Gastrointestinal Stromal Tumors: The GIST of Precision Medicine.download.xuebalib.com/4g8zA74awXOb.pdf · Gastrointestinal Stromal Tumors: The GIST of Precision Medicine ... in many

TRECAN 221 No. of Pages 18

Review

Gastrointestinal Stromal Tumors: The GISTof Precision Medicine

Lin Mei,1 Steven C. Smith,2 Anthony C. Faber,3 Jonathan Trent,4 Steven R. Grossman,1

Constantine A. Stratakis,5 and Sosipatros A. Boikos1,*

HighlightsOver 99%of all gastrointestinal stromaltumors (GISTs) can be attributed togenetic or epigenetic alterations withonly a few cases remainingunclassified.

Succinate dehydrogenase (SDH) sub-unit B (SDHB) immunostaining can beused to classify GISTs, categorizingthem into either a SDH-competentcluster with a normal methylation pat-tern or a SDH-deficient cluster with ahypermethylator phenotype.

SDH-deficient GISTs are familial orsyndromic in more than 90% ofpatients.

Imatinib has limited activity in SDH-deficient GISTs.

Hypermethylation of the SDHC genepromoter region is the molecular sig-nature of the Carney triad.

Hypermethylation of the SDHC genepromoter region was found by epige-netic profiling to also be present inmostly pediatric wild-type GISTs.

Surveillance for paragangliomas andother tumors is indicated for patientswith inherited SDH-deficient GISTs.

1VCU Massey Cancer Center, VirginiaCommonwealth University, Richmond,VA, USA2Departments of Pathology andSurgery, VCU School of Medicine,Richmond, VA, USA3VCU [635_TD$DIFF]Phillips Institute for Oral HealthResearch, School of Dentistry andMassey Cancer Center, VirginiaCommonwealth University, Richmond,VA, USA4Sylvester Comprehensive Cancer

The discovery of activated KITmutations in gastrointestinal (GI) stromal tumors(GISTs) in 1998 triggered a sea change in our understanding of these tumorsand has ushered in a newparadigm for the use ofmolecular genetic diagnosticsto guide targeted therapies.KIT andPDGFRAmutations account for 85–90%ofGISTs; subsequent genetic studies have led to the identification of mutation/epimutation of additional genes, including the succinate dehydrogenase (SDH)subunit A, B, C, and D genes. This review focuses on integrating findings fromclinicopathologic, genetic, and epigenetic studies, which classify GISTs intotwo distinct clusters: an SDH-competent group and an SDH-deficient group.This development is important since it revolutionizes our current managementof affected patients and their relatives, fundamentally, based on the GISTgenotype.

Milestones in GIST Research and DiscoveryGIST is the most common mesenchymal tumor of the GI system, with more than 5000 newlydiagnosed cases in the USA each year [1]. The incidence of these tumors is geographicallyvariable, from as low as 4.3–6.8 cases per million to as high as 19–22 cases per million [2]. Thereported median age is in the mid-50s in most studies [2]. The stomach is the most frequentlocation for the primary site (55%), followed by the small intestine (30%) and rectum (5%) [1,2].Exceptionally rarely, GISTs have been reported to arise in other GI locations, from clinicallyunclear primary sites, or from viscera outside the GI tract. Historically, GISTs were initiallyclassified as GI sarcomas, leiomyosarcoma, leiomyoma, plexosarcomas, leiomyoblastoma, GIautonomic nerve tumors (GANTs), or malignant fibrous histiocytomas.

In 1998 it was demonstrated that the driver mutation in the majority of GISTs is in the V-KITHardy–Zuckerman 4 feline sarcoma viral [636_TD$DIFF]oncogene homolog (KIT) proto-oncogene. Later, thefirst patient with advanced GIST was treated with imatinib, a tyrosine kinase inhibitor of KIT.Historically, smooth muscle was considered the cell type of origin of GISTs, given the predomi-nant spindle cell morphology and variable expression of smooth muscle cell markers in thesetumors [3]. Further studies utilizing electron microscopy and immunohistochemistry (IHC)identified features divergent from those of classic leiomyosarcoma, leading to the term ‘stromaltumor’ [4]. A key finding for GIST classification was the discovery of its similarity to interstitialcells of Cajal, stromal cells that serve as the pacemaker for the coordination of smooth musclecontraction in the GI tract. The receptor tyrosine kinase KIT (CD117), which is commonlyexpressed on both interstitial cells of Cajal and GISTs, is crucial for tumor growth [5,6]. The KITgain-of-function mutation is now well established as the driver mutation in the majority of GISTsand is known as an important diagnostic feature [7]; less frequently seen are gain-of-functionmutations in the homologous receptor tyrosine kinase platelet-derived growth factor (PDGF)receptor a (PDGFRA) [8]. Around the same time that Hirota and colleagues identified KIT

Trends in Cancer, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.trecan.2017.11.006 1© 2017 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/j.trecan.2017.11.006


Center, Miami, FL, USA5Eunice Kennedy Shriver NationalInstitute of Child Health and HumanDevelopment, Rockville, MD, USA

*Correspondence:[email protected](S.A. Boikos).

mutation in GIST [6], imatinib, a tyrosine kinase inhibitor, was under evaluation in a clinical trialfor BCR-ABL-positive chronic myeloid leukemia (CML). The structural similarity of the KIT,PDGFRA, and ABL kinase domains led to the successful use of imatinib in an index patient withadvanced disease and to eventual clinical trials evaluating the efficacy of imatinib for GISTs. TheFDA granted approval for the use of imatinib in patients with advanced GIST in February 2002.In the intervening years, �85–90% of GISTs were found to harbor KIT or PDGFRA mutations,while a 10–15% subset of GISTs remained genetically unclassified and described as KIT/PDGFRA wild-type GIST or just ‘wild-type GIST’.

In 1977 Carney described the association of gastric leiomyosarcomas with functional para-gangliomas and pulmonary chondromas. This particular pattern of syndromic GISTs affectedprimarily women [637_TD$DIFF]. The young age, the multifocal pattern of gastric GISTs [638_TD$DIFF]and the frequentconcurrent paragangliomas or chondromas suggested a germline etiology. This associationwas later referred to as the Carney triad and provided the first evidence that wild-type GISTsmight have a distinct genetic etiology. In 1999 Carney reported another 79 cases of Carneytriad. These, however, were mostly female sporadic cases, suggesting that the disease mightnot be inherited. In that study only two of the 79 patients had a family history of paragangliomas,while the rest of the patients had no family history of any of the tumors. In 2002 Stratakis andCarney identified what was later called Carney–Stratakis syndrome (CSS) or dyad [9]. Althoughthese patients exhibited some features similar to those of Carney triad patients, their syndromeencompassed only two types of tumor (GISTs and paragangliomas) and appeared to beinherited as an autosomal dominant trait. Later, in 2007, Stratakis et al. identified mutations inthe subunits of the mitochondrial SDH complex (or complex II) as the genetic defects respon-sible for CSS [10,11]. Additionally, comparative genomic hybridization studies using specimensfrom 37 Carney triad patients demonstrated deletions in 1q21–q23.3, where the SDHC generesides, indicating for the first time that the SDHC gene is specifically involved in the Carneytriad, whereas any SDH subunit (SDHA, SDHB, SDHC, and SDHD) may bemutated in the dyador CSS.

Shortly thereafter, in 2008, the Pediatric and Wildtype GIST Clinic at the US National Institutesof Health (NIH) was established by Drs Constantine A. Stratakis [National Institute of ChildHealth and Human Development (NICHD)] and Lee Helman [National Cancer Institute (NCI)] asa collaborative effort between clinicians and scientists to elucidate the unique genetic andclinical characteristics of patients with wild-type GISTs. Since 2008 more than 14 clinics havebeen organized. In a seminal paper for the field, the clinic established in 2011 that SDH defectsare relatively common in wild-type GISTs [12]. In addition, Stratakis and his group showed thatSDHB immunoreactivity can be used to identify SDH-deficient GISTs regardless of the causa-tive SDH subunit defect [13]. Two years later it became clear from studies of tumors of patientsfrom the clinic that SDH deficiency led to increased methylation of the genome in these GISTs[14]. Finally, in 2014, a report from the NIH clinic demonstrated that wild-type GISTs could beclassified into two distinct diagnostic groups: SDH-competent GISTs (sharing features withclassic KIT/PDGFRA-mutated GISTs) and SDH-deficient GISTs (frequently syndromal andharboring molecular lesions of SDH subunits) [15].

Recent studies have led to the identification of additional genetic mutations in this intriguinggroup of so-calledwild-typeGISTs, which has prompted us (and others) to reconsider the ‘wild-type’ terminology in light of the expanding molecular spectrum. Here we review the state ofknowledge regarding the molecular classification of these tumors and distill the overall classifi-cation of GISTs into SDH-competent and SDH-deficient subgroups, whether sporadic orfamilial/genetic. SDH-competent GISTs include tumors with mutations of KIT, PDGFRA,

2 Trends in Cancer, Month Year, Vol. xx, No. yy

mailto:[email protected]


NF1, and BRAF as well as more recently identified genes, including ARID1A, ARID1B, CBL,PIK3CA, NRAS, HRAS, KRAS, FGFR1, MAX, and MEN1, and even novel gene fusions,including KIT–PDGFRA and ETV6–NTRK3 [15–20] (Figure 1, Key Figure). SDH-deficient GISTs,by contrast, include the rare syndromic GISTs arising in both the Carney triad and CSS

Key Figure

Gastrointestinal Stromal Tumors (GISTs): Two Distinct Clusters

(A) (A) α. SDHB IHC

β. Muta ons/epimuta ons

γ. Tumor global methyla on

γ

β

α

(B)

(B)

SDH competentSDH deficient

KIT muta onsPDGFRA muta onsNF1 muta onsBRAF muta ons

SDHx muta onsSDHC epimuta ons

Other

Methyla on centristMethyla on deviator

YesVariable

Median age


[9,10,21]. In the Carney triad, hypermethylation of the SDHC promoter contributes to epige-netic inactivation of SDH [22,23]. As mentioned, CSS is associated with germline mutations ofthe SDH subunit genes [24–27]. In this review we focus on research from the past two decadesthat has led to the definition of these SDH-competent and SDH-deficient GIST groups and howour understanding of this disease has largely reshaped its management.

SDH-Competent GISTsKIT-Mutated GISTThe landmark discovery of activating mutations of KIT in GISTs was reported in 1998 [6]. It isnow well established that �75% of GISTs harbor KIT mutations and the rapid translation ofthese mutational data into effective targeted kinase inhibitor therapies has borne out theirimportance in GIST pathogenesis. The KIT gene is mapped to 4q12 and encodes the KITreceptor tyrosine kinase, a transmembrane type III tyrosine kinase receptor that is the receptorfor stem cell factor (SCF). The binding of ligand induces KIT dimerization, receptor activation,and downstream signaling mobilization, including the JAK–STAT3, phosphatidylinositide-3-kinase (PI3K)–AKT–mTOR, and RAS–MAPK pathways [28]. Two years after the discovery ofactivating KITmutations in GISTs, imatinib was demonstrated to be a potent antagonist of KITin an in vitromodel [29]. Only 1 year subsequently, a case report described a favorable outcomewith the use of imatinib for the treatment of metastatic GIST [30]. Unsurprisingly, a subsequentlarge-cohort clinical trial achieved remarkable success using imatinib as therapy for patientswith advanced GIST [31]. In the intervening years, the treatment of GISTs has been revolu-tionized by a wave of targeted therapies, in many ways establishing a paradigm for precisionmedicine.

The most common oncogenic mutation in GIST is in KIT exon 11, which abrogates theautoinhibitory function of the KIT juxtamembrane domain resulting in constitutive activity.Among the various forms of mutation, such as in-frame deletion, single nucleotide substitution,and insertion, in-frame deletions are the most frequent type, followed by single nucleotidesubstitution. Generally, the conformational changes in KIT due to exon 11mutations disrupt theautoinhibitory domain of the receptor and permit continuous kinase activation [32]. The vastmajority (>80%) of exon 11-mutatedGISTs are located in the stomach, although theymay ariseessentially anywhere in the GI tract. Typically these tumors showmore spindled than epithelioidhistology [33]. Deletion of codon 557 or 558 is the most common mutation [34] and thesemutations have been shown to be associated with a higher mitotic rate and a worse prognosisin patients with gastric GISTs treated surgically in the European Contica GIST cohort [35].Likewise, Yamaguchi et al. found that exon 11 mutations were involved in the development ofliver metastasis and were associated with a worse clinical outcome in the pre-imatinib era [36].

KIT exon 9 mutations account for 8–10% of GISTs, among which 95% tend to be duplicationsof codons 502 and 503, which are in the extracellular domain [37]. The resultant conformationalalteration is thought to mimic the binding of SCF, thus leading to dimerization and constitutiveactivation [38]. Rarely, mutation of codon 476 has been reported [1]. Intriguingly, KIT exon 9-mutant GISTs have been shown to have a higher prevalence of primary resistance to imatinibthan KIT exon 11 mutants [39]. Additionally, these tumors have a greater predilection for arisingin the small or large bowel than in other sites in the GI tract, such that only 2% of gastric GISTsharbor exon 9 mutations. In vitro studies have demonstrated that the exon 9 mutation confersreduced sensitivity to imatinib [38]. Unsurprisingly, clinical trials have demonstrated that, inunresectable metastatic GISTs, exon 9 mutation is an adverse marker in terms of overallsurvival and progression-free survival (PFS). However, this relative resistance could be



overcome by treating patients with a higher dose of imatinib (800 mg vs 400 mg), obtainingresponse rates nearly comparable with those in tumors harboring KIT exon 11 mutations [40].

Exon 13 mutations, such as the 1945A>G substitution, occur rarely in an estimated 1% ofGISTs. These tumors, which harbor a mutation changing residues in the ATP-binding pocket[41], usually arise in the stomach and show spindle cell histology. The functional consequenceof these mutations in these tumors remains unclear; several reports suggest that they aresensitive to imatinib [41,42]. However, a recent report of clinical aggression was noted in arecurrent GIST with exon 13 mutation after imatinib and sunitinib treatment failures [43,44].

Mutations of exon 17, which localize to the activation loop of KIT, are generally uncommon. Themajority of these mutations involve codon 822, of which the 2487T>A substitution mutation isfrequent [41]. Although in vitro findings have suggested that such mutants would be lesssensitive to imatinib, clinical responses have been reported in primary exon 17-mutant GISTs[45]. Similar to the aforementioned exon 9 mutants, exon 17-mutant GISTs appear to arisetwice as frequently in the small bowel as in the stomach and to share spindle cell morphology[33,46]. Notably, despite the suggestion of relative resistance to imatinib, these tumors show aresponse to regorafenib [47].

To date there have been 31 kindreds reported to harbor germline KIT-mutant GISTs [48,49].The mean age at diagnosis of patients with germline (familial) KIT-mutant GISTs is approxi-mately 40–50 years, with no gender predominance. As expected for an activating oncogenicmutation, the predisposition to GISTs in affected individuals is inherited in an autosomaldominant pattern, with high penetrance. Similar to sporadic KIT-mutant GISTs, familial KIT-mutant GISTs tend to show more spindled than epithelioid cytomorphology [48]. Other clinicalfindings among affected individuals include hyperplastic interstitial cells of Cajal, skin hyper-pigmentation, sporadic non-GI stromal tumors, and melanoma, which may all result from theperturbation of KIT signaling. Importantly, individuals from families with germline KITmutationsthat are predicted to be imatinib sensitive develop tumors that respond favorably to imatinibtherapy [50]. The D816V mutation of KIT found in GISTs can also cause familial mastocytosiswithout detectable GISTs, indicating genotype–phenotype discordance [51].

PDGFRA-Mutated GISTPDGFRA is the second most commonly mutated oncogene in GISTs. The PDGFRA locus hasbeen mapped to 4q12, indicating that it potentially shares a common evolutionary origin withKIT. PDGFRA is a type III tyrosine kinase receptor and a close protein sequence homolog of KIT,serving as the receptor of several PDGF isoforms [37]. PDGFRA mutation causes hyperfunc-tional kinase activation and interacts with KIT. Consistent with their functional overlap, PDGFRAand KIT mutations are mutually exclusive in GISTs [52–54]. The majority of PDGFRA-mutatedGISTs occur in the stomach, usually with epithelioid or mixed epithelioid and spindle cellhistology, often with myxoid stromal change [55]. Overall, KIT- and PDGFRA-mutated GISTsshare a similar IHC profile, including expression of Anoctamin 1 (ANO1) (DOG-1) and proteinkinase C-u [56,57]. These markers are highly specific for GISTs rather than other mesenchymaltumors of the GI tract. In addition, cytogenetic similarities are observed in KIT and PDGFRA-mutated GISTs, including, for example, loss of chromosome 14 and/or chromosome 22[52,58].

Although the activated pathways downstream are identical to KIT mutations, PDGFRA-mutated GISTs tend to have a lower risk of recurrence [1]. A prospective cohort study inFrance revealed that KIT and PDGFRA mutations were detected in 71% and 15% of patients,

Trends in Cancer, Month Year, Vol. xx, No. yy 5


respectively. However, among metastatic GISTs only 2.1% showed PDGFRA mutation com-pared with 82.8% in those with KIT mutations [59]. A similar trend has been observed in otherseries [1], indicating that PDGFRA-mutated GISTs may show subtle differences in theirpathological and genetic profile. For example, Subramanian et al. provided evidence ofdifferential gene expression, including of ezrin, p70S6K, and PKCe, which are known to havekey roles in KIT or PDGFRA signaling [60]. Also, PDGFRA mutations may be present in thegermline, and present as familial KIT-negative GISTs [61].

Most PDGFRA mutations in GISTs have been identified in exon 18 and are believed toaberrantly stabilize the kinase activation loop [62]. The most frequent single mutation,D842V, represents �70% of PDGFRA mutations and �5% of metastatic GISTs [8]. It isconsidered the most common cause of primary resistance to imatinib [45] and median survivalis only 12.8 months compared with 48–60 months on average for imatinib-treated GISTs [54].Besides D842V, the second most frequent mutation of exon 18 occurs as the deletion ofcodons 842 to 845, which confers imatinib sensitivity [63]. Recently, Fanta et al. reported apatient with aPDGFRADIM842–844 deletionwith a partial response (PR) to treatment [64]. Thiscase is another example of the variability of response to imatinib of PDGFRA-mutated GISTs. In2005 Corless et al. reported 289 cases of PDGFRA-mutant GISTs in which they identifiedmutations associated with varying sensitivity to imatinib [8].

Intriguingly, a novel, potent PDGFRA inhibitor, crenolanib, has been reported that can inhibit theaforementioned imatinib-resistant D842V mutation in vitro. A Phase III clinical trial(NCT02847429) designed to test the efficacy of crenolanib in advanced GIST is ongoing[63]. Additionally, the suppression of PDGFRA signaling by crenolanib was reported to disruptc-KIT–ETV1 positive feedback signaling, suggesting potential promise for the treatment ofimatinib-resistant KIT-mutant GISTs as well [65].

Exon 12 mutation is the second most common form of PDGFRA-mutant GIST, thought torepresent�1–2% of GISTs overall [1,37]. Exon 12mutation usually manifests as deletion ratherthan duplication and 1821T>A is the common site, resulting in Val561Asp substitution at theprotein level [33]. The PDGFRA juxtamembrane domain is thought to mediate an autoinhibitoryfunction and mutation in this inhibitory domain induces hyperactivation [62]. Pasini et al.encountered a patient with a PDGFRA exon 12 V561D mutation presenting with a gastricGIST combined with multiple fibrous polyps and a lipoma of the small intestine [11]. Fortunately,in vitro and clinical studies suggest that exon 12 PDGFRA mutations are sensitive to imatinibtreatment, with high response rates and durable effects [40,45].

Rarely, PDGFRAmutations occur also in exon 14, frequently clustering at codon 659 [33]. Exon14 mutations are one of the less studied groups of PDGFRA-mutated GISTs. Exon 14 is closeto exon 12; accordingly, it also may contribute to the autoinhibitory function of the juxtamem-brane domain and displays a similar phenotype. Ricci et al. reported two familial GIST caseswith PDGFRA exon 14 mutation (P653L) [66,67]. Some data have indicated that exon 14mutations may be a marker for a favorable prognosis [55].

To the best of our knowledge, germline PDGFRA-mutated GISTs have been reported in onlythree kindreds and one apparently sporadic case [48]. These tumors have arisen exclusively inthe stomach, showed inflammatory fibroid polyp-like histologic features, and seem to havebeen under-recognized diagnostically. Similar to the germline KIT-mutant GISTs, these germ-line PDGFRA-mutant familial GISTs show an autosomal dominant pattern of inheritance;however, there may be a predilection for occurrence in females. Additionally, no phenomenon



of hyperplasia of background interstitial cells of Cajal has been noted. Most of the histopathol-ogy reported has been of the epithelioid pattern and association with GI tract lipomas or largehands has been described [48].

Recently, Heinrich et al. presented data describing a Phase I study (NCT2508532) in advancedGIST to assess the safety and clinical activity of BLU-285, a potent, highly selective oral inhibitorthat targets PDGFRA D842V and KIT exon 17 mutants. Adult patients with unresectable GISTswho had received two or more kinase inhibitors previously were given BLU-285 once daily.Among 17 patients with tumors harboring PDGFRA D842V mutations, seven had a PR whileten had stable disease (SD). Among 11 patients with tumors harboring KIT exon 17 mutations,two had a PR and five had SD. Overall, the findings were interpreted as suggestive thatprecision-targeted therapy with BLU-285 was associated with significant activity againsttumors previously resistant to other GIST therapies. Therapy with this compound was associ-ated with a favorable side-effect profile, including mainly grade 1 or 2 toxicity.

Neurofibromatosis Type 1 (NF-1)The NF1 gene is located on chromosome 17q11.2 and is one of the largest human genes, withmore than 60 exons. NF1 encodes neurofibromin, a tumor suppressor gene that down-regulates the RAS–RAF–MEK–ERK signaling pathway. NF-1, previously known as von Reck-linghausen disease, is a relatively frequent autosomal genetic disorder. A NIH consensusdevelopment conference has previously identified seven clinical features at least two of whichhave to be present for the diagnosis of NF-1. These comprise six or more café-au-lait spots witha longest diameter at least 5 mm in prepubertal patients or a longest diameter at least 15 mm inpostpubertal patients; more than two neurofibromas or any plexiform neurofibroma; freckling ofthe skin in inguinal or axillary regions; any of a group of distinctive bone lesions, includingsphenoid wing dysplasia and thinning of the cortex of the long bones with or without pseu-doarthrosis; optic glioma (optic pathway glioma); two or more Lisch nodules (hamartomas ofthe iris); or a first-degree relative with neurofibromatosis based on the above criteria. Approxi-mately 7% of NF-1 patients develop a GIST during their lifetime [68]. Most NF-1-associatedGISTs arise in the small intestine, including the duodenum, with infrequent gastric exceptions.NF-1-associated GISTs show spindle cell cytomorphology and are associated with Cajal cellhyperplasia and associated GI motility disorder. The reported prognosis of NF1-associatedGISTs is controversial. One series reported an overall good prognosis with long-term follow-up,with only five of 35 patients succumbing to metastatic disease [69]. Conversely, two casereports have described NF1-mutated GISTs that either only initially responded to imatinib [70]or were completely resistant to imatinib [71]. Of note, these studies report substantiallydiscrepant parameters for GIST proliferative status, mitotic count, and tumor size, whichmay explain the different outcomes. Paragangliomas are not common in NF-1; these arereported in not more than 5.7% of affected patients [639_TD$DIFF]and are generally diagnosed in the fourthdecade. The utility of adjuvant treatment with imatinib in NF1-mutant GISTs remains contro-versial [71]. Since only aminority of NF-1 patients developGISTs, from an abundance of cautionwe recommend testing GISTs arising in this setting for canonical mutations (KIT and PDGFRA)associated with sporadic GISTs. NF1-mutated GISTs have also been recently identified in non-hereditary, sporadic cases [72,73]. Currently, there is an ongoing trial for patients with NF1-mutated GIST using a MEK inhibitor, selumetinib (NCT03109301).

BRAF and KRASAs a key intracellular protein kinase, BRAF is also involved in the canonical RAS–RAF–MEK–ERK signaling pathway. Strikingly, >90% of BRAFmutations occur in exon 15, resulting in theexchange of valine for glutamic acid (V600E) [74]. In terms of prevalence, in a study profiling a



total of 61KIT/PDGFRAwild-type GIST patients, three (5%) showed V600EBRAFmutations, allof which shared a similar clinical picture [75]. The BRAFmutation-associated GISTs showed apredilection for the small intestine, arose in middle-aged females, and exhibited a high mitoticrate and early metastasis. Similar results were reported in a subsequent study, which found twoof 28 (7%) KIT/PDGFRA wild-type GIST patients harboring a BRAF V600E mutation [76].Accumulating data suggest that BRAF-mutated GISTs are primary imatinib-resistant GISTs,although these tumors may respond to BRAF inhibitors such as dabrafenib [77].

Surprisingly, two independent GIST cohorts studied have shown that (targeted therapy-naïve)GISTs may rarely (2%) show concomitant BRAF and KIT/PDGFRA mutations. In vitro experi-ments exploring the function of this double-mutant phenotype have indicated that imatinib caninhibit the mutated KIT activity but not the downstream signaling mediated by the concomitantBRAF [78]. This finding may document a new (albeit infrequent) mechanism for primaryimatinib-resistant GISTs. Similarly, it stands to reason that concomitant mutation of upstream(KRAS) or downstream (MEK) mediators of canonical signaling downstream from KIT orPDGFRA might be implicated in rare cases of primary imatinib resistance as well. As high-throughput sequencing studies becomemore widely available, we suspect that additional GISTcases with multiple mutations will be observed and combination targeted therapies contem-plated [15].

Other GenesPIK3CA encodes the p110a subunit of PI3K, which is a downstream mediator of KIT kinasesignaling. Across advanced cancers, mutation of PIK3CA is frequently associated with muta-tions of BRAF and KRAS [79]. Thus, it is not entirely surprising that in 2011 a PIK3CAmutation(H1047L) was documented in a KIT exon 11-mutated GIST [80]. Subsequent studies havesuggested that the prevalence of PIK3CA mutation in GIST is low, estimated as one of 27patients (�4%) [81]. The H1047R gain-of-function mutation seen in GISTs is also the mostcommon PIK3CAmutation seen in other advanced human cancers [82]. Thus, the PI3K–AKT–mTOR pathway has been implicated as a key mediator of the transformation, progression, andtherapeutic resistance of GISTs.

Lasota et al. evaluated 529 imatinib-naïve GISTs, identifying eight PIK3CA mutations (1.5%)[83]. Overall, the PIK3CA-mutated GISTs were large (�14 cm) with variable mitotic activity (0–72/50 HPF). Resistance frequently developed in this PIK3CA-mutated group, which may berelated to a proliferative advantage during progression and rescue of KIT inhibition by thehyperactivated PI3K-dependent downstream signaling [83]. Treatment with PI3K/mTOR inhib-itors have shown promise in an early-phase clinical trial [84]. However, the potential utility of thistherapeutic angle in PIK3CA-mutant GISTs will require further examination and follow up.

Additionally, multiple other somatic mutations have been recently found in GISTs, includingMAX, FGFR1,CBL, ARID1A, BCOR, APC, TP53,MEN1, andCHD3. The remarkable functionalrange of these proteins, ranging from oncogenes to tumor suppressors, demonstrates howheterogeneous GISTs can be [15,17,18,72]. Presently, the number of patients with thesemutations remains small, such that genotype–phenotype correlations are not yet possible.

Gene FusionsTo date several reports have described the ETV6–NTRK3 fusion gene in GIST [17]. As early as in2010, Chi et al. discovered overexpression of the ETV1 transcription factor in clinical samples,suggesting that it might represent a key mediator in KITmutation-associated GIST tumorigen-esis [85]. The cooperative function of these two factors has been implicated in the development



and progression of GISTs [85]. ETV1 expression appears to be highly specific for GISTs and isrequired for tumor growth. These findings have raised interest in the potential function of proto-oncogenic ETS-family transcription factors like ETV1 in GIST. Associated in vitro studies havealso indicated that the combination of MEK and KIT inhibition, both of which result in decreasedETV1 protein degradation, might yield increased GIST inhibitory effects [86]. A new study fromthe same group established that ETV1 was required for GIST initiation and proliferation via anovel positive feedback circuit with KIT as a key regulator of target genes [87,88]. Notably,using MEK162, a MEK inhibitor, they confirmed its synergistic effect with imatinib. Currently, aPhase Ib/II clinical trial (NCT01991379) is accruing patients to test imatinib/MEK162 combi-nation therapy in untreated advanced GIST, highlighting the ability to rapidly translate molecularfindings from model systems to clinical studies using the panoply of contemporary availablesmall-molecule inhibitors. Two other fusion genes involving FGFR1 have been found in threecases ofKIT/PDGFRAwild-type GIST (FGFR1–HOOK3 and FGFR1–TACC1) [18], while a seriesof other fusion events has been recently reported (KIT–PDGFRA, SPRED2–NELFCD, andMARK2–PPFIA1) [15,19].

SDH-Deficient GISTsSDH-deficient GISTs comprise the majority of pediatric GISTs, some sporadic cases, and twoclasses of syndromic GISTs (Carney triad and CSS). SDH is a mitochondrial enzyme (complexII) comprising four subunits (SDHA, SDHB, SDHC, and SDHD) mapped to 5p15.33, 1p36.13,1q23.3, and 11q23.1, respectively. For simplicity we refer herein to all four subunits collectivelyas SDHx. Subunits A and B are the catalytic proteins while the anchoring componentcomprises C and D. The heterotetrameric complex catalyzes the oxidization of succinate tofumarate, performing a key role in the Krebs cycle and electron transport chain. It has beenshown recently that genetic alteration in any SDHx subunit can lead to SDH dysfunction andsubsequent loss of expression of the subunit SDHB due to is apparent instability outside thecomplex. For that reason, SDHB IHC is used currently as a surrogate marker of SDH deficiency[89]. Deficiency of SDH complex function results in intracellular accumulation of succinate,which competitively inhibits hypoxia-inducible factor (HIF) prolyl hydroxylases, leading tostabilization of HIF1a. Given that HIF1a is physiologically (under normoxia) targeted for rapiddegradation, its stabilization and nuclear accumulation induces constitutive activation ofhypoxic signaling and tumorigenesis [90]. In parallel, succinate accumulation also inhibits otherdioxygenases, including the TET family of DNA hydroxylases and JmjC domain-containinghistone demethylases (KDMs). Inhibition of TET and KDM in turn leads to hypermethylation ofDNA and histones, respectively [14]. Germline mutations in these SDH subunit proteins canlead to GISTs, paragangliomas, a distinctive type of SDH-deficient renal cell carcinoma [91,92],and, rarely, pituitary tumors [93].

SDH-deficient GISTs occur nearly exclusively in the stomach [94]. Usually these tumorsmanifest at a young age, predominantly in females. Among older adults, these tumors showsomewhat less gender predilection. Histologically, SDH-deficient GISTs exhibit a primarilymultinodular and plexiform pattern, with epithelioid morphology, early lymphovascular invasion,and/or nodal involvement, and frequent metastasis to the liver and the peritoneal cavity. Chouet al. recently observed that insulin-like growth factor 1 receptor (IGF1R) was overexpressed asanother characteristic of SDH-deficient GISTs, which may be related to genetic amplification ofIGF1R in some cases [95]. As a result, IGF1R signaling is activated, and several studies havedemonstrated that upregulation of IGF1R is highly specific in SDH-deficient GISTs [93]. Patientswith GISTs due to SDHx germline mutations may exhibit a spectrum of endocrine andneuroendocrine pathologies ranging from hyperplasia to neoplasia, including paragangliomas,pituitary tumors, and adrenal nodules, while recently hypothyroidism in these patients was



Table 1. Familial Syndromes

Disease (phenotypeMIM number)

Gene Type of inheritance(penetrance)

Main features

KIT-mutatedsyndrome (606764)i

KIT Autosomal dominant (highpenetrance)

GIST, skin hyperpigmentation,dysphagia, hyperplastic interstitialcells of Cajal, sporadic non-GISTtumors, melanoma, rarely mast celldisorders

PDGFRA-mutatedfamilial syndrome(173490)ii

PDGFRA Autosomal dominant (highpenetrance)

GIST, lipomas, large hands (patientshave no interstitial cell of Cajalhyperplasia)

NF-1 (162200)iii NF1 Autosomal dominant (variablepenetrance)

Café-au-lait spots, neurofibromas,Lisch nodules, axillary and inguinalfreckling, osseous lesions, opticgliomas, pheochromocytomas

Carney triad(604287)iv

SDHC promoterhypermethylation(rarely SDHxmutations havebeen found)

No inheritance in patients withSDHC promoter methylation

GIST, paragangliomas, chondromas,adrenal cortical adenomas

CSS (606864)v SDHx genesSDHASDHBSDHCSDHD

Autosomal dominant(incomplete penetrance)

GIST, paragangliomas, pituitaryadenoma (rarely), SDH-deficient renalcell carcinoma (rarely)

found to correlate with tumor size [15,96–98]. SDH-deficient GISTs can be sporadic, with noother clinical manifestations, or may present as a component of one of two separate recognizedsyndromes, the Carney triad and CSS, as described below (Table 1 and Figure 1).

Carney Triad (Predominantly SDHC Promoter Hypermethylation)The Carney triad was first described in 1977 as a triad of ‘gastric leiomyosarcomas’ (nowknown as GISTs, most commonly of the gastric antrum), paragangliomas, and pulmonarychondromas [21]. Compared with KIT- or PDGFRA-mutated GISTs, Carney triad GISTs have ahigher incidence of lymph node metastasis. Approximately 15% of patients succumb tometastatic disease [99]. Primarily these tumors occur in females, and may be associated withesophageal leiomyoma and adrenal cortical adenoma [100]; despite the increased rates ofmetastasis, the course remains comparatively indolent. Pleomorphism and epithelioid mor-phology are characteristic; however, mitotic counts are generally low, resulting in its classifi-cation as a low-risk tumor [99].

Overall, the etiology of Carney triad remains poorly characterized, although recent data haveshed light on the genomic aspects of this disease and implicated SDHC. In Carney triad GISTs,the tumor cells are sometimes positive for KIT expression on IHC. However, these tumors showSDH deficiency on IHC, such that consideration of Carney triad or CSS is recommended if aGIST is negative on IHC [13]. In a study of 37 patients with the Carney triad, nomutations of KIT,PDGFRA, or any of the SDH complex subunits were identified. Instead, the 1q12–q21 region(which includes SDHC) was identified as frequently deleted, and this was found to be the mostfrequent and largest contiguous genomic change in these cases [101]. With recent advances inepigenetics, further studies have suggested that hypermethylation of SDHCmay be the causeof the Carney triad. Haller et al. were the first to report that recurrent aberrant dense DNA



methylation at the locus of SDHC led to reduced mRNA expression of SDHC, providing aplausible mechanism of carcinogenesis [23]. In addition, Killian et al. performed genome-wideDNA methylation profiling studies showing that six of 15 Carney triad patients had SDHC‘epimutation’ (hypermethylation), providing further evidence in support of this interpretation[22]. Overall, further studies will be necessary to determine the relative prevalences of SDHCepimutation versus deletion versus potentially other, as-yet-uncharacterized SDHC changes inthe Carney triad.

CSS (SDHx Mutation)CSS was first described as familial gastric GIST and paraganglioma separated from the Carneytriad [9]. It was found to be inherited in an autosomal dominant manner with incompletepenetrance and, similar to the Carney triad, presented more frequently in young females, withmedian age of 35 years. Inactivating mutations of SDHB, SDHC, or SDHD were then identifiedin patients affected by CSS [10,102], with more frequent mutation of subunits B and D.Germline SDHA loss-of-function mutation has been also associated with CSS [25]. AmongSDH-deficient GIST patients, the subset harboringSDHAmutations exhibited impressively longsurvival with the use of sunitinib after imatinib [103]. In a recent study combining data fromclinical observations, a functional yeast model, and a computational model, SDHA alterations inpatients with GISTs identified previously as variants of unknown significance (VUSs) werereevaluated for pathogenicity. In that study, 73% of the alterations described previously asVUSs were found to be pathogenic, highlighting the need for a more thorough assessment ofinherited SDH variants. [104] Among SDH-deficient GIST patients, �30% exhibit the clinicalpicture of CSS [24]; their tumors furthermore tend to show poor responses to traditionalimatinib therapy [27], with increased lymphovascular invasion and higher morbidity frommetastasis [24]. Overall, the efficacy of newer-generation tyrosine kinase inhibitors needsgreater study in these patients.

SDH-Deficient GISTs: Therapeutic Implications?Multiple studies have previously demonstrated that KIT/PDGFRAwild-type GISTs (a majority ofwhich tend to be SDH deficient) are characterized by poor responses to standard imatinibtherapy. A subgroup analysis in the EORTC Phase III trial 62005 using imatinib has demon-strated that KIT/PDGFRA wild-type GIST patients had a 76% greater risk of death comparedwith KIT exon 11 mutants [105]. In another Phase I/II study in 97 patients with metastaticimatinib-resistant GISTs including nine wild-type GIST patients, sunitinib was shown to bemoreactive in KIT exon 9 mutations and wild-type GISTs compared with KIT exon 11 mutations. Inanother study, a potential response to pazopanib (an inhibitor of KIT, PDGFRA, and VEGFR)was demonstrated in heavily pretreated patients, although only five wild-type GIST patientswere recruited in this Phase II study [106]. In studies using imatinib in the adjuvant setting,subanalyses of wild-type GISTs in both the ACOSOG Z9001 trial [107] (32 patients) and theSSGXVIII (19 patients) [108] did not detect any benefit. A recent report from the NIH Pediatricand Wildtype GIST Clinic demonstrated that the vast majority of the patients gained no clinicalbenefit from imatinib: only one of 49 patients treated with imatinib mesylate had a PR [15]. Bycontrast, in the same study, seven of 38 patients with SDH-deficient GISTs showed responsesto sunitinib (one complete, three partial, three mixed). In another recent study, six patients withSDH-deficient GISTs (KIT/PDGFRA wild-type GISTs) experienced clinical benefit from regor-afenib with tumor response or SD for at least 16 weeks [109]. Since wild-type GISTs frequentlyoverexpress IGF1R [110,111], the SARC 022 Phase II trial tested a new kinase inhibitor,linsitinib, that resulted in significant inhibition of IGF1R [112]. Unfortunately, preliminary findingswere not very promising, with no objective response observed. PFS at 9 months was 52%[113], although final reporting for this trial is still pending. There are currently two clinical trials



Table 2. GIST Clinical Characteristics and Treatment Options According to Genotype

Genetic/epige-netic defect

Exon Median age Location Histology Imatinibtreatment

Other treatmentchoices

KIT Exon 11 Adult (median 63years)

Mainly stomach, all sitesof GI tract

Spindle> epithelioid Imatinib 400 mg SunitinibRegorfenibDCC-2618 trial(NCT02571036)vi,BLU-285(NCT02508532)vii

Exon 9 More in small or largebowel

Spindle> epithelioid Imatinib 800 mg

Other (exon8, 13, 17)

More in small bowel Spindle >epithelioid/mixed

Imatinib 400 mg

PDGFRA Exon 18(D842V)a

Stomach, mesentery,omentum

Epithelioid > spindle Imatinib resistant Dasatinib,crenolanib trial(NCT02847429)viii,DCC-2618 trial(NCT02571036)vi,BLU-285(NCT02508532)vii

Exon 12 All sites Epithelioid > spindle Imatinib 400 mg Sunitinib/regorafenib/DCC-2618 trial(NCT02571036)vi

Exon 14 Stomach Epithelioid > spindle Imatinib 400 mg

NF1 NA Adult (median 50years)

Small intestine andduodenum, multifocal

Spindle (small cell,mitotically inactive)

Imatinib(controversial)

MEK inhibitor trial(selumetinib)(NCT03109301)ix

BRAF BRAF V600E Adult Small intestine Spindle, high mitoticindex

Imatinib resistant BRAF-inhibitors

SDHA, B, C, D NA Pediatric/youngadult/adult(median 23years)

Stomach, multifocal EpithelioidPlexiform histology

Imatinib resistant SunitnibRegorafenibglutaminase inhibitortrial(NCT02071862)x

Guadecitabine trial(SGI-110)(NCT03165721)xi

SDHCme NA Pediatric, youngadult (median 15years)

Stomach, multifocal EpithelioidPlexiform histology

Imatinib resistant

aNot all PDGFRA exon 18 alterations are imatinib resistant. Often deletions at position 842 lead to imatinib sensitivity.

operating specifically for SDH-deficient tumors, one using the glutaminase inhibitor CB-839(NCT02071862) and one using a new-generation DNA methyltransferase inhibitor, guadeci-tabine (SGI-110) (NCT03165721). These trials are ongoing and results have not beenannounced (Table 2).

GIST Management: Genetic Counseling and ScreeningOne of the most important recommendations that we make regarding patients with GISTs andclinical features consistent with syndromic/inherited GIST (Table 1) or a family history of GISTs,paragangliomas, renal cell carcinoma, or pituitary tumors is referral to a genetic counselor forconsideration of germline genetic testing. Although patients with KIT/PDGFRA-mutated GISTsonly very rarely have a familial/germline form of their causative mutation, more than 80% withSDHx-mutated GISTs have been found to have a germline mutation. If a germline mutation isfound in any of these genes (including KIT, PDGFRA, NF1, or SDHx), genetic testing for thesame mutation and counseling if it is germline should be offered to all first-degree relatives. Atpresent, available data suggest that patients with SDHC promoter epimutation and no SDHxmutation do not generally need genetic testing given the apparent rarity of transgenerational



GIST management according to genotype and germline status

No

Yes

Yes

Yes

Yes

No

Gene c/epigene ctes ng,THC

1. Next-genera onsequencing formul ple genesincluding KIT,PDGFRA, NF1,BRAF, SDHA, B, C, D

2. SDHB IHC

3. SDHB methyla onstatus

Gene

SDHCme

SDHx

NF1

KIT

PDGFRA

Other

Germline tes ng(when to check)

No inheritance of SDHCme,no tes ng is needed

Check always germlinestatus

Check germlinestatus if clinicalfeatures orfamily historyare sugges veof a clinicalsyndrome

First screening of pa ents or carriers

Physical examina on, blood pressure monitoring,metanephrine level determina on, head and neckplus thoracic–abdominal–pelvic contrasted MRI

Physical examina on, blood pressure monitoring,metanephrine level determina on, head and neckplus thoracic–abdominal–pelvic contrasted MRI,ophthalmologic examina on, skin examina on

Physical examina on, skin examina on for melanoma, thoracic–abdominal–pelvic CT

Physical examina on,thoracic–abdominal–pelvic CT

Figure 2. Gastrointestinal Stromal Tumor (GIST) Management According to Genotype and Germline Status. In this schema we propose an algorithm forthe germline genetic testing and screening of patients or carriers based on the initial tumor mutation findings, succinate dehydrogenase (SDH) subunit B (SDHB)immunohistochemistry (IHC), and SDHC methylation status. All patients should undergo physical examination and chest/abdominal/pelvic CT for staging purposes.Patients or carriers with germline SDHA, B, C, or D or NF1 mutation and patients with somatic SDHC epimutation are at risk for paragangliomas and should undergoblood pressure monitoring, metanephrine level determination, and potentially additional head and neck imaging. Patients with germline NF1 or KIT mutation shouldadditionally undergo a complete ophthalmologic examination or skin examination for melanoma, respectively.

heritability of the Carney triad [100]. The NCI currently has the ability to test patients for SDHCepimutation at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

Screening for paragangliomas/pheochromocytomas in patients with SDHx germline mutationsor SDHC epimutation is very important, since early detection may lead to better disease controland because data support the relative aggressiveness of SDH-deficient paragangliomas [114].There is no consensus yet on the frequency or the specific imaging modalities recommendedfor surveillance, but yearly whole-body MRI seems to be favored presently, along with yearlymeasurement of plasma and urine catecholamines. Other useful imaging modalities for para-gangliomas are 68 [634_TD$DIFF]Ga-DOTATATE, 18F-DOPA, and 18F-FDA [48]. Carriers of SDHx mutationsshould also undergo at least baseline whole-body MRI and catecholamine screening, while thefrequency of subsequent testing should be based on specific symptoms, like tachycardia andhigh blood pressure (Figure 2).

Concluding RemarksOver the past 20 years, genetic and genomic studies have provided tremendous insights intothe classification of GISTs. It is now evident that GISTs are a genetically heterogeneous group oftumors that can be classified into either SDH-competent or SDH-deficient types, each withdistinct clinical and genetic characteristics. Identification of their genetic etiology is crucial, notonly for systemic treatment and surgical planning but also for surveillance and genetic



Outstanding QuestionsWhat is the biological mechanism ofthe SDHC promoter methylation andfemale predominance in Carney triadpatients?

Although rare, what is the prevalenceof sporadic (non-germline) somaticSDH subunit mutation in SDH-defi-cient GISTs?

What is an effective future treatmentapproach for SDH-deficient GISTs?

screening of relatives. Within the SDH-competent GISTs, this heterogeneous group of tumorsprimarily comprisesKIT/PDGFRA/BRAF/NF1-mutated GISTswith normal genomicmethylationpatterns, in most cases presenting as sporadic tumors. These GISTs are diagnosed primarily inolder adults for whom imatinib can play a key therapeutic role in a personalized and genotype-specific manner. The primary site of these GISTs, their histology, and the metastatic patternmay vary, but the vastmajority of SDH-competent GISTs arise in either the stomach or the smallbowel, show spindle cell histology, and tend not to metastasize to lymph nodes. We note thetrend that, as technologies for molecular profiling have improved in recent years, increasingly apriori wild-type SDH-competent GISTs have shown identifiable lesions, including many kinasemutations, allowing their assignment to ever-smaller, less-frequent SDH-competent molecularcategories. The recent identification of a mutation in CBL, known to be downstream of KITsignaling, and of a cryptic fusion of KIT and PDGFRA by RNA-seq analysis [15] raises thepossibility that additional subgroups of SDH-competent GISTs defined by various activatingmutations will be found in the future [16].

SDH-deficient GISTs, by contrast, include sporadic GISTs (with somatic SDHx mutations),CSS-associated GISTs (with germline SDHx mutations), and Carney triad-associated GISTs(often with SDHC promoter methylation) [15]. Very few patients with the Carney triad have beenfound to have SDHx germline mutations [98]; however, both CSS and Carney triad patientshave been found to have defective mitochondria [115]. Thus, CSS and the triad may representtwo disorders on a spectrum of SDH deficiency. SDH-deficient GISTs are characterized by apattern of global, genome-wide DNA hypermethylation and are diagnosed primarily in pediatricpatients or young adults. SDH-deficient GISTs almost always arise in the stomach, showprevalent epithelioid histology, and undergo early metastasis to liver and lymph nodes, belying anonetheless relatively indolent long-term course. For these reasons, conventional risk stratifi-cation parameters appear not to predict metastatic progression of disease [116].

These differences between SDH-competent and SDH-deficient GISTs, alongwith the individualcharacteristics of the various subgroups, have major implications for clinical management,genetic testing, and cancer screening (Figure 2). Patients with SDH-deficient GISTs would notbenefit from preoperative imatinib, since imatinib has a very limited role in SDH-deficient GIST.The early metastases in liver and lymph nodes and the multifocal nature are prohibiting factorsin the planning of any radical or repeated surgery for SDH-deficient GISTs. Such approachesare almost never curative in SDH-deficient syndromic GISTs (Carney triad and CSS), althoughsurgery may still have an important role in sporadic SDH-deficient GISTs with only somaticSDHx subunit mutations (thus unlikely to be multifocal). Overall, the dogma regarding surgicalmanagement in syndromic GISTs is that surgery should be primarily palliative, including incases of gastrointestinal hemorrhage, pain, or obstruction [117]. By contrast, a recent retro-spective cohort study of 392 adolescent and young adults with no genomic informationshowed that operative management is associated with improved overall survival and GIST-specific survival [118].

Since each GIST genotype has a different impact on considerations as diverse as the initialtherapeutic approach (whether surgical or systemic), the need for surveillance modalities, andthe genetic screening of relatives, the need for a precision-medicine approach in GISTs is morecrucial than ever. Ultimately, we find that much of the question for any given tumor boils down toa main dichotomy between the majority of GISTs, which are SDH competent, and the distinctminority of GISTs that are SDH deficient. Despite recent progress in our understanding of thegenetics and biology of SDH-deficient tumors, important questions remain for Carney triadpatients (see Outstanding Questions). It remains an enigma why Carney triad patients are



almost exclusively female. Additionally, it still unclear what the underlying genetic defect is thatleads to targeted SDHCmethylation, andmolecular studies are under way. As high-throughputsequencing modalities have become even more prevalent, multiple new oncogenic mutationsbeen characterized among previously wild-type GISTs, such that, going forward, considerationof the term ‘unclassified’ may be more appropriate than wild type [16].

Resourcesiwww.omim.org/entry/606764beiiwww.omim.org/entry/173490iiiwww.omim.org/entry/162200ivwww.omim.org/entry/604287vwww.omim.org/entry/606864viclinicaltrials.gov/ct2/show/NCT02571036viiclinicaltrials.gov/ct2/show/NCT02508532viiiclinicaltrials.gov/ct2/show/NCT02847429ixclinicaltrials.gov/ct2/show/NCT03109301xclinicaltrials.gov/ct2/show/NCT02071862xiclinicaltrials.gov/ct2/show/NCT03165721

References

1. Barnett, C.M. et al. (2013) Gastrointestinal stromal tumors:

molecular markers and genetic subtypes. Hematol. Oncol. Clin.North Am. 27, 871–888

2. Soreide, K. et al. (2016) Global epidemiology of gastrointestinalstromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 40, 39–46

3. Schroeder, B. et al. (2016) Targeting gastrointestinal stromaltumors: the role of regorafenib. Onco Targets Ther. 9, 3009–3016

4. Mazur, M.T. and Clark, H.B. (1983) Gastric stromal tumors.Reappraisal of histogenesis. Am. J. Surg. Pathol. 7, 507–519

5. Kindblom, L.G. et al. (1998) Gastrointestinal pacemaker celltumor (GIPACT): gastrointestinal stromal tumors show pheno-typic characteristics of the interstitial cells of Cajal. Am. J. Pathol.152, 1259–1269

6. Hirota, S. et al. (1998) Gain-of-function mutations of c-kit inhuman gastrointestinal stromal tumors. Science 279, 577–580

7. Hirota, S. et al. (2000) Effects of loss-of-function and gain-of-function mutations of c-kit on the gastrointestinal tract. J. Gas-troenterol. 35 (Suppl. 12), 75–79

8. Corless, C.L. et al. (2005) PDGFRA mutations in gastrointestinalstromal tumors: frequency, spectrum and in vitro sensitivity toimatinib. J. Clin. Oncol. 23, 5357–5364

9. Carney, J.A. and Stratakis, C.A. (2002) Familial paragangliomaand gastric stromal sarcoma: a new syndrome distinct from theCarney triad. Am. J. Med. Genet. 108, 132–139

10. McWhinney, S.R. et al. (2007) Familial gastrointestinal stromaltumors and germ-line mutations. N. Engl. J. Med. 357, 1054–1056

11. Pasini, B. et al. (2007) Multiple gastrointestinal stromal and othertumors caused by platelet-derived growth factor receptor alphagene mutations: a case associated with a germline V561Ddefect. J. Clin. Endocrinol. Metab. 92, 3728–3732

12. Janeway, K.A. et al. (2011) Defects in succinate dehydrogenasein gastrointestinal stromal tumors lacking KIT and PDGFRAmutations. Proc. Natl. Acad. Sci. U. S. A. 108, 314–318

13. Gaal, J. et al. (2011) SDHB immunohistochemistry: a useful toolin the diagnosis of Carney–Stratakis and Carney triad gastroin-testinal stromal tumors. Mod. Pathol. 24, 147–151

14. Killian, J.K. et al. (2013) Succinate dehydrogenase mutationunderlies global epigenomic divergence in gastrointestinal stro-mal tumor. Cancer Discov. 3, 648–657

15. Boikos, S.A. et al. (2016) Molecular subtypes of KIT/PDGFRAwild-type gastrointestinal stromal tumors: a report from theNational Institutes of Health Gastrointestinal Stromal TumorClinic. JAMA Oncol. 2, 922–928

16. Alkhuziem, M. et al. (2017) The call of “the wild”-type GIST: it’stime for domestication. J. Natl. Compr. Canc. Netw. 15, 551–554

17. Brenca, M. et al. (2016) Transcriptome sequencing identifiesETV6–NTRK3 as a gene fusion involved in GIST. J. Pathol. 238,543–549

18. Shi, E. et al. (2016) FGFR1 and NTRK3 actionable alterations in“wild-type” gastrointestinal stromal tumors. J. Transl. Med. 14,339

19. Pantaleo, M.A. et al. (2017) Genome-wide analysis identifiesMEN1 and MAX mutations and a neuroendocrine-like molecularheterogeneity in quadrupleWTGIST.Mol. Cancer Res. 15, 553–562

20. Nannini, M. et al. (2017) The progressive fragmentation of theKIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors(GIST). J. Transl. Med. 15, 113

21. Carney, J.A. et al. (1977) The triad of gastric leiomyosarcoma,functioning extra-adrenal paraganglioma and pulmonary chon-droma. N. Engl. J. Med. 296, 1517–1518

22. Killian, J.K. et al. (2014) Recurrent epimutation of SDHC ingastrointestinal stromal tumors. Sci. Transl. Med. 6, 268ra177

23. Haller, F. et al. (2014) Aberrant DNA hypermethylation of SDHC:a novel mechanism of tumor development in Carney triad.Endocr. Relat. Cancer 21, 567–577

24. Miettinen, M. et al. (2013) Immunohistochemical loss of succi-nate dehydrogenase subunit A (SDHA) in gastrointestinal stro-mal tumors (GISTs) signals SDHA germline mutation. Am. J.Surg. Pathol. 37, 234–240

25. Dwight, T. et al. (2013) Loss of SDHA expression identifiesSDHA mutations in succinate dehydrogenase-deficient gastro-intestinal stromal tumors. Am. J. Surg. Pathol. 37, 226–233

26. Gopie, P. et al. (2017) Classification of gastrointestinal stromaltumor syndromes. Endocr. Relat. Cancer Published onlineNovember 23. http://dx.doi.org/10.1530/ERC-17-0329

27. Pasini, B. et al. (2008) Clinical and molecular genetics of patientswith the Carney–Stratakis syndrome and germline mutations ofthe genes coding for the succinate dehydrogenase subunitsSDHB, SDHC, and SDHD. Eur. J. Hum. Genet. 16, 79–88


http://www.omim.org/entry/606764behttp://www.omim.org/entry/173490http://www.omim.org/entry/162200http://www.omim.org/entry/604287http://www.omim.org/entry/606864http://clinicaltrials.gov/ct2/show/NCT02571036http://clinicaltrials.gov/ct2/show/NCT02508532http://clinicaltrials.gov/ct2/show/NCT02847429http://clinicaltrials.gov/ct2/show/NCT03109301http://clinicaltrials.gov/ct2/show/NCT02071862http://clinicaltrials.gov/ct2/show/NCT03165721http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0005http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0005http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0005http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0010http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0010http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0010http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0015http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0015http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0015http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0020http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0020http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0025http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0025http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0025http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0025http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0030http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0030http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0035http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0035http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0035http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0040http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0040http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0040http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0045http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0045http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0045http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0050http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0050http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0050http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0055http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0055http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0055http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0055http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0060http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0060http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0060http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0065http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0065http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0065http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0070http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0070http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0070http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0075http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0075http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0075http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0075http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0080http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0080http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0080http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0085http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0085http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0085http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0090http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0090http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0090http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0095http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0095http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0095http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0095http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0100http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0100http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0100http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0105http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0105http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0105http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0110http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0110http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0115http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0115http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0115http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0120http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0120http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0120http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0120http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0125http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0125http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0125http://dx.doi.org/10.1530/ERC-17-0329http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0135http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0135http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0135http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0135


28. Bauer, S. et al. (2007) KIT oncogenic signaling mechanisms inimatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26, 7560–7568

29. Heinrich, M.C. et al. (2000) Inhibition of c-kit receptor tyrosinekinase activity by STI 571, a selective tyrosine kinase inhibitor.Blood 96, 925–932

30. Joensuu, H. et al. (2001) Effect of the tyrosine kinase inhibitorSTI571 in a patient with a metastatic gastrointestinal stromaltumor. N. Engl. J. Med. 344, 1052–1056

31. Demetri, G.D. et al. (2002) Efficacy and safety of imatinib mesy-late in advanced gastrointestinal stromal tumors. N. Engl. J.Med. 347, 472–480

32. Mol, C.D. et al. (2004) Structural basis for the autoinhibition andSTI-571 inhibition of c-Kit tyrosine kinase. J. Biol. Chem. 279,31655–31663

33. Chetty, R. and Serra, S. (2016) Molecular and morphologicalcorrelation in gastrointestinal stromal tumours (GISTs): anupdate and primer. J. Clin. Pathol. 69, 754–760

34. Martin, J. et al. (2005) Deletions affecting codons 557–558 of thec-KIT gene indicate a poor prognosis in patients with completelyresected gastrointestinal stromal tumors: a study by the SpanishGroup for Sarcoma Research (GEIS). J. Clin. Oncol. 23, 6190–6198

35. Wozniak, A. et al. (2014) Tumor genotype is an independentprognostic factor in primary gastrointestinal stromal tumors ofgastric origin: a European multicenter analysis based on Con-ticaGIST. Clin. Cancer Res. 20, 6105–6116

36. Yamaguchi, M. et al. (2000) Specific mutation in exon 11 of c-kitproto-oncogene in a malignant gastrointestinal stromal tumor ofthe rectum. J. Gastroenterol. 35, 779–783

37. Joensuu, H. and DeMatteo, R.P. (2012) The management ofgastrointestinal stromal tumors: a model for targeted and mul-tidisciplinary therapy of malignancy. Annu. Rev. Med. 63, 247–258

38. Yuzawa, S. et al. (2007) Structural basis for activation of thereceptor tyrosine kinase KIT by stem cell factor. Cell 130, 323–334

39. Lee, J.H. et al. (2013) Correlation of imatinib resistance with themutational status of KIT and PDGFRA genes in gastrointestinalstromal tumors: a meta-analysis. J. Gastrointestin. Liver Dis. 22,413–418

40. Heinrich, M.C. et al. (2008) Correlation of kinase genotype andclinical outcome in the North American Intergroup Phase III Trialof imatinib mesylate for treatment of advanced gastrointestinalstromal tumor: CALGB 150105 Study by Cancer and LeukemiaGroup B and Southwest Oncology Group. J. Clin. Oncol. 26,5360–5367

41. Lasota, J. et al. (2008) Clinicopathologic profile of gastrointesti-nal stromal tumors (GISTs) with primary KIT exon 13 or exon 17mutations: a multicenter study on 54 cases. Mod. Pathol. 21,476–484

42. Lux, M.L. et al. (2000) KIT extracellular and kinase domainmutations in gastrointestinal stromal tumors. Am. J. Pathol.156, 791–795

43. Kikuchi, H. et al. (2012) Rapid relapse after resection of asunitinib-resistant gastrointestinal stromal tumor harboring asecondary mutation in exon 13 of the c-KIT gene. AnticancerRes. 32, 4105–4109

44. Kang, W. et al. (2015) KIT gene mutations in gastrointestinalstromal tumor. Front. Biosci. (Landmark Ed.) 20, 919–926

45. Heinrich, M.C. et al. (2003) Kinase mutations and imatinibresponse in patients with metastatic gastrointestinal stromaltumor. J. Clin. Oncol. 21, 4342–4349

46. Lasota, J. and Miettinen, M. (2008) Clinical significance of onco-genic KIT and PDGFRA mutations in gastrointestinal stromaltumours. Histopathology 53, 245–266

47. Van Looy, T. et al. (2014) Characterization and assessment ofthe sensitivity and resistance of a newly established humangastrointestinal stromal tumour xenograft model to treatmentwith tyrosine kinase inhibitors. Clin. Sarcoma Res. 4, 10


48. Ricci, R. (2016) Syndromic gastrointestinal stromal tumors.Hered. Cancer Clin. Pract. 14, 1–15

49. Forde, P.M. et al. (2016) Familial GI stromal tumor with loss ofheterozygosity and amplification of mutant KIT. J. Clin. Oncol.34, e13–e16

50. Kleinbaum, E.P. et al. (2008) Clinical, histopathologic, molecularand therapeutic findings in a large kindred with gastrointestinalstromal tumor. Int. J. Cancer 122, 711–718

51. Speight, R.A. et al. (2013) Rare, germline mutation of KIT withimatinib-resistant multiple GI stromal tumors and mastocytosis.J. Clin. Oncol. 31, e245–e247

52. Heinrich, M.C. et al. (2003) PDGFRA activating mutations ingastrointestinal stromal tumors. Science 299, 708–710

53. Hirota, S. et al. (2003) Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinalstromal tumors. Gastroenterology 125, 660–667

54. Corless, C.L. et al. (2011) Gastrointestinal stromal tumours:origin and molecular oncology. Nat. Rev. Cancer 11, 865–878

55. Lasota, J. et al. (2006) GISTs with PDGFRA exon 14 mutationsrepresent subset of clinically favorable gastric tumors with epi-thelioid morphology. Lab. Invest. 86, 94–100

56. Duensing, A. et al. (2004) Protein kinase C theta (PKCu) expres-sion and constitutive activation in gastrointestinal stromaltumors (GISTs). Cancer Res. 64, 5127–5131

57. West, R.B. et al. (2004) The novel marker, DOG1, is expressedubiquitously in gastrointestinal stromal tumors irrespective of KITor PDGFRA mutation status. Am. J. Pathol. 165, 107–113

58. Wozniak, A. et al. (2007) Array CGH analysis in primary gastro-intestinal stromal tumors: cytogenetic profile correlates withanatomic site and tumor aggressiveness, irrespective of muta-tional status. Genes Chromosomes Cancer 46, 261–276

59. Emile, J.F. et al. (2012) Frequencies of KIT and PDGFRA muta-tions in the MolecGIST prospective population-based studydiffer from those of advanced GISTs. Med. Oncol. 29, 1765–1772

60. Subramanian, S. et al. (2004) Gastrointestinal stromal tumors(GISTs) with KIT and PDGFRA mutations have distinct geneexpression profiles. Oncogene 23, 7780–7790

61. de Raedt, T. et al. (2006) Intestinal neurofibromatosis is a sub-type of familial GIST and results from a dominant activatingmutation in PDGFRA. Gastroenterology 131, 1907–1912

62. Dibb, N.J. et al. (2004) Switching on kinases: oncogenic activa-tion of BRAF and the PDGFR family. Nat. Rev. Cancer 4, 718–727

63. Heinrich, M.C. et al. (2012) Crenolanib inhibits the drug-resistantPDGFRA D842V mutation associated with imatinib-resistantgastrointestinal stromal tumors. Clin. Cancer Res. 18, 4375–4384

64. Fanta, P.T. et al. (2015) In vivo imatinib sensitivity in a patient withGI stromal tumor bearing a PDGFRA deletion DIM842–844. J.Clin. Oncol. 33, e41–e44

65. Hayashi, Y. et al. (2015) Platelet-derived growth factor receptor-alpha regulates proliferation of gastrointestinal stromal tumorcells with mutations in KIT by stabilizing ETV1.Gastroenterology149, 420–32.e16

66. Ricci, R. et al. (2016) Divergent gastrointestinal stromal tumors insyndromic settings. Cancer Genet. 209, 354–358

67. Ricci, R. et al. (2015) PDGFRA-mutant syndrome. Mod. Pathol.28, 954–964

68. Zoller, M.E. et al. (1997) Malignant and benign tumors in patientswith neurofibromatosis type 1 in a defined Swedish population.Cancer 79, 2125–2131

69. Miettinen, M. et al. (2006) Gastrointestinal stromal tumors inpatients with neurofibromatosis 1: a clinicopathologic andmolecular genetic study of 45 cases. Am. J. Surg. Pathol. 30,90–96

70. Lee, J.L. et al. (2006) Response to imatinib in KIT- and PDGFRA-wild type gastrointestinal stromal associated with neurofibroma-tosis type 1. Dig. Dis. Sci. 51, 1043–1046

http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0140http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0140http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0140http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0145http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0145http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0145http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0150http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0150http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0150http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0155http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0155http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0155http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0160http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0160http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0160http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0165http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0165http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0165http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0170http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0170http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0170http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0170http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0170http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0175http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0175http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0175http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0175http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0180http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0180http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0180http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0185http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0185http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0185http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0185http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0190http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0190http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0190http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0195http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0195http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0195http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0195http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0200http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0200http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0200http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0200http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0200http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0200http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0205http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0205http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0205http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0205http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0210http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0210http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0210http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0215http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0215http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0215http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0215http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0220http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0220http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0225http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0225http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0225http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0230http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0230http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0230http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0235http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0235http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0235http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0235http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0240http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0240http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0245http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0245http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0245http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0250http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0250http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0250http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0255http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0255http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0255http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0260http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0260http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0265http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0265http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0265http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0270http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0270http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0275http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0275http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0275http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0280http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0280http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0280http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0285http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0285http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0285http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0290http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0290http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0290http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0290http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0295http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0295http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0295http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0295http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0300http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0300http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0300http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0305http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0305http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0305http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0310http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0310http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0310http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0315http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0315http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0315http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0315http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0320http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0320http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0320http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0325http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0325http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0325http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0325http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0330http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0330http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0335http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0335http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0340http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0340http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0340http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0345http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0345http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0345http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0345http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0350http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0350http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0350


71. Mussi, C. et al. (2008) Therapeutic consequences from molec-ular biology for gastrointestinal stromal tumor patients affectedby neurofibromatosis type 1. Clin. Cancer Res. 14, 4550–4555

72. Belinsky, M.G. et al. (2015) Somatic loss of function mutations inneurofibromin 1 and MYC associated factor X genes identifiedby exome-wide sequencing in a wild-type GIST case. BMCCancer 15, 887

73. Burgoyne, A.M. et al. (2017) Duodenal–jejunal flexure GI stromaltumor frequently heralds somatic NF1 and Notch pathwaymutations. JCO Precis. Oncol. 1, 1–12

74. Huss, S. et al. (2015) Classification of KIT/PDGFRA wild-typegastrointestinal stromal tumors: implications for therapy. ExpertRev. Anticancer Ther. 15, 623–628

75. Agaram, N.P. et al. (2008) Novel V600E BRAF mutations inimatinib-naive and imatinib-resistant gastrointestinal stromaltumors. Genes Chromosomes Cancer 47, 853–859

76. Agaimy, A. et al. (2009) V600E BRAF mutations are alternativeearly molecular events in a subset of KIT/PDGFRA wild-typegastrointestinal stromal tumours. J. Clin. Pathol. 62, 613–616

77. Falchook, G.S. et al. (2013) BRAF mutant gastrointestinal stro-mal tumor: first report of regression with BRAF inhibitor dabra-fenib (GSK2118436) and whole exomic sequencing for analysisof acquired resistance. Oncotarget 4, 310–315

78. Miranda, C. et al. (2012) KRAS and BRAF mutations predictprimary resistance to imatinib in gastrointestinal stromal tumors.Clin. Cancer Res. 18, 1769–1776

79. Janku, F. et al. (2011) PIK3CA mutations frequently coexist withRAS and BRAF mutations in patients with advanced cancers.PLoS One 6, e22769

80. Daniels, M. et al. (2011) Spectrum of KIT/PDGFRA/BRAF muta-tions and phosphatidylinositol-3-kinase pathway gene altera-tions in gastrointestinal stromal tumors (GIST).Cancer Lett. 312,43–54

81. Serrano, C. et al. (2015) KRAS and KIT gatekeeper mutationsconfer polyclonal primary imatinib resistance in GI stromaltumors: relevance of concomitant phosphatidylinositol 3-kinase/AKT dysregulation. J. Clin. Oncol. 33, e93–e96

82. Janku, F. et al. (2012) PIK3CA mutations in advanced cancers:characteristics and outcomes. Oncotarget 3, 1566–1575

83. Lasota, J. et al. (2016) Frequency and clinicopathologic profile ofPIK3CA mutant GISTs: molecular genetic study of 529 cases.Mod. Pathol. 29, 275–282

84. Janku, F. et al. (2013) PIK3CA mutation H1047R is associatedwith response to PI3K/AKT/mTOR signaling pathway inhibitorsin early-phase clinical trials. Cancer Res. 73, 276–284

85. Chi, P. et al. (2010) ETV1 is a lineage survival factor that coop-erates with KIT in gastrointestinal stromal tumours. Nature 467,849–853

86. Cioffi, A. and Maki, R.G. (2015) GI stromal tumors: 15 years oflessons from a rare cancer. J. Clin. Oncol. 33, 1849–1854

87. Duensing, A. (2015) Targeting ETV1 in gastrointestinal stromaltumors: tripping the circuit breaker in GIST? Cancer Discov. 5,231–233

88. Ran, L. et al. (2015) Combined inhibition of MAP kinase and KITsignaling synergistically destabilizes ETV1 and suppresses GISTtumor growth. Cancer Discov. 5, 304–315

89. Gill, A.J. et al. (2010) Immunohistochemistry for SDHB triagesgenetic testing of SDHB, SDHC, and SDHD in paraganglioma–pheochromocytoma syndromes. Hum. Pathol. 41, 805–814

90. Favier, J. et al. (2015) Paraganglioma and phaeochromocytoma:from genetics to personalized medicine. Nat. Rev. Endocrinol.11, 101–111

91. Gill, A.J. et al. (2011) Renal tumors associated with germlineSDHB mutation show distinctive morphology. Am. J. Surg.Pathol. 35, 1578–1585

92. Williamson, S.R. et al. (2015) Succinate dehydrogenase-defi-cient renal cell carcinoma: detailed characterization of 11 tumorsdefining a unique subtype of renal cell carcinoma. Mod. Pathol.28, 80–94

93. Wang, Y.M. et al. (2015) Succinate dehydrogenase-deficientgastrointestinal stromal tumors. World J. Gastroenterol. 21,2303–2314

94. Miettinen, M. et al. (2011) Succinate dehydrogenase-deficientGISTs: a clinicopathologic, immunohistochemical, and molecu-lar genetic study of 66 gastric GISTs with predilection to youngage. Am. J. Surg. Pathol. 35, 1712–1721

95. Chou, A. et al. (2012) Succinate dehydrogenase-deficient GISTsare characterized by IGF1R overexpression. Mod. Pathol. 25,1307–1313

96. Boikos, S.A. et al. (2014) Thyroid hormone inactivation in gas-trointestinal stromal tumors. N. Engl. J. Med. 371, 85–86

97. Boikos, S.A. and Stratakis, C.A. (2014) The genetic landscape ofgastrointestinal stromal tumor lacking KIT and PDGFRA muta-tions. Endocrine 47, 401–408

98. Boikos, S.A. et al. (2016) Carney triad can be (rarely) associatedwith germline succinate dehydrogenase defects. Eur. J. Hum.Genet. 24, 569–573

99. Zhang, L. et al. (2010) Gastric stromal tumors in Carney triad aredifferent clinically, pathologically, and behaviorally from sporadicgastric gastrointestinal stromal tumors: findings in 104 cases.Am. J. Surg. Pathol. 34, 53–64

100. Carney, J.A. (1999) Gastric stromal sarcoma, pulmonary chon-droma, and extra-adrenal paraganglioma (Carney triad): naturalhistory, adrenocortical component, and possible familial occur-rence. Mayo Clin. Proc. 74, 543–552

101. Matyakhina, L. et al. (2007) Genetics of carney triad: recurrentlosses at chromosome 1 but lack of germline mutations in genesassociated with paragangliomas and gastrointestinal stromaltumors. J. Clin. Endocrinol. Metab. 92, 2938–2943

102. Benn, D.E. et al. (2006) Clinical presentation and penetrance ofpheochromocytoma/paraganglioma syndromes. J. Clin. Endo-crinol. Metab. 91, 827–836

103. Pantaleo, M.A. et al. (2015) Good survival outcome of metastaticSDH-deficient gastrointestinal stromal tumors harboring SDHAmutations. Genet. Med. 17, 391–395

104. Bannon, A.E. et al. (2017) Biochemical, molecular, and clinicalcharacterization of succinate dehydrogenase subunit A variantsof unknown significance. Clin. Cancer Res. 23, 6733–6743

105. Debiec-Rychter, M. et al. (2006) KIT mutations and dose selec-tion for imatinib in patients with advanced gastrointestinal stro-mal tumours. Eur. J. Cancer 42, 1093–1103

106. Ganjoo, K.N. et al. (2014) A multicenter Phase II study of pazo-panib in patients with advanced gastrointestinal stromal tumors(GIST) following failure of at least imatinib and sunitinib. Ann.Oncol. 25, 236–240

107. Corless, C.L. et al. (2014) Pathologic and molecular featurescorrelate with long-term outcome after adjuvant therapy ofresected primary GI stromal tumor: the ACOSOG Z9001 trial.J. Clin. Oncol. 32, 1563–1570

108. Joensuu, H. et al. (2012) One vs three years of adjuvant imatinibfor operable gastrointestinal stromal tumor: a randomized trial.JAMA 307, 1265–1272

109. Ben-Ami, E. et al. (2016) Long-term follow-up results of themulticenter Phase II trial of regorafenib in patients with meta-static and/or unresectable GI stromal tumor after failure ofstandard tyrosine kinase inhibitor therapy. Ann. Oncol. 27,1794–1799

110. Nannini, M. et al. (2013) Expression of IGF-1 receptor in KIT/PDGF receptor-alpha wild-type gastrointestinal stromal tumorswith succinate dehydrogenase complex dysfunction. FutureOncol. 9, 121–126

111. Lasota, J. et al. (2013) Expression of the receptor for type iinsulin-like growth factor (IGF1R) in gastrointestinal stromaltumors: an immunohistochemical study of 1078 cases withdiagnostic and therapeutic implications. Am. J. Surg. Pathol.37, 114–119

112. Mahadevan, D. et al. (2014) Phase 1b study of safety, tolerabilityand efficacy of R1507, a monoclonal antibody to IGF-1R incombination with multiple standard oncology regimens in


http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0355http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0355http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0355http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0360http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0360http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0360http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0360http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0365http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0365http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0365http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0370http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0370http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0370http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0375http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0375http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0375http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0380http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0380http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0380http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0385http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0385http://refhub.elsevier.com/S2405-8033(17)30218-2/sbref0385http://refhub.elsevier.com/S2405-8033(17)3021

Documents

Gastrointestinal Stromal Tumors: The GIST of Precision Medicine.download.xuebalib.com/4g8zA74awXOb.pdf · Gastrointestinal Stromal Tumors: The GIST of Precision Medicine ... in many