Growth Factor Receptor Alpha Gene Research Articles

Understanding Gastric GIST: From Pathophysiology to Personalized Treatment.

Background: Gastric gastrointestinal stromal tumors (GISTs) represent a subset of gastrointestinal tumors predominantly found in the stomach. Despite their rarity, these tumors carry significant implications for patient health and management. GISTs are potentially malignant tumors with unpredictable progression. They originate from the interstitial cells of Cajal, which are positioned between the intramural neurons and the smooth muscle cells of the digestive tract. These tumors are characterized primarily by mutations in the c-Kit gene, as well as other mutations such as those in the platelet-derived growth factor receptor alpha (PDGFRA) gene. Methods: Our comprehensive search across five databases initially yielded 2976 articles. After eliminating 197 duplicates, we screened the titles and abstracts of 2779 articles, excluding 2692 for not meeting the inclusion criteria. During the full-text screening, 16 more articles were excluded. Ultimately, 71 papers met the inclusion criteria and were included in our analysis. Results: Due to differences in study designs, inclusion criteria for patients, and reported outcomes, a meta-analysis was not conducted. The accurate diagnosis of GIST is established through histopathological examination and immunohistochemistry. Histopathologically, GISTs are classified into three main types: spindle cell, epithelioid, and mixed. The therapeutic management of GIST involves surgery, endoscopic treatment, and chemotherapy. Conclusions: The prognosis for GIST patients depends on various factors, including risk category, disease stage, applied treatments, and recurrence post-treatment. A significant recent advancement comes from artificial intelligence, which can be increasingly involved in both the diagnosis and treatment of this tumor.

Association between Platelet-Derived Growth Factor Receptor Alpha Gene Polymorphisms and Platelet-Rich Plasma's Efficiency in Treating Lateral Elbow Tendinopathy-A Prospective Cohort Study.

Individual differences in the response to platelet-rich plasma (PRP) therapy can be observed among patients. The genetic background may be the cause of this variability. The current study focused on the impact of genetic variants on the effectiveness of PRP. The aim of the present study was to analyze the impact of single nucleotide polymorphisms (SNP) of the platelet-derived growth factor receptor alpha (PDGFRA) gene on the effectiveness of treating lateral elbow tendinopathy (LET) with PRP. The treatment's efficacy was analyzed over time (2, 4, 8, 12, 24, 52 and 104 weeks after the PRP injection) on 107 patients using patient-reported outcome measures (PROM) and achievement of a minimal clinically important difference (MCID). Four SNPs of the PDGFRA gene (rs7668190, rs6554164, rs869978 and rs1316926) were genotyped using the TaqMan assay method. Patients with the AA genotypes of the rs7668190 and the rs1316926 polymorphisms, as well as carriers of the T allele of rs6554164 showed greater effectiveness of PRP therapy than carriers of other genotypes. Moreover, the studied SNPs influenced the platelets' parameters both in whole blood and in PRP. These results showed that PDGFRA gene polymorphisms affect the effectiveness of PRP treatment. Genotyping the rs6554164 and the rs1316926 SNPs may be considered for use in individualized patient selection for PRP therapy.

Surgery for multiple gastric gastrointestinal stromal tumors and large esophageal diverticulum related to germline mutation of the KIT gene: a case report

BackgroundFamilial gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract caused by germline gain-of-function mutations in the KIT gene or platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations cause not only multiple GISTs but also diffuse hyperplasia of interstitial cells of Cajal (ICCs), which is related to esophageal motility disorder.Case presentationA 53-year-old man was referred to our hospital because of anemia and dysphagia. Fifteen years earlier, he had undergone a laparoscopic partial gastrectomy for multiple gastric GISTs with a germline mutation in exon 17 of the KIT gene. An upper gastrointestinal endoscopy revealed that the patient had multiple gastric GISTs and a large esophageal diverticulum directly above the esophagogastric junction. The largest gastric tumor was 7 cm, with a delle that might cause bleeding. Because the patient presented with dysphagia, we performed video-assisted thoracic esophagectomy and laparoscopic-assisted proximal gastrectomy simultaneously. The patient had survived without metastasis for 4 years after surgery and dysphagia had improved.ConclusionsThis is the first report of successful laparoscopic–thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.

Association of PDGFRA polymorphisms with the risk of corneal astigmatism in a Japanese population

Corneal astigmatism is reportedly associated with polymorphisms of the platelet-derived growth factor receptor alpha (PDGFRA) gene region in Asian populations of Chinese, Malay, and Indian ancestry and populations of European ancestry. In this study, we investigated whether these PDGFRA polymorphisms are associated with corneal astigmatism in a Japanese population. We recruited 1,535 cases with corneal astigmatism (mean corneal cylinder power across both eyes: ≤ − 0.75 diopters [D]) and 842 controls (> − 0.75 D) to genotype 13 single-nucleotide polymorphisms (SNPs) in the PDGFRA gene region. We also performed imputation analysis in the region, with 179 imputed SNPs included in the statistical analyses. The PDGFRA SNPs were not significantly associated with the cases with corneal astigmatism ≤ − 0.75 D. However, the odds ratios (ORs) of the minor alleles of SNPs in the upstream region of PDGFRA, including rs7673984, rs4864857, and rs11133315, tended to increase according to the degree of corneal astigmatism, and these SNPs were significantly associated with the cases with corneal astigmatism ≤ − 1.25 D or ≤ − 1.50 D (Pc < 0.05, OR = 1.34–1.39). These results suggest that PDGFRA SNPs play a potential role in the development of greater corneal astigmatism.

Morphological, immunohistochemical, and genetic analyses of epithelioid gastrointestinal stromal tumors

Epithelioid gastrointestinal stromal tumors (GISTs) are rare and may be confused with other tumors with epithelioid morphology. Therefore, herein, we collected 12 epithelioid GIST samples and summarized their morphological and immunohistochemical characteristics. Through genetic testing, we explored the correlation between morphology and gene mutations. The results showed that eight tumors showed focal or diffuse myxoid stromal changes with less cohesively arranged rhabdoid tumor cells; among these, five showed platelet-derived growth factor receptor alpha gene (PDGFRA) mutations. Signet ring cells with sclerosing stroma and receptor tyrosine kinase type III gene (KIT) mutations were present in two cases, which might be a KIT mutation-associated growth pattern in epithelioid GISTs. Succinate dehydrogenase gene (SDH) mutations were detected in three cases. Simultaneously, PDGFRA mutations were detected in two cases, and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation was detected in another case. SDH-subunit B (SDHB) expression was partially weak and strongly diffuse in two cases with concurrent PDGFRA and SDHD mutations, respectively. The coexistence of PDGFRA and SDHD mutations may have affected SDHB expression. Altogether, we concluded that PDGFRA mutations may play an important role in co-mutant GIST pathogenesis.

A STUDY ON RETROSPECTIVE ANALYSIS OF GASTROINTESTINAL STROMA TUMOURS.

Introduction:.Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal (GI) tract. They are believed to originate from the interstitial cells of Cajal (ICCs) or from the precursors of ICCs. Most GISTs show an activating mutation in either the c-kit or platelet-derived growth factor receptor alpha (PDGFRA) gene. Tumor size, mitotic rate, and anatomic location correlate with potential malignancy and recurrence rate. The aim of our study is to Aim &amp; Objectivesobserve the demographic and clinical characteristics of GIST in our clinical environment.Method- 30 patients who are diagnosed with GIST managed during the period from Jun 2017 to July 2022 were reviewed in terms of demographics, clinical presentation, location of tumor, characteristics, management, histopathology, IHC analysis, post op follow up &amp; recurrence.The risk stratication in terms of size, mitotic index, site of tumour was observed &amp; classied using modied NIH classication. Results- Out of 30 cases male patient's- 73% (n- 22); female patients27%(n-8). Mean age was 60 years with a range of 44-81 years. Most common clinical presentation was abdominal mass, Abdominal pain. Commonly involved sites are stomach and small bowel.4 cases who underwent multiple organ resection 2 cases developed recurrence in which 1 underwent palliative Whipple's procedure and one was medically managed. GIST Conclusion- s are rare entities with a variety of clinical features, Common sites for GIST are stomach &amp; small intestine. Surgery is the main stay of management in GIST. Neo adjuvant therapy will help in down staging the tumour. Wedge resection &amp; resection &amp;anastomosis will be adequate for stomach in small bowel GIST. En-bloc resection should be considered if adjacent structures are involved. Overall GIST has favourable prognosis if diagnosed early

Myxoid glioneuronal tumor: Histopathologic, neuroradiologic, and molecular features in a single center series

BackgroundMyxoid glioneuronal tumor (MGT) is a benign glioneuronal neoplasm recently introduced in the World Health Organization (WHO) classification of the central nervous system (CNS) tumors. MGTs are typically located in the septum pellucidum, foramen of Monro or periventricular white matter of the lateral ventricle. They were previously diagnosed as dysembryoplastic neuroepithelial tumors (DNT), showing histological features almost indistinguishable from classical cortical DNT. Despite that, MGTs have been associated with a specific dinucleotide substitution at codon 385 in the platelet-derived growth factor receptor alpha (PDGFRA) gene, replacing a lysine residue with either leucine or isoleucine (p. LysK385Leu/Iso). This genetic variation has never been described in any other CNS tumor. Materials and methodsThirty-one consecutive tumors, previously diagnosed as DNTs at the Meyer Children's Hospital IRCCS between January 2010 and June 2021 were collected for a comprehensive study of their clinical, imaging, pathological features, and molecular profile. ResultsIn six out of the thirty-one tumors we had previously diagnosed as DNTs, we identified the recurrent dinucleotide mutation in the PDGFRA. All six tumors were typically located within the periventricular white matter of the lateral ventricle and in the septum pellucidum. We then renamed these lesions as MGT, according to the latest WHO CNS classification. In all patients we observed an indolent clinical course, without recurrence. ConclusionMGT represent a rare but distinct group of neoplasm with a typical molecular profiling, a characteristic localization, and a relative indolent clinical course.

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications.

Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60-70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10-15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.

Association of MTOR and PDGFRA gene polymorphisms with different degrees of myopia severity

This study aims to investigate the associations of SNPs in the mammalian target of rapamycin (MTOR) and the platelet derived growth factor receptor alpha (PDGFRA) genes with different degrees of myopia severity in Han and Zhuang populations. The SNPs of MTOR (rs1057079, rs1064261, and rs2536) and PDGFRA (rs1800812, rs35597368, rs4358459, rs6554162, and rs7677751) were analyzed among 1347 patients with myopia (849 patients with high myopia and 498 patients with mild to moderate myopia) and 453 controls without myopia in Guangxi, China (collected 2016–2018). Genetic model association analysis was performed on each SNP in different myopia subgroups. The associations of rs1057079 and rs1064261 with mild to moderate myopia were observed under the dominant models (rs1057079: OR = 1.324, 95%CI: 1.005–1.744, P = 0.046; rs1064261: OR = 1.597, 95%CI: 1.099–2.319, P = 0.014). However, the association of SNP rs1057079 could not withstand multiple correction. The number of adverse genotypes in each sample was counted. Results showed that in the high myopia group, the levels of risk of myopia in patients carrying three to four and five to eight adverse genotypes were 1.734 and 2.062 times the level of risk in patients carrying two or lower genotypes, respectively. After the stratified analyses of Han and Zhuang populations, the Zhuang populations consistently had high frequencies of myopia. This study provides evidence suggesting that the MTOR and PDGFRA genes are associated with different degrees of myopia severity and have gene–gene interactions. In addition, this study discovered a new SNP of MTOR (rs1064261) that is associated with myopia. Thus, further longitudinal studies are warranted.

An oncogenic splice variant of PDGFR\u03b1 in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors

Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3’-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.

Extensive Degenerative Change Masquerading Histomorphology in a Giant Cystic Gastrointestinal Stromal Tumor With Rare PDGFRA Mutation

Gastrointestinal stromal tumors (GISTs) are the most frequent type of mesenchymal tumors of the gastrointestinal (GI) tract, and most of the time they acquire the mutation of special kinds of genes. GISTs may be familial or inherited and affect several family members of the family or can be sporadic. The risk of GIST is increased in people with mutations in the receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) genes. In this report, we present a case of a large GIST with extensive cystic and degenerative change in a 76-year-old female patient with a rare Asp842-His845 deletion mutation detected in PDGFRA exon 18, that required subtotal gastrectomy with en bloc resection.

Recent advances in the management of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is a rare but an important clinical entity seen in our clinical practice. It is the most common mesenchymal tumor of the gastrointestinal tract and most common malignancy of the small intestine. Although the exact prevalence of GIST is not known, the incidence of GIST has been increasing. GISTs arise from interstitial cells of Cajal. Most of the GISTs occur due to mutation in c-kit gene or platelet derived growth factor receptor alpha gene. 15% of GISTs do not have these mutations and they are called wild-type GISTs. Almost all GISTs express KIT receptor tyrosine kinase. Histologically, GISTs look like spindle cell tumors most of the time but they can be epitheloid or mixed type. The median size of GISTs varies from 2.7 cm to 8.9 cm. Clinically, patients with small GISTs remain asymptomatic but as the GIST size increases, patients present with various symptoms depending on the location of the GIST. Most of GISTs are located in the stomach or small bowel. Diagnosis is suspected on imaging and endoscopic studies, and confirmed by tissue acquisition with immunohistochemical staining. The aggressiveness of GISTs depends on the size, mitotic index and location. Surgical resection is the treatment of choice. But various endoscopic modalities of resection are increasingly being tried. Tyrosine kinase inhibitors are extremely useful in the management of large GISTs, unresectable GISTs and metastatic GISTs. Treatment options for metastatic GISTs also include radiotherapy, chemotherapy, hepatic artery embolization, chemoembolization and radiofrequency ablation.

Retrospective Analysis of Clinical Epidemiology in Gastrointestinal Stromal Tumour

Abstract Background Gastrointestinal Stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract (GIT) i.e. sarcoma. GIST is classified into mutation in KIT (cluster of differentiation 117, CD117) oncogene (85%), Platelet — derived growth factor receptor alpha gene (PDGFRA) (10%) or rarely B-Raf gene. C.Kit - which is mutated &amp; activated in 80% of GIST- is an oncogene which encodes cell surface receptor Tyrosine Kinase TK (CD 117) which is responsible for activation of multiple signaling cascades leading to cellular proliferation. Aim of the Work to explore the best management options of care for patients at Ain Shams University Hospitals (ASUH) by retrospectively analyzing epidemiological factors in Gastrointestinal stromal tumor patients and correlate them to clinical outcome; these factors are either patient or disease ones, while outcome include clinical benefits, survival and encountered toxicities. Patients and Methods this is a retrospective study. This study included 34 patients with GIST treated at the department of Clinical Oncology and Nuclear medicine, Ain Shams University between 2011 -2017 and followed up till 1-2017. Results many prognostic factors were selected for analysis to evaluate their impact on overall survival. Age, gender, site and size of tumor, mitotic index, histopathology, presence of metastasis at time of presentation and anemia all had no statistically significant impact on overall survival. Conclusion the prognosis of GIST is undoubtedly better than other sarcomas. No clear risk factor of GIST. Patient selection is paramount as to minimize the high cost of treatment. Tumor density must be known by Hounsfield unit before treatment to detect pseudo progression. Molecular analysis by PCR is very important to know sensitivity to treatment as a predictive biomarker. Patients should be kept on follow up for early detection of recurrence.

Abstract 1058: Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: Analyses of clinopathological characteristics related with success

Abstract BACKGROUND: The gastrointestinal stromal tumor (GIST) has activating mutations in either KIT or platelet-derived growth factor receptor alpha (PDGFRa) gene, and tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib and regorafenib remain the mainstay of anti-GIST treatment. Patient-derived xenografts (PDXs) are useful preclinical models in cancer research, owing to their demonstration of more real tumor heterogeneity and complexity, compared with cell lines and cell line-based xenograft models. PDX models have been established using numerous tumor types, however, there are only a few PDX models of GIST because of its very low success rate. As we have been establishing PDXs from GIST patients since 2012, in this study, we report the established PDXs and the clinopathological characteristics related to the successful establishment of GIST PDXs. MATERIALS and METHODS: PDXs have been established in NOD-scid Il2rg-/- (NSG) mice by implanting GIST tumor fragments from 185 patients who underwent surgical resection prior to and after tyrosine kinase inhibitors from July, 2012 to July, 2017. The established PDXs passaged greater than F2 generation. Chi-square test and logistic regression were used for comparison. RESULTS: Of a total of 185 patients, 66 (35.7%) patients were TKI-naïve, 21 (11.4%) had residual disease after control with TKIs, and the remaining 98 (53.0%) showed disease progression after TKIs at the time of surgical resection. The success rate of establishment of GIST PDXs was 16.8% (31/185). In univariate analyses, a higher engraftment rate was observed for tumors derived from patients with disease progression after TKIs (TKI-naïve vs residual disease vs progressive disease; p&amp;lt;0.001), larger tumor size (≤50 mm vs 50-100 mm vs &amp;gt;100 mm; p&amp;lt;0.001), more mitotic count (≤10/50 HPFs vs &amp;gt;10/50 HPFs; p&amp;lt;0.001), higher Ki-67 index (&amp;lt;1/3 vs ≥1/3; p&amp;lt;0.001), higher cellularity (low vs high; p&amp;lt;0.001), or tumor necrosis (absence vs presence; p=0.001). In addition, PDX engraftment success rate was higher with tumors harboring primary mutation in KIT exon11 (vs other mutations; p=0.025) or with metastatic tumor lesions (vs primary site; p&amp;lt;0.001). In multivariate analysis including significant factors in the univariate analyses, Ki-67 index (p=0.001) and largest tumor size (p=0.058) were independent factors for success of PDX establishment. CONCLUSION: Clinicopathologic factors such as disease progression after TKIs, larger tumor size, more mitotic count, higher Ki-67 index, higher cellularity or tumor necrosis were associated with higher success rate of PDX establishment. Especially, largest tumor size and Ki-67 index were independent factors for successful PDX engraftment. These findings will be helpful to establish PDX models more efficiently in GIST. Citation Format: Young-Soon Na, Min-Hee Ryu, Young Soo Park, Chae-Won Lee, Ju-Kyung Lee, Yangsoon Park, Jung Min Park, Jungeun Ma, Yoon-Koo Kang. Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: Analyses of clinopathological characteristics related with success [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1058.

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.

Invasive inflammatory fibroid polyp of the stomach: a case report and literature review

BackgroundInflammatory fibroid polyps (IFPs) are rare mesenchymal lesions that affect the gastrointestinal tract. IFPs are generally considered benign, noninvasive lesions; however, we report a case of an invasive gastric IFP. To the best of our knowledge, this is only the second case report of an invasive gastric IFP.Case presentationA 62-year-old woman presented with complaints of epigastric pain and vomiting. Computed tomography showed a 27-mm, hyper-enhancing tumor in the prepyloric antrum. Upper endoscopy also showed a submucosal tumor causing subtotal obstruction of the gastric outlet. Because a gastrointestinal stromal tumor was suspected, distal gastrectomy was performed. Histopathological examination revealed spindle cell proliferation in the submucosal layer. The spindle cells had invaded the muscularis propria layer and extended to the subserosal layer. The tumor was finally diagnosed as an IFP based on immunohistochemical findings. No mutations were identified in the platelet-derived growth factor receptor alpha (PDGFRA) gene via molecular genetic analysis.Discussion and conclusionsAfter the discovery that IFPs often harbor PDGFRA mutations, these growths have been considered neoplastic lesions rather than reactive lesions. Based on the present case, IFPs might be considered not only neoplastic but also potentially invasive lesions.

Differential diagnosis of gastrointestinal stromal tumor by histopathology and immunohistochemistry.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract. GISTs account for approximately 80% of the clinically relevant GI mesenchymal tumors. Although most GISTs show spindle cell morphology, 10-15% of GISTs show pure epithelioid configuration. Therefore, not only spindle cell tumors but also epithelioid cell ones developing in the GI tract are subject to the differential diagnoses of GISTs. GISTs are basically positive for KIT, a receptor tyrosine kinase (RTK) encoded by protooncogene c-kit, by immunohistochemistry, but approximately 5% of GISTs are only weakly or barely positive for KIT. Since almost all spindle cell type GISTs are strongly and diffusely positive for KIT regardless of different genetic subtypes, diagnosis of the spindle cell type GISTs is not difficult. On the other hand, epithelioid cell type GISTs show different staining patterns of KIT in different genetic backgrounds. Approximately half of the epithelioid cell type GISTs with platelet-derived growth factor receptor alpha (PDGFRA) gene mutation might show weak or undetectable staining of KIT. On the other hand, almost all GISTs are negative for desmin, which is a positive marker for mature smooth muscle cells, and S100 protein, which is a Schwann cell marker. Smooth muscle tumors such as leiomyomas and leiomyosarcomas, which usually show the spindle cell morphology, consist of approximately 10% of the clinically relevant GI mesenchymal tumors and are almost positive for desmin and negative for KIT and S100 protein. Schwannomas which nearly always show the spindle cell pattern, comprise up to 5% of the GI mesenchymal tumors, and almost all of them are positive for S100 protein and negative for KIT and desmin. Thus, most GI mesenchymal tumors are differentially diagnosed by immunohistochemistry (IHC) of KIT, desmin and S100 protein. However, mesenchymal tumors such as desmoids, solitary fibrous tumors (SFTs), inflammatory myofibroblastic tumors (IMTs), perivascular epithelioid cell tumors (PEComas), inflammatory fibroid polyps (IFPs), rarely develop in the GI tract, and have to be correctly diagnosed through detection of specific immunohistochemical markers and/or unique genetic aberrations.

Comprehensive molecular screening by next generation sequencing reveals a distinctive mutational profile of KIT/PDGFRA genes and novel genomic alterations: results from a 20-year cohort of patients with GIST from north-western Greece

IntroductionGastrointestinal stromal tumours (GIST) are mesenchymal neoplasms that usually carry an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes with predictive and prognostic significance. We investigated the extended mutational status of GIST in a patient population of north-western Greece in order to look at geopraphic/genotypic distinctive traits.Patient and methodsClinicopathological and molecular data of 38 patients diagnosed from 1996 to 2016 with GIST in the region of Epirus in Greece were retrospectively assessed. Formalin-fixed paraffin-embedded tumours were successfully analysed for mutations in 54 genes with oncogenic potential. Next generation sequencing was conducted by using the Ion AmpliSeqCancer Hotspot Panel V.2 for DNA analysis (Thermofisher Scientific).ResultsAmong 38 tumours, 24 (63.16%) and seven (18.42%) of the tumours harboured mutations in the KIT and PDGFRA genes, respectively, while seven (18.42%) tumours were negative for either KIT or PDGFRA mutation. No mutations were detected in five (13.16%) cases. Concomitant mutations of BRAF and fibroblast growth factor receptor 3 (FGFR3) genes were observed in two patients with KIT gene mutation. Two patients with KIT/PDGFRA wild-type GIST had mutations in either KRAS or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) genes. There was no significant survival difference regarding the exonic site of mutation in either KIT or PDGFRA gene. The presence of a mutation in pathway effectors downstream of KIT or PDGFRA, such as BRAF, KRAS or PIK3CA, was associated with poor prognosis. Adverse prognosticators were also high mitotic index and the advanced disease status at diagnosis.ConclusionsWe report comparable incidence of KIT and PDGFRA mutation in patients with GIST from north-western Greece as compared with cohorts from other regions. Interestingly, we identified rare mutations on RAS, BRAF and PIK3CA genes in patients with poor prognosis.

Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein–ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.

A genome-wide association study of corneal astigmatism: The CREAM Consortium

To identify genes and genetic markers associated with corneal astigmatism. A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.