedly reduced Treatment of patients with inherited GIST SDHB protein expression compared to patients with Although various germline mutations have been asso- KIT mutant GIST. This further suggests the important ciated with heterogeneous clinical syndromes, no data role of SDH in the pathogenesis of GIST, in addition to currently exist that inherited GIST should be treated dif- cases where a germline mutation in SDH is found [50]. ferently from its sporadic counterpart. Nevertheless, on a The finding of absent or low levels of SDH protein in theoretical basis, increasing knowledge of the various patients with CSS was confirmed by a study showing germline mutations associated with hereditary GIST sug- that none of the four patients with CSS had positive gests that different clinical approaches may ultimately immunohistochemical staining for SDHB, even though show increased benefit. For example, when GIST is only one was found to have a germline mutation. This present in patients with paragangliomas (Carney-Stratakis Postow and Robson Clinical Sarcoma Research 2012, 2:16 Page 5 of 7 http://www.clinicalsarcomaresearch.com/content/2/1/16 Syndrome), due to the lack of mutations in KIT and GIST, particularly wild-type inherited GIST, may lead to PDGFRA (WT GIST), these tumors theoretically may be improved understanding of perturbed molecular path- less sensitive to imatinib. This may also be true for inher- ways in sporadic GIST as well. For instance, the recogni- ited GIST associated with NF1 mutations as KIT muta- tion of genetic abnormalities in SDH in GISTs that are tions are only found in small proportions of NF1 GIST. not associated with KIT and PDGFRA mutations intro- Clinical data are not yet available to address these theoret- duces a new avenue of research that may have relevance ical speculations. for sporadic disease. Inherited GIST associated with CSS has been shown to Abbreviations be related to deficits in SDH, and improved understand- CSS: Carney-Stratakis syndrome; CT: Carney triad; GIST: Gastrointestinal ing of the mechanisms surrounding SDH regulation may stromal tumor; NF1: Neurofibromatosis-1; NF2: Neurofibromatosis-2; PDGFRA: Platelet derived growth factor receptor-alpha; SEER: Surveillance lead to future therapeutic approaches. Unfortunately, epidemiology and end results; SDH: Succinate dehydrogenase; WT: Wild patients with advanced WT GIST when treated with type. imatinib had decreased objective response, time to Competing interests tumor progression, and overall survival compared to The authors declare that they have no competing interests. patients with KIT exon 11 mutations [54]. Mutations in SDH and NF1 may explain the non-KIT mediated Authors’ contributions pathogenesis in patients with WT GIST, and patients MP collected the references and wrote the first draft of the manuscript. MR revised the manuscript and provided intellectual guidance in support of the with inherited SDH mutations, and possibly NF1 muta- content of this project. Both authors read and approved the final manuscript. tions, may ultimately benefit from alternative targeted treatment. The relationship between SDH and NF1 to Authors’ information MP is a medical oncology fellow in the Melanoma/Sarcoma Oncology GIST pathogenesis will first need to be further clarified. Service at Memorial Sloan-Kettering Cancer Center. MR is the clinic director Patients whose GISTs are characterized by a deficiency of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in SDHB by immunohistochemistry have been described and a member of the Breast Cancer Medicine Service. to have a somewhat different clinical course from the Acknowledgements majority of GIST patients. Specifically, one study found None. that deficiency of SDHB was associated with a female Author details predominance, gastric primary location, lymph node in- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New volvement, and similar morphology to GIST arising in York, NY, USA. Clinical Genetics and Breast Cancer Medicine Services, pediatric patients [55]. Since these patients’ GISTs fol- Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Weill Cornell Medical College of Cornell University, New York, NY, USA. lowed a more indolent course, SDHB deficient tumors may ultimately need to be managed differently. Received: 12 August 2011 Accepted: 19 December 2011 Sunitinib may be particularly helpful for patients with Published: 4 October 2012 GIST who develop resistance or intolerance to imatinib. References A study involving 97 patients with metastatic, imatinib- 1. Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, Corless CL, resistant/intolerant GIST, demonstrated the particular Debiec-Rychter M, DeMatteo RP, Ettinger DS, Fisher GA, Fletcher CD, efficacy of sunitinib in patients with primary exon 9 and Gronchi A, Hohenberger P, Hughes M, Joensuu H, Judson I, Le Cesne A, Maki RG, Morse M, Pappo AS, Pisters PW, Raut CP, Reichardt P, Tyler DS, WT GIST [56,57]. 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Wozniak A, Floris G, Debiec-Rychter M, Sciot R, Schöffski P: Implications of • Thorough peer review mutational analysis for the management of patients with • No space constraints or color figure charges gastrointestinal stromal tumors and the application of targeted therapies. Cancer Invest 2010, 28:839–848. • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar doi:10.1186/2045-3329-2-16 Cite this article as: Postow and Robson: Inherited gastrointestinal • Research which is freely available for redistribution stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clinical Sarcoma Research 2012 2:16. Submit your manuscript at www.biomedcentral.com/submit

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