Sporadic Gastrointestinal Stromal Tumors Research Articles

Gastrointestinal stromal tumours (GIST) in children: An update of this orphan disease

Gastrointestinal stromal tumours (GIST) are tumours of the digestive tract that mainly develop in adults. Recommendations for the management of GIST in pediatrics are limited. We performed an updated review of the literature serving as a basis for the development of diagnostic and therapeutic recommendations for GIST in children and young adults (YA). GIST in pediatric population can have a sporadic presentation but occur more often in a syndromic and/or familial context. Currently more than 170 cases of sporadic GIST or in association with Carney-Stratakis syndrome or Carney's triad family cases of familial GIST have been described in children and YA. These syndromes are frequently associated with germline or somatic alterations in a sub-unit of Succinate Dehydrogenase (SDH). In contrast, the frequency of somatic KIT and PDGFRα oncogene mutations (±15%) is significantly lower as compared to adults with GIST. The recommendations for the management of children with GIST are generally comparable to those used for adult patients, although certain biological differences influence the therapeutic attitude. International collaborations have been deployed in order to increase the clinical and biological knowledge of this orphan pathology in pediatrics.

Characteristics of gastrointestinal stromal tumors associated to other tumors: Características de los tumores del estroma gastrointestinal asociados a otras neoplasias.

IntroductionOur aim is to analyze the differences between sporadic gastrointestinal stromal tumors and those associated with other tumors. MethodsRetrospective cohort study including patients with diagnosis of gastrointestinal stromal tumors operated at our center. Patients were divided into two groups, according to whether or not they had associated other tumors, both synchronously and metachronously. Disease free survival and overall survival were calculated for both groups. Results96 patients were included, 60 (62.5%) were male, with a median age of 66.8 (35–84). An association with other tumors was found in 33 cases (34.3%); 12 were synchronous (36.3%) and 21 metachronous (63.7%). The presence of mutations in associated tumors was 70% and in non-associated tumors 75%. Associated tumors were classified as low risk tumors based on Fletcher’s stratification scale (p = 0.001) as they usually were smaller in size and had less than ≤5 mitosis per 50 HPF compared to non-associated tumors. When analyzing overall survival, there were statistically significant differences (p = 0,035) between both groups. ConclusionThe relatively high proportion of gastrointestinal stromal tumors cases with associated tumors suggests the need to carry out a study to rule out presence of a second neoplasm and a long-term follow-up should be carried out in order to diagnose a possible second neoplasm. Gastrointestinal stromal tumors associated with other tumors have usually low risk of recurrence with a good long-term prognosis.

A Rare PDGFRA Exon 15 Germline Mutation Identified in a Patient With Phenotypic Manifestations Concerning for GIST-Plus Syndrome: A Case Report and Review of Literature.

Molecular alterations in PDGFRA are well-described as drivers of sporadic gastrointestinal stromal tumors (GISTs) and inflammatory fibroid polyps (IFPs). However, a small number of families with germline PDGFRA mutations in exons 12, 14, and 18 have been reported, forming the basis of an autosomal dominant inherited disorder with incomplete penetrance and variable expressivity, now referred to as PDGFRA-mutant syndrome or GIST-plus syndrome. Phenotypic manifestations of this rare syndrome include multiple gastrointestinal GISTS, IFPs, fibrous tumors, and other variable features. Herein, we report the case of a 58-year-old female who presented with a gastric GIST and numerous small intestinal IFPs, found to harbor a previously undescribed germline PDGFRA exon 15 p.G680R mutation. Somatic tumor testing was performed on the GIST, a duodenal IFP, and an ileal IFP utilizing a targeted next-generation sequencing panel, revealing additional and distinct secondary PDGFRA exon 12 somatic mutations in each of the 3 tumors. Our findings raise important considerations regarding mechanisms of tumor development in patients with underlying germline PDGFRA alterations and highlight the potential utility of expanding currently available germline and somatic testing panels to include exons outside the typical hotspot regions.

Neurofibromatosis type 1-associated gastrointestinal stromal tumor: A case report and review of the literature

Introduction: Gastrointestinal stromal tumors (GIST), although very rare, are the most common mesenchymal neoplasms of the gastrointestinal tract and develop in approximately 5–25% of patients with neurofibromatosis type 1 (NF1). Neurofibromatosis type 1-associated GIST (NF1-GIST) differ phenotypically and genotypically from sporadic GIST, neither present receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor-alfa (PDGFR-alfa) mutation and have propensity to be multifocal and to occur in the small bowel. Case Report: We present a case of NF1-GIST, with multiple primary lesions, initially diagnosed as metastatic GIST, with treatment implications. Conclusion: Different characteristics of NF1-GIST should be empathized so the evidence of multifocal GIST not be confused with advanced/metastatic GIST, influencing treatment options. Identifying this tumor early allows surgical treatment with potential cure, because GIST are mostly treatable tumors with indolent behavior. Currently, no standard drug therapy for unresectable or relapsed NF1-GIST has been established.

Clinicopathological characteristics and prognosis of patients with sporadic multiple primary gastrointestinal stromal tumors

Objective: To investigate the clinicopathological characteristics and prognosis of sporadic multiple primary gastrointestinal stromal tumor (GIST). Methods: A retrospective cohort study was conducted. Case inclusion criteria: (1) postoperative pathological diagnosis of GIST; (2) primary GIST with single lesion or sporadic multiple primary GIST (sporadic GIST was defined as primary GIST other than familial and syndrome-related GIST, and multiple primary GIST was defined as the number of primary GISTs in the same patient ≥ 2); (3) patients with complete clinicopathological data. Those with tumor recurrence or distant metastasis, and with other malignancies were excluded. Medical records of patients with primary GIST who underwent surgical resection in the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2010 to December 2020 were collected. Patients were divided into sporadic multiple primary GIST group and single primary GIST group according to the number of primary GIST lesions. The clinicopathological data and prognosis of the two groups were observed and compared. Results: A total of 1200 patients with primary GIST were enrolled in this study, including 628 males (52.3%) and 572 females (47.7%), with a median onset age of 58 (19-93) years. Among them, 1165 cases (97.1%) were sporadic primary GIST with single lesion; 35 cases (2.9%) were sporadic multiple primary GIST. Among 35 cases of sporadic multiple primary GIST, 3 cases (8.6%) had acid reflux as the first symptom, which was higher than the single primary GIST group (22/1165, 1.9%) (χ(2)=7.437, P=0.006). There were no significant differences in other clinical characteristics between the two groups (all P>0.05). Patients in the sporadic multiple primary GIST group contained a total of 80 primary tumors. Compared with the single primary GIST group, the sporadic multiple primary GIST group had a higher proportion of tumors originating in the stomach [87.5% (70/80) vs. 59.1% (689/1165)], lower proportion of spindle cell in histology [85.0% (68/80) vs. 93.7% (1092/1165)], higher proportion of positive CD34 [97.5% (78/80) vs. 87.6% (1021/1165)], smaller maximum diameter [maximum diameter ≤2.0 cm: 61.2% (49/80) vs. 28.8% (335/1165)], lower mitotic rate [≤5/50 high-power fields (HPF): 93.8% (75/80) vs. 74.5% (868/1165)], lower risk of recurrence [60.0% (48/80) vs. 23.3% (271/1165)], and the differences were all statistically significant (all P<0.05). The 3-year recurrence-free survival rate in the sporadic multiple primary group and the single primary GIST group was 96.6% and 89.3% respectively (P=0.160), and the 3-year overall survival rate was 100.0% and 92.8%, respectively (P=0.088). Conclusions: The most common type of sporadic multiple primary GIST is multiple tumors originating in the stomach at the same time. Compared with primary GIST with single lesion, sporadic multiple primary GIST presents smaller maximum diameter and lower mitotic rate. The prognosis of patients between two groups is not significantly different.

Multiple jejunal gastrointestinal stromal tumors and Neurofibromatosis type 1: A rare association.

Introduction and importanceThe association between gastrointestinal stromal tumor (GIST), mesenchymal tumor arising from the interstitial cells of cajal and Neurofibromatosis type 1 (NF1), an autosomal dominant disease has been reported in the literature. GIST in NF1 patients are multiple and located in the small intestine. Tumorigenesis in NF1 associated GIST is different to that of sporadic GIST and hence the treatment. Here we report a rare case of an NF1 patient with multiple jejunal GISTs.Case presentationWe here present a rare case of a 57-year-old male diagnosed with NF1 30 years back, presented in our emergency department with complaints of black, tarry stools later diagnosed to have multiple GIST in jejunum. Contrast enhanced computed tomography (CECT) of the abdomen showed a large 10.1 × 7.33 × 6.2 cm heterogeneous, exophytic, solid mass with cystic areas originating from the jejunum. The microscopic examination of the specimen showed spindle shaped tumor cells while immunohistochemistry showed CD117 (c-KIT) and DOG-1 positivity. The primary treatment was complete surgical excision of the tumor.Clinical discussionThe incidence of GISTs in NF1 patient is around 6–7%; however, concomitant presence of multiple GISTs is rare. CECT of abdomen along with histopathological and immunohistochemistry studies are diagnostic. The management of GIST includes surgical and adjuvant therapy methods based on the tumorigenesis and recurrent risk stratification.ConclusionEarly clinical suspicion and imaging aids in early detection of the tumor in patients with NF1 presenting with gastrointestinal symptoms. Postoperatively, screening for recurrence with radiology is of utmost importance.

Identification of SDHA germline mutations in sporadic SDHA mutant gastrointestinal stromal tumors (GIST): The need of a genetic counselling.

11537 Background: SDH- deficient GIST, as defined by the loss of expression of SDHB, account up to about 10% of all gastric GIST and generally affect younger population. Germline mutations in SDHB, SDHC, and SDHD occur in about 20–30% of SDH- deficient, that may be referred to a hereditary condition known as hereditary GIST-paraganglioma syndrome (Carney-Stratakis Syndrome), whereas germline SDHA mutations have been rarely described in apparently sporadic cases. Currently, even germline testing is recommended for SDH- deficient GIST, there are no clear guidelines for genetic counselling and follow-up of SDH x mutation carriers and relatives, especially for SDHA mutant GIST not yet linked to well-defined hereditary syndrome. The aim of this work was to study the SDHA gene in the normal DNA of patients with SDHA mutant GIST. Methods: Thirteen patients carrying SDHA-mutant GIST were studied (8F/5M). Median age of diagnosis was 45,9 years (range 25-74). All GIST were located in the stomach and 3 patients out 13 presented a metastatic disease. In all cases except one, the GIST was the only cancer presentation and no personal or familial history of cancer was revealed. All cases were negative for SDHB immunohistochemistry. Germline mutations were identified through Sanger sequencing of SDHA in the normal counterpart. Results: Germline mutations were identified in all patients for which normal counterpart was available: 4 cases harboured truncating mutations (S384X, R31X and W119X); 5 cases carried pathogenic missense mutations (G233V, R171H, R589Q, G257A and R600Q) and 2 cases had splice site alterations (c.457-3_457-1 delCAG and c.456+9 C &gt; T). In 8 cases the tumor DNA showed the loss of the corresponding wild-type allele, while in the other 3 cases compound heterozygosity for an additional somatic mutation was detected (R589W, R451C,and R171C). In 2 patients, unfortunately, normal DNA was not available, however both tumours carried two mutational hits on SDHA (one with heterozygous G419R and E564K, and one with homozygous R585Q). Of note, 5 patients presented un-usaul SDHA related clinical characteristics as were not young adult ( &gt; 50 years-old) or no multifocal GIST. Conclusions: We demonstrated that germline SDHA mutations are highly frequent in SDHA- deficient GIST. Therefore, although a clear syndrome has not been defined, genetic counselling and follow-up of SDHA mutation carriers and relatives should be clarified.

Clinicopathologic characteristics, diagnostic clues, and prognoses of patients with multiple sporadic gastrointestinal stromal tumors: a case series and review of the literature

BackgroundMost sporadic gastrointestinal stromal tumors (GISTs) occur as solitary tumors, while multiple sporadic GISTs are extremely rare and often misdiagnosed as metastatic GISTs, leading to inappropriate treatment. This study aimed to investigate the clinicopathological characteristics, diagnostic clues, and prognoses of multiple sporadic GISTs.MethodsTwenty-seven patients with multiple sporadic GISTs and 11 patients with metastatic GISTs mimicking sporadic GISTs were analyzed. The clinicopathological characteristics, genetic mutation types, and prognoses were summarized. In addition, 1066 cases of primary GISTs with a single lesion diagnosed at the same hospital were included as controls.ResultsCompared with 1066 cases of primary GIST with a single lesion, multiple sporadic GISTs occurred at an older age, were more common in women than in men, and were located mainly in the stomach. They were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Mutation analysis of all available lesions revealed different KIT/PDGFRA mutation patterns among tumors from the same patients. No patient relapsed during the follow-up period. Among 11 patients with metastatic GISTs that mimicked multiple sporadic GISTs, multiple lesions from the same patient always had concordant pathological and mutational characteristics; namely, they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high.ConclusionsThe prognoses of patients with multiple sporadic GISTs were not worse than those of patients with a single lesion of the same risk under the same treatment. When it was difficult to distinguish multiple sporadic GISTs from metastatic GISTs, multiple lesions in the same patient carried different KIT/PDGFRA mutation patterns, which supported tumor multiplicity, while the concordant hypermitotic phase in multiple lesions of GISTs suggested that the tumor was metastatic.

Gastrointestinal stromal tumors: Do we follow the current guidelines? A self-critique

Background: Despite its rarity, gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Several guidelines are currently present where, among other recommendations, mutational analysis and referral to specialized centers have been mentioned. However, this might be difficult to apply at times. Aim: The aim of the study is to explore our experience in the management of GIST. Patients and Methods: Histopathologically-proven GISTs, encountered in our hospital in the period from June 2012 to November 2018, were included in the study. Results: We identified 14 patients, 8 males and 6 females, with a mean age of 58.6 years. Thirteen patients were sporadic GIST, while one was syndromic (associated with neurofibromatosis, multifocal, and arose from the small gut). Twelve patients presented in an emergency situation, while two presented in an elective setting. Thirteen cases were primary localized GISTs and one was metastatic. The organs involved were the stomach in five cases, ileum in four cases, jejunum in two cases, duodenum in two cases, and rectum in one case. In 13 cases, the patient's complaint led to the diagnosis, while in one case, it was discovered incidentally on investigations for another illness. The main clinical features were abdominal pain in five cases, melena and anemia in four cases, hematemesis and melena in one case, rectal bleeding in one case, abdominal pain and mass in one case, intestinal obstruction in one case, and urinary retention and constipation in one case. The mean diameter of the cyst on computed tomography was 8.7 cm. An endoscopic biopsy was performed in six occasions and missed the diagnosis in four of them, whereas percutaneous biopsy was performed in five occasions and was suggestive in two cases and diagnostic in the remaining three. According to a combination of stage, (primary, metastatic, or recurrent) size, risk stratification, mode of presentation, performance status, and comorbidities, treatment was planned. Five patients received surgery only, three patients received surgery followed by imatinib, one patient left to be treated elsewhere, and three patients received surgery to be followed by imatinib but did not show up, one patient received imatinib only, and one patient is still under evaluation. The mean duration of follow-up was 65.7 months, where the disease showed no recurrence in four cases, metastasized to the liver in two cases, and death occurred in two cases, while five cases were lost to follow-up. In this series, no mutational analysis was performed as imatinib was the only drug used, and no referral to specialized centers was done. Conclusion: Surgical resection and kit inhibitors, either alone or in sequence, are the main pillars of treatment of GIST. Risk stratification, in addition to the mode of presentation, the presence or absence of metastasis and comorbidities, dictates which plan to follow. Except for mutational analysis, and referral to specialized centers, our practices are in line with the current guidelines to a reasonable extent.

A Giant Jejunal Gastrointestinal Stromal Tumor Misconceived as Pancreatic Cystic Neoplasm : A case report

Introduction: Gastrointestinal stromal tumors(GIST) are the most common mesenchymal tumors of the gastrointestinal tract. The most common site of these tumors is the stomach. Jejunal GIST is a rare type. This report describes a patient with large sporadic GIST in the proximal jejunum that mimicking the pancreatic cystic neoplasm by preoperative imaging study. Method: A 59-year-old Thai female presented with unexplained weight loss and palpable left upper abdominal mass for 6 months. Computed tomography of the abdomen demonstrated a heterogeneously enhanced mass at pancreatic body and tail measuring 10 cm in diameter. The mucinous cystadenoma was the preoperative diagnosis. The distal pancreatectomy and splenectomy were planned. Result: Laparotomy allowed the identification of extramural tumor originated from proximal jejunum and closed to the ligament of Treitz. The tumor just only abut the body of pancreas. Enbloc resection of the tumor with proximal jejunal segment were mandated. Conclusion: Finally, histopathological and immunohistochemical examination revealed this tumor was the GIST.

Unusual occurrence of two sister tumours in the same patient- gastrointestinal stromal tumour and gastrointestinal autonomic nerve tumour

Gastrointestinal stromal tumours (GIST) account for less than 1% of gastrointestinal tumours, whereas Gastrointestinal autonomic nerve tumour (GANT) is a rare variant of gastrointestinal stromal tumour (GIST) and occurs at an estimated frequency of 1% of all malignant gastrointestinal tumours. We report the case of a 38-year old male which represents the rarity in the incidence of a Gastrointestinal Stromal tumour as well as the occurrence of a gastrointestinal autonomic nerve tumour together in the same patient which presented as a jejunal lump along with a terminal ileocecal intussusception. Multiple GISTs are associated with familial or hereditary syndromes are described only in few case reports whereas multiple sporadic GISTs have been rarely reported. This review aims to report the multiple sporadic occurrence of two types of GISTs as well as discuss highlight the features and prognosis of GANTs as surgeons and gastroenterologists are unaware of the existence of such an entity.

Survivin is a novel transcription regulator of KIT and is downregulated by miRNA-494 in gastrointestinal stromal tumors.

Gain‐of‐function mutations of KIT are pathognomonic in sporadic gastrointestinal stromal tumors (GISTs). Several microRNAs have been shown to be dysregulated in GISTs and impact KIT expression. Little is known though on KIT‐independent targets of KIT‐regulating mRNAs. We sought to investigate how miR‐494 inhibits GIST proliferation and to identify novel target gene. We used microarray‐based gene expression analyses to identify pathways and target genes affected by miR‐494. The expressional relationship between survivin and miR‐494 was determined in 35 GIST tissues. Cell proliferation assay, FACS analysis, colony formation assay, promoter assays and chromatin immunoprecipitation (ChiP) were performed to clarify the roles of survivin in GIST progression. Gene expression microarray analysis revealed that miR‐494 inhibited GISTs by affecting multiple genes in the cell cycle pathway. Survivin (BIRC5) was a key target of miR‐494, and its expression showed an inverse correlation with miR‐494 expression in 35 GIST tissues (Pearson's correlation coefficient, r = −0.418, p = 0.012). Downregulation of survivin inhibited proliferation and colony formation, and resulted in cell cycle alteration. Induced survivin overexpression relieved miR‐494‐mediated inhibition of GIST progression. Targeting PI3K effectively suppressed proliferation of GISTs with downregulation of survivin. Survivin also regulated KIT expression at the transcription level. Immunohistochemical analysis using 113 GISTs revealed that survivin expression was significantly correlated with overall survival of GIST patients (p = 0.004). Our findings indicated that miR‐494 synergistically suppressed GISTs by concomitantly targeting survivin and KIT.

Abstract A15: Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation

Abstract Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma, characterized by activating mutations in KIT, PDGFRA, BRAF, N/H/KRAS, and loss of function genetic/epigenetic alterations in NF1, SDH-complex. Despite clinical advances for KIT/PDGFRA-mutant GIST, the scientific and clinical advances for KIT/PDGFRA-wild type GISTs have remained extremely limited due to the lack of model systems. Due to the lack of ICC-lineage specific cre system, modeling for sporadic GIST has not been feasible. ETV1 has recently been described as an ICC and GIST-lineage specific master regulator. Here, using the cre-activated Rosa26CAGGS-LSL-EYFP system, we demonstrate that Etv1CREERT2 preferentially activates cre in the Etv1-expressing ICC lineage by tamoxifen. Using the BrafCA conditional allele for cre-activated BrafV600E, we observed that BrafV600E alone, while leading to development of ICC hyperplasia, is not sufficient to drive GIST tumorigenesis. Combination of BrafV600E activation and Trp53 loss not only gives rise to ICC hyperplasia, but also leads to multifocal GIST-like tumors in mouse GI tract with 100% penetrance. We further demonstrate that the BrafV600E; Tp53-/- sporadic GIST mouse models are amenable for therapeutic intervention and recapitulate clinical responses to RAF inhibitors in human GIST. Our observations provide the first in vivo model for understanding the pathogenesis and therapeutic responses in BRAF-mutant GISTs. Importantly, these observations provide the proof of principle for modeling sporadic GIST in adult mice using the Etv1CREERT2 system and establish the feasibility and utility of establishing model systems for human GISTs that do not have any model systems available for mechanistic studies and therapeutic development. Citation Format: Leili Ran, Devan Murphy, Jessica Sher, Zhen Cao, Shangqian Wang, Edward Walczak, Youxin Guan, Yuanyuan Xie, Shipra Shukla, Yu Zhan, Cristina R. Antonescu, Yu Chen, Ping Chi. Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A15.

Abstract B088: Identification of a novel regulator in GIST tumorigenesis

Abstract Purpose: Gain-of-function mutations of KIT are pathognomonic in the majority of sporadic gastrointestinal stromal tumors (GISTs). Several micro-RNAs have been shown to be dysregulated in GISTs and impact KIT expression levels. Little is known, though, about KIT-independent targets of KIT-regulating mRNAs. We sought to investigate how miR-494 inhibits GIST proliferation and to identify novel target gene. Experimental Design: We used gene expression analyses to identify pathways and target genes affected by miR-494. The expressional relationship between Survivin and miR-494 was determined in 35 GIST tissues. Cell proliferation assay, FACS analysis, colony formation assay, and promoter assays were performed to clarify the roles of Survivin in GIST progression. Results: Gene expression microarray analysis revealed that miR-494 inhibited GISTs by affecting multiple genes in the cell cycle pathway. Survivin was a key target gene of miR-494. Analysis of the 35 GISTs revealed that there was an inverse correlation between Survivin and miR-494 expression (Pearson’s correlation coefficient, r = -0.418, P = 0.012). Downregulation of Survivin inhibited proliferation and colony formation, and resulted in cell cycle alteration. Induced Survivin overexpression relieved miR-494 mediated inhibition of GIST progression. Targeting PI3K effectively suppressed proliferation of GISTs with downregulation of Survivin. Survivin regulated KIT expression at the transcription level. Immunohistochemical analysis using 113 GIST tissues revealed that Survivin expression was significantly correlated with overall survival of GIST patients (P = 0.004). Conclusion: Our findings indicated that miR-494 synergistically suppressed GISTs by concomitantly targeting Survivin and KIT, with accompanying vertical blockade of the PI3K pathways. Citation Format: Seongju Yun, Won Kyu Kim, Hoguen Kim. Identification of a novel regulator in GIST tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B088.

Abstract 1330: HSP90 inhibitor has a possibility to overcome imatinib resistance in gastrointestinal stromal tumors

Abstract [Background] Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract and are reported to harbor gain-of-function mutations in the KIT gene, which contribute to the development of sporadic GISTs. This knowledge has facilitated the development of targeted therapies with tyrosine kinase inhibitors and the revolutionary chemotherapeutic drug imatinib mesylate (IM). In clinical trials, the disease control rate was nearly 85%, and corresponding 2-year overall survival rates ranged from 70-80%, indicating markedly improved patient outcomes compared with anecdotal data in the pre-IM era. Despite its effectiveness, half of GISTs treated with IM develop resistance within 2 years, largely due to the accumulation of additional kinase domain mutations accompanied by concomitant re-activation of the KIT tyrosine kinase, even in the presence of IM. Heat shock protein 90 (HSP90) is one of chaperon molecules required for the proper folding, function, and stability of various client proteins such as KIT. The aim of this study is to clarify the efficacy of HSP90 inhibitor against IM resistant GIST. [Material and Method] We used the established human GIST cell line GIST-T1, and two IM-resistant cell lines (GIST-T1R8, GIST-T1R9), which had additional kinase domain mutations accompanied by concomitant re-activation of the KIT tyrosine kinase same as clinical samples, by exposure to IM. These resistant cell lines exhibited imatinib IC50 values (&amp;gt;10 μM) that were &amp;gt;1000-fold higher than the parental cell line. We investigated the cytotoxicity and signaling inhibition by HSP90 inhibitor using by the WST-8 assay, caspase3/7 apoptosis assay and western blotting. Immunobolts for KIT and for KIT-depending signaling pathways were observed at 12 hours of treatment. Caspase 3/7 apoptosis assay was measured after 24h. [Result] HSP90 inhibitor showed growth inhibition not only for GIST T1 but also GIST-T1R8 and GIST-T1R9. Apoptosis induction of these cell lines were also confirmed by the exposure to HSP90 inhibitor in a dose-dependent manner. To find the mechanism of apoptosis induced by HSP90 inhibitor, we investigated the signaling pathway depending on KIT. HSP90 inhibitor showed inhibition of phosphorylated-KIT, a client for HSP90, in both IM sensitive and resistant GIST cell lines. And, it also inhibited downstream of KIT signaling, e.g. p-ERK and p-AKT. [Conclusions]HSP90 inhibitor showed the anti-tumor efficacy for imatinib resistant GIST in vitro. It might have a possibility to apply for clinical use. Citation Format: Yurina Saito, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Koji Tanaka, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka. HSP90 inhibitor has a possibility to overcome imatinib resistance in gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1330. doi:10.1158/1538-7445.AM2017-1330

MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation

KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.

Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome.

The majority of gastrointestinal stromal tumors (GIST) are driven by KIT, PDGFRA, or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs. Twenty-two sporadic quadruple-negative GISTs with no prior association with Neurofibromatosis Type 1 syndrome were molecularly profiled for a panel of genes belonging to tyrosine kinase pathways or previously implicated in GISTs. For comparison purposes, 24 GISTs carrying KIT, PDGFRA, or SDH gene mutations were also analyzed. Molecular findings were correlated to clinicopathologic features. Most quadruple-negative GISTs featured intestinal localization, with a female predilection. About 60% (13/22) of quadruple-negative tumors carried NF1 pathogenic mutations, often associated with biallelic inactivation. The analysis of normal tissues, available in 11 cases, indicated the constitutional nature of the NF1 mutation in 7 of 11 cases, unveiling an unrecognized Neurofibromatosis Type 1 syndromic condition. Multifocality and a multinodular pattern of growth were common findings in NF1-mutated quadruple-negative GISTs. NF1 gene mutations are frequent in quadruple-negative GISTs and are often constitutional, indicating that a significant fraction of patients with apparently sporadic quadruple-negative GISTs are affected by unrecognized Neurofibromatosis Type 1 syndrome. Hence, a diagnosis of quadruple-negative GIST, especially if multifocal or with a multinodular growth pattern and a nongastric location, should alert the clinician to a possible Neurofibromatosis Type 1 syndromic condition. Clin Cancer Res; 23(1); 273-82. ©2016 AACR.

Syndromic gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract. They feature heterogeneous triggering mechanisms, implying relevant clinical differences. The vast majority of GISTs are sporadic tumors. Rarely, however, GIST-prone syndromes occur, mostly depending on heritable GIST predisposing molecular defects involving the entire organism. These conditions need to be properly identified in order to plan appropriate diagnostic, prognostic and therapeutic procedures.Clinically, GIST-prone syndromes must be thought of whenever GISTs are multiple and/or associated with accompanying signs peculiar to the background tumorigenic trigger, either in single individuals or in kindreds. Moreover, syndromic GISTs, individually considered, tend to show distinctive features depending on the underlying condition. When applicable, genotyping is usually confirmatory.In GIST-prone conditions, the prognostic features of each GIST, defined according to the criteria routinely applied to sporadic GISTs, combine with the characters proper to the background syndromes, defining peculiar clinical settings which challenge physicians to undertake complex decisions. The latter concern preventive therapy and single tumor therapy, implying possible surgical and molecularly targeted options.In the absence of specific comprehensive guidelines, this review will highlight the traits characteristic of GIST-predisposing syndromes, with particular emphasis on diagnostic, prognostic and therapeutic implications, which can help the clinical management of these rare diseases.

Multiple Gastric Gastrointestinal Stromal Tumors in a Patient with Neurofibromatosis Type 1.

Gastrointestinal stromal tumors (GISTs) are relatively common in neurofibromatosis type 1 (NF 1) patients. Approximately 90% of GISTs associated with NF 1 are located in the small intestine, while sporadic GISTs are most commonly located in the stomach. Here we report an extremely rare case of an NF 1 patient with multiple gastric GITs (90 or more) but without multiple small intestinal tumors. A 63-year-old female patient who had a history of NF 1 underwent surgery for a gastric neuroendocrine tumor and gastric submucosal tumor (SMT). During the operation, multiple small nodules were identified on the serosal surface of the upper stomach. SMT and multiple nodules on the serosal surface were diagnosed as GISTs consisting of spindle cells positive for KIT, CD34, and DOG-1. Both GIST and the normal gastric mucosa showed no mutations not only in the c-kit gene (exons 8, 9, 11, 13, and 17) but also in the PDGFRA gene (exons 12, 14, and 18). This patient is being followed up without the administration of a tyrosine kinase inhibitor.

Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case.

BackgroundApproximately 10–15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these “wild type” GISTs.MethodsPaired tumor and normal DNA from an SDH-intact wild-type GIST case was subjected to whole exome sequencing to identify the pathogenic mechanism(s) in this tumor. Selected findings were further investigated in panels of GIST tumors through Sanger DNA sequencing, quantitative real-time PCR, and immunohistochemical approaches.ResultsA hemizygous frameshift mutation (p.His2261Leufs*4), in the neurofibromin 1 (NF1) gene was identified in the patient’s GIST; however, no germline NF1 mutation was found. A somatic frameshift mutation (p.Lys54Argfs*31) in the MYC associated factor X (MAX) gene was also identified. Immunohistochemical analysis for MAX on a large panel of GISTs identified loss of MAX expression in the MAX-mutated GIST and in a subset of mainly KIT-mutated tumors.ConclusionThis study suggests that inactivating NF1 mutations outside the context of neurofibromatosis may be the oncogenic mechanism for a subset of sporadic GIST. In addition, loss of function mutation of the MAX gene was identified for the first time in GIST, and a broader role for MAX in GIST progression was suggested.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1872-y) contains supplementary material, which is available to authorized users.