RESUMO
O6-Alkylguanine DNA adducts are repaired by the suicide enzyme alkylguanine alkyltransferase (AGT). AGT facilitates repair by binding DNA in the minor groove, flipping out the damaged base, and transferring the O6-alkyl group to a cysteine residue in the enzyme's active site. Despite there being significant knowledge concerning the mechanism of AGT repair, there is limited insight regarding how altered interactions of the adduct with its complementary base in the DNA duplex influence its recognition and repair. In this study, the relationship of base pairing interactions and repair by human AGT (hAGT) was tested in the frequently mutated codon 12 of the KRAS gene with complementary sequences containing each canonical DNA base. The rate of O6-MeG repair decreased 2-fold when O6-MeG was paired with G, whereas all other canonical bases had no impact on the repair rate. We used a combination of biochemical studies, molecular modeling, and artificial nucleobases to elucidate the mechanism accounting for the 2-fold decrease. Our results suggest that the reduced rate of repair is due to O6-MeG adopting a syn conformation about the glycosidic bond precluding the formation of a repair-active complex. These data provide a novel chemical basis for how direct reversion repair may be impeded through modification of the base pair partner and support the use of artificial nucleobases as tools to probe the biochemistry of damage repair processes.
Assuntos
Códon/genética , Adutos de DNA/metabolismo , Reparo do DNA , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Pareamento de Bases , Códon/metabolismo , Adutos de DNA/genética , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Modelos Moleculares , Mutação , TermodinâmicaRESUMO
Bioactivation as well as DNA repair affects the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents. We evaluated the influence of cellular bioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent acylfulvene (AF). We compared the cytotoxicity and RNA synthesis inhibition by AF and its synthetic activated analogue iso-M0 in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC-NER) or global genome nucleotide excision repair (GG-NER). We related these data to the inherent bioactivation capacity of each cell type on the basis of mRNA levels. We demonstrated that specific inactivation of TC-NER by siRNA had the largest positive impact on AF activity in a cancer cell line. These findings establish that transcription-coupled DNA repair reduces cellular sensitivity to AF, independent of the requirement for bioactivation.
Assuntos
Reparo do DNA , Sesquiterpenos/farmacologia , Compostos de Espiro/farmacologia , Transcrição Gênica/efeitos dos fármacos , Ativação Metabólica , Linhagem Celular , Humanos , Sesquiterpenos/farmacocinética , Compostos de Espiro/farmacocinéticaRESUMO
Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. © 2016 Wiley Periodicals, Inc.
Assuntos
Biomarcadores Tumorais/genética , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular/genética , Criança , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 7/genética , Endopeptidases/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nectinas , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Prognóstico , Proto-Oncogene MasRESUMO
Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category.
Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Tumores do Estroma Gastrointestinal/genética , Perfilação da Expressão Gênica , Osteopontina/genética , Ilhas de CpG , Epigênese Genética , Seguimentos , Tumores do Estroma Gastrointestinal/mortalidade , Genoma Humano , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Regiões Promotoras Genéticas/genética , Taxa de SobrevidaRESUMO
Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.
Assuntos
Condroma/genética , Metilação de DNA , Leiomiossarcoma/genética , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Paraganglioma Extrassuprarrenal/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Condroma/metabolismo , Ilhas de CpG , Regulação para Baixo , Epigênese Genética , Feminino , Humanos , Leiomiossarcoma/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mutação , Paraganglioma Extrassuprarrenal/metabolismo , Neoplasias Gástricas/metabolismo , Adulto JovemRESUMO
BACKGROUND: In term newborns meconium ileus is frequently associated with cystic fibrosis. Reports on meconium ileus in preterm infants being diagnosed with cystic fibrosis early after birth are very scarce. Associations between genotype and phenotype in cystic fibrosis and its particular comorbidities have been reported. CASE PRESENTATION: Two extremely preterm twin infants (26 weeks of gestation) born from a Malaysian mother and a Caucasian father were presented with typical signs of meconium ileus. Despite immediate surgery both displayed a unique and finally lethal course. Mutation analysis revealed a novel, probably pathogenic cystic fibrosis mutation, p.Cys524Tyr. The novel mutation might explain the severity of disease next to typical sequelae of prematurity. CONCLUSION: Preterm neonates with meconium ileus have to be evaluated for cystic fibrosis beyond ethnical boundaries, but may take devastating clinical courses despite early treatment. The novel, potentially pathogenic CF mutation p.Cys524Tyr might be associated with severe meconium ileus in neonates. Disease-modifying loci are important targets for intestinal comorbidity of cystic fibrosis.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/complicações , Fibrose Cística/genética , Doenças em Gêmeos/genética , Íleus/genética , Doenças do Prematuro/genética , Mecônio , Evolução Fatal , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , MutaçãoRESUMO
AIMS: Rhabdoid morphology resembling that of the aggressive paediatric rhabdoid tumours occurs in various malignancies usually lacking characteristic SMARCB1 (INI1) loss. Little is known about the clinicopathological and molecular characteristics of the rhabdoid phenotype in gastrointestinal stromal tumours (GISTs). METHODS AND RESULTS: Six gastric rhabdoid GISTs were examined by immunohistochemistry, KIT and platelet-derived growth factor receptor-α gene (PDGFRA) mutation analysis, and comparative genomic hybridization (CGH). All tumours expressed KIT, PDGFRA, DOG-1, and SMARCB1 (two of six with a mosaic pattern). Five of six tumours harboured PDGFRA mutations (D842V in four; N659K in one), and one case was wild type for KIT/PDGFRA and succinate dehydrogenase (SDH) A-negative and SDHB-negative by immunohistochemistry. CGH revealed aberrations typical of GISTs (-1p, -14, and -22q in three, five, and three cases, respectively), with a mean of 1.7 aberrations in the epithelioid component and 2.7 in the rhabdoid component. None showed progression (mean follow-up of 25 months). CONCLUSIONS: Rhabdoid gastric GISTs are associated with epithelioid morphology and PDGFRA mutations. They harbour CGH aberrations that are typical of ordinary GISTs in both tumour components. The presence of additional genetic alterations in the rhabdoid areas indicates evolution from the epithelioid components, and possible genetic and biological progression. On the basis of our series and previous reports, rhabdoid morphology in GISTs presumably does not imply aggressiveness.
Assuntos
Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mutação , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Proteínas Cromossômicas não Histona/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteína SMARCB1 , Fatores de Transcrição/genéticaRESUMO
AIMS: Genotyping is a prerequisite for tyrosine kinase inhibitor therapy in high risk and malignant GIST. About 10% of GISTs are wild-type for KIT but carry PDGFRA mutations. Applying the traditional approach, mutation analysis of these cases is associated with higher costs if all hotspots regions in KIT (exon 9, 11, 13, 17) are performed at first. Our aim was to evaluate the predictive value of a combined histomorphological-immunohistochemical pattern analysis of PDGFRA-mutated GISTs to efficiently direct KIT and PDGFRA mutation analysis. METHODS: The histomorphology and PDGFRA immunostaining pattern was studied in a test cohort of 26 PDGFRA mutants. This was then validated on a cohort of 94 surgically resected GISTs with mutations in KIT (n=72), PDGFRA (n=15) or with wild-type status (n=7) on a tissue microarray. The histological subtype (spindled, epithelioid, mixed), PDGFRA staining pattern (paranuclear dot-like/Golgi, cytoplasmic and/or membranous), and extent of staining were determined without knowledge of the genotype. The combination of histomorphology and immunophenotype were used to classify tumors either as PDGFRA- or non-PDGFRA phenotype. RESULTS: PDGFRA-mutated GISTs were significantly more often epithelioid (p<0.001) and had a higher PDGFRA expression, compared to KIT-mutants (p<0.001). Paranuclear PDGFRA immunostaining was almost exclusively observed in PDGFRA mutants (p<0.001). The sensitivity and specificity of this combined histological-immunohistochemical approach to predict the PDGFRA-genotype was 100% and 99%, respectively (p=6x10(-16)). CONCLUSION: A combination of histomorphology and PDGFRA immunostaining is a reliable predictor of PDGFRA genotype in GIST. This approach allows direct selection of the "gene/exons of relevance" to be analyzed and may help to reduce costs and work load and shorten processing time of GIST genotyping by mutation analysis.
Assuntos
Biomarcadores Tumorais/análise , Forma Celular , Células Epitelioides/patologia , Neoplasias Gastrointestinais/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Imuno-Histoquímica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/análise , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Neoplasias Gastrointestinais/química , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/química , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Predisposição Genética para Doença , Humanos , Mutação , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Reprodutibilidade dos Testes , Análise Serial de TecidosRESUMO
BACKGROUND: Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality. CASE PRESENTATION: We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1. CONCLUSION: To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana/complicações , Transplante de Pulmão , Pneumonia Viral/complicações , Pneumonia/etiologia , Fibrose Pulmonar/cirurgia , Idoso , Broncoscopia , Evolução Fatal , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A/isolamento & purificação , Influenza Humana/virologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/virologia , Infecções Oportunistas/complicações , Infecções Oportunistas/virologia , Pneumonia/diagnóstico , Pneumonia/patologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Fibrose Pulmonar/patologia , RadiografiaRESUMO
Histological subclassification of non-small cell lung cancer (NSCLC) has growing therapeutic impact. In advanced cancer stages tissue specimens are usually bioptically collected. These small samples are of extraordinary value since molecular analyses are gaining importance for targeted therapies. We therefore studied the feasibility, diagnostic accuracy, economic and prognostic effects of a tissue sparing simultaneous multi-antibody assay for subclassification of NSCLC. Of 265 NSCLC patients tissue multi arrays (TMA) were constructed to simulate biopsy samples. TMAs were stained by a simultaneous bi-color multi-antibody assay consisting of TTF1, Vimentin, p63 and neuroendocrine markers (CD56, chromogranin A, synaptophysin). Classification was based mainly on the current proposal of the IASLC with a hierarchical decision tree for subclassification into adenocarcinoma (LAC), squamous cell carcinoma (SCC), large cell neuroendocrine carcinoma (LCNEC) and NSCLC not otherwise specified. Investigation of tumor heterogeneity showed an explicit lower variation for immunohistochemical analyses compared to conventional classification. Furthermore, survival analysis of our combined immunohistochemical classification revealed distinct separation of each entity's survival curve. This was statistically significant for therapeutically important subgroups (pâ=â0.045). As morphological and molecular cancer testing is emerging, our multi-antibody assay in combination with standardized classification delivers accurate and reliable separation of histomorphological diagnoses. Additionally, it permits clinically relevant subtyping of NSCLC including LCNEC. Our multi-antibody assay may therefore be of special value, especially in diagnosing small biopsies. It futher delivers substantial prognostic information with therapeutic consequences. Integration of immunohistochemical subtyping including investigation of neuroendocrine differentiation into standard histopathological classification of NSCLC must, therefore, be considered.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Idoso , Antígeno CD56/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Cromogranina A/análise , Feminino , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Masculino , Proteínas Nucleares/análise , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Coloração e Rotulagem , Sinaptofisina/análise , Fator Nuclear 1 de Tireoide , Análise Serial de Tecidos/métodos , Fatores de Transcrição/análise , Proteínas Supressoras de Tumor/análise , Vimentina/análiseRESUMO
Lung cancer is the leading cause of death among malignant diseases in humans worldwide. In the last decade development of new targeted drugs for the treatment of non-small cell lung cancer proved to be a promising approach to prolong the otherwise very poor prognosis of patients with advanced UICC stages. Epidermal growth factor receptor (EGFR) has been in the focus of this lung cancer science and specific activating mutations are eligible for the treatment with specific tyrosine kinase inhibitors like gefitinib or erlotinib. Beside typical deletions in exon 19 and point mutations in exons 18 and 21 several insertions in exon 19 have been described and attributed activating properties as well. This is the first European and overall the 5th description in English literature of one of these specific insertions. To elucidate its structural changes leading to the activating properties we performed molecular modeling studies. These revealed conformational and electrostatic force field changes in the kinase domain of EGFR. To not miss uncommon mutations thorough and precise characterization of EGFR hotspots, i. e. at least exons 18, 19 and 21, should therefore be conducted to provide best medical care and to offer lung cancer patients appropriate cancer treatment. VIRTUAL SLIDES: The vistual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2209889658102062.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Modelos Moleculares , Mutagênese Insercional , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/química , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Análise Mutacional de DNA , Ativação Enzimática , Receptores ErbB/química , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Proteínas Nucleares/análise , Fenótipo , Conformação Proteica , Relação Estrutura-Atividade , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/análiseRESUMO
Hodgkin and Reed/Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) show constitutive activation of nuclear factor (NF)-κB. Several genetic lesions contribute to this deregulated NF-κB activity. Here, we analysed two further NF-κB regulators for genetic lesions, the inhibitory factor TRAF3 and the key signalling component of the alternative NF-κB pathway, MAP3K14 (NIK). Single nucleotide polymorphism (SNP) array analysis of cHL cell lines revealed a uniparental disomy of the long arm of chromosome 14 associated with a biallelic deletion of TRAF3 located on this chromosome in cell line U-HO1. Cloning of the deletion breakpoint showed a 123 371 bp deletion. No inactivating mutations of TRAF3 were found in six other cHL cell lines or in microdissected HRS cells from seven cHL. However, in primary cHL samples interphase cytogenetic analyses revealed signal patterns indicating monoallelic deletion of TRAF3 in 3/20 other cases. SNP array analysis revealed a gain of copy number for MAP3K14 in three cHL cell lines. Gains of MAP3K14 were detected in 5/16 cases of primary cHL. In conclusion, in rare instances, HRS cells harbour inactivating mutations of the TRAF3 gene and recurrently show gains of MAP3K14, indicating that more components of NF-κB signalling show genetic lesions in HRS cells than previously known.
Assuntos
Doença de Hodgkin/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Fator 3 Associado a Receptor de TNF/genética , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Criança , Análise Citogenética , Feminino , Deleção de Genes , Dosagem de Genes , Doença de Hodgkin/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transativadores/genética , Transativadores/metabolismo , Quinase Induzida por NF-kappaBRESUMO
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract usually occurring in the 6th to 7th decade of life, while their occurrence in children is rare (1-2%). Carney triad (CT), a non-hereditary association of gastric GIST with pulmonary chondroma and/or extraadrenal paraganglioma, is an even much rarer disease (to date ~120 cases reported worldwide) usually affecting young adult females. Pediatric GISTs differ from CT-associated GISTs solely by the absence of other components of the triad and are completely different from sporadic GISTs of the adult. Both, pediatric and CT-GISTs, metastasize frequently to regional lymph nodes (29%) and are usually wild type (WT) for common KIT-/PDGFRA mutations. CASE PRESENTATION AND RESULTS: We compare one new CT GIST with two pediatric/young adult multifocal gastric GISTs presenting with lymph node metastases. We put special focus on histomorphological growth pattern in the primary tumors and in the metastases. The two cases of pediatric/young adult GIST without the other components of CT showed all the features of the triad: female gender, young age, multifocal antral-based gastric GIST with biphasic histological growth pattern, lymph node metastases, hypercellularity and WT status for common KIT-, PDGFRA- and B-RAF mutations. DISCUSSION AND CONCLUSION: Pediatric/CT-associated GISTs and sporadic GISTs of the adults differ significantly from each other with regard to patients' age, gender, tumor localisation, histomorphological growth pattern, mutational status and risk for metastasis. Our cases of pediatric/young adult GISTs show all characteristics of CT except for the absence of other components of the triad. Therefore these GISTs are probably not sporadic, but may represent either early manifestation or forme fruste of the CT. Thus, these patients need to be regularly examined for the development of extraadrenal paraganglioma or pulmonary chondroma.