RESUMEN
HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.
Asunto(s)
Variaciones en el Número de Copia de ADN , Factor de Transcripción GATA3 , PPAR gamma , Receptor ErbB-2 , Humanos , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Femenino , PPAR gamma/genética , PPAR gamma/metabolismo , Masculino , Neoplasias Urológicas/genética , Neoplasias Urológicas/patología , Anciano , Persona de Mediana Edad , Amplificación de Genes , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Regulación Neoplásica de la Expresión GénicaRESUMEN
CONTEXT.: Evidence of T-cell clonality is often critical in supporting the diagnosis of a T-cell lymphoma. OBJECTIVES.: To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing. DESIGN.: Targeted next-generation sequencing data from 139 tissue biopsies, including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples, were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2. RESULTS.: We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high numbers of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2. CONCLUSIONS.: Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.
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Enfermedad de Hodgkin , Linfoma de Células B , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Variaciones en el Número de Copia de ADN , Homocigoto , Estudios Retrospectivos , Linfocitos T , Eliminación de Secuencia , Linfoma de Células B/genética , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T Periférico/genética , Biopsia , Cromosomas , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Introduction: Tumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study. Methods: We retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest. Results: Among 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months vs 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months vs 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy. Conclusions: In a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment.
RESUMEN
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. METHODS: We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. RESULTS: Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. CONCLUSIONS: The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.
RESUMEN
Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Glioma/genética , Mutación/genética , Adolescente , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Niño , Preescolar , Epigénesis Genética/genética , Receptores ErbB/genética , Femenino , Glioma/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
PURPOSE: To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma. DESIGN: Cohort study. PARTICIPANTS: Thirty-two children with retinoblastoma. METHODS: We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing. MAIN OUTCOME MEASURES: Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features. RESULTS: Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease. CONCLUSIONS: Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.
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Silenciador del Gen , Mutación de Línea Germinal , Neoplasias de la Retina/genética , Neoplasias de la Retina/patología , Proteínas de Unión a Retinoblastoma/genética , Retinoblastoma/genética , Retinoblastoma/patología , Ubiquitina-Proteína Ligasas/genética , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Enucleación del Ojo , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Adhesión en Parafina , Neoplasias de la Retina/cirugía , Retinoblastoma/cirugía , Fijación del TejidoAsunto(s)
Predisposición Genética a la Enfermedad/genética , Glioma/patología , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Mutación de Línea Germinal/genética , Glioma/genética , Humanos , Masculino , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6-25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma-like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1-WT1 fusion provides a definitive diagnosis of DSRCT. Genome-wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.
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Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Tumor Desmoplásico de Células Pequeñas Redondas/genética , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Adolescente , Adulto , Niño , Humanos , Masculino , Adulto JovenRESUMEN
"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
Asunto(s)
Neoplasias Encefálicas/patología , Cuerpo Calloso/patología , Glioma/patología , Ventrículos Laterales/patología , Mutación , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias del Ventrículo Cerebral/diagnóstico por imagen , Neoplasias del Ventrículo Cerebral/genética , Neoplasias del Ventrículo Cerebral/patología , Niño , Cuerpo Calloso/diagnóstico por imagen , Femenino , Glioma/diagnóstico por imagen , Glioma/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ventrículos Laterales/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Tabique Pelúcido/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.
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Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Adolescente , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/genética , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteína p300 Asociada a E1A/genética , Exones , Femenino , Genómica , Glioma/genética , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Factor de Transcripción 2 de los Oligodendrocitos/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Telomerasa/genética , Factores de Transcripción/genéticaAsunto(s)
Glioma/genética , Histonas/genética , Mutación/genética , Neoplasias de la Médula Espinal/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Femenino , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Médula Espinal/patología , Neoplasias de la Médula Espinal/patología , Adulto JovenRESUMEN
Combined hepatocellular-cholangiocarcinomas (CHC) are mixed tumours with both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) components. CHC prognosis is similar to intrahepatic CC (ICC) and worse than HCC; staging and treatment generally follow ICC algorithms. However, the molecular biology of CHC remains poorly characterised. We performed capture-based next-generation sequencing of 20 CHC and, for comparison, 10 ICC arising in cirrhosis. Intratumour heterogeneity was assessed by separately sequencing the HCC and CC components of nine CHC. CHC demonstrated molecular profiles similar to HCC, even in the CC component. CHC harboured recurrent alterations in TERT (80%), TP53 (80%), cell cycle genes (40%; CCND1, CCNE1, CDKN2A), receptor tyrosine kinase/Ras/PI3-kinase pathway genes (55%; MET, ERBB2, KRAS, PTEN), chromatin regulators (20%; ARID1A, ARID2) and Wnt pathway genes (20%; CTNNB1, AXIN, APC). No CHC had alterations in IDH1, IDH2, FGFR2 or BAP1, genes typically mutated in ICC. TERT promoter mutations were consistently identified in both HCC and CC components, supporting TERT alteration as an early event in CHC evolution. TP53 mutations were present in both components in slightly over half the TP53-altered cases. By contrast, focal amplifications of CCND1, MET and ERRB2, as well as Wnt pathway alterations, were most often exclusive to one component, suggesting that these are late events in CHC evolution. ICC in cirrhosis demonstrated alterations similar to ICC in non-cirrhotic liver, including in IDH1 or IDH2 (30%), CDKN2A (40%), FGFR2 (20%), PBRM1 (20%), ARID1A (10%) and BAP1 (10%). TERT promoter and TP53 mutation were present in only one ICC each. Our data demonstrate that CHC genetics are distinct from ICC (even in cirrhosis) and similar to HCC, which has diagnostic utility and implications for treatment. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Colangiocarcinoma/genética , Perfilación de la Expresión Génica , Neoplasias Hepáticas/genética , Neoplasias Complejas y Mixtas/genética , Transcriptoma , Adulto , Anciano , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Femenino , Dosificación de Gen , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Complejas y Mixtas/patologíaAsunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , ARN Helicasas DEAD-box/genética , Ribonucleasa III/genética , Sarcoma/genética , Sarcoma/patología , Niño , Femenino , Humanos , Cuerpos de Inclusión/patología , Masculino , Mutación Missense , Neurofibromatosis 1/complicaciones , Adulto JovenRESUMEN
Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Glioma/radioterapia , Adolescente , Adulto , Astrocitoma/radioterapia , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/radioterapia , Niño , Preescolar , Femenino , Genómica , Homocigoto , Humanos , Masculino , Mutación/genética , Eliminación de Secuencia/genética , Telomerasa/genética , Adulto JovenRESUMEN
Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in adenomatoid tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.
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Mesotelioma/genética , Neoplasias Peritoneales/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Proteína de Unión al GTP cdc42/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Mesotelioma/patología , Persona de Mediana Edad , Mutación , Neoplasias Peritoneales/patologíaAsunto(s)
Neoplasias Encefálicas/genética , Cromosomas Humanos Par 19/genética , Isocitrato Deshidrogenasa/genética , Oligodendroglioma/genética , Regiones Promotoras Genéticas/genética , Telomerasa/genética , Adolescente , Neoplasias Encefálicas/diagnóstico por imagen , Niño , Femenino , Humanos , Masculino , Mutación/genética , Oligodendroglioma/diagnóstico por imagenAsunto(s)
Metilación de ADN/genética , Ventrículos Laterales/patología , Mutación/genética , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Tabique Pelúcido/patología , Adulto , Niño , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Femenino , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Ventrículos Laterales/diagnóstico por imagen , Lisina/genética , Imagen por Resonancia Magnética , Masculino , Neoplasias Neuroepiteliales/diagnóstico por imagen , Tabique Pelúcido/diagnóstico por imagen , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the ß3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.
Asunto(s)
Neoplasias Encefálicas/genética , Ganglioglioma/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Transducción de Señal/genética , Adolescente , Adulto , Neoplasias Encefálicas/patología , Niño , Preescolar , Estudios de Cohortes , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Ganglioglioma/patología , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/genética , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.