RESUMO
PURPOSE: Transforming growth factor-beta receptor 3-like (TGFBR3L) is a pituitary enriched membrane protein selectively detected in gonadotroph cells. TGFBR3L is named after transforming growth factor-beta receptor 3 (TGFBR3), an inhibin A co-receptor in mice, due to sequence identity to the C-terminal region. We aimed to characterize TGFBR3L detection in a well-characterized, prospectively collected cohort of non-functioning pituitary neuroendocrine tumours (NF-PitNETs) and correlate it to clinical data. METHODS: 144 patients operated for clinically NF-PitNETs were included. Clinical, radiological and biochemical data were recorded. Immunohistochemical (IHC) staining for FSHß and LHß was scored using the immunoreactive score (IRS), TGFBR3L and TGFBR3 were scored by the percentage of positive stained cells. RESULTS: TGFBR3L staining was selectively present in 52% of gonadotroph tumours. TGFBR3L was associated to IRS of LHß (median 2 [IQR 0-3] in TGFBR3L negative and median 6 [IQR 3-9] in TGFBR3L positive tumours, p < 0.001), but not to the IRS of FSHß (p = 0.32). The presence of TGFBR3L was negatively associated with plasma gonadotropin concentrations in males (P-FSH median 5.5 IU/L [IQR 2.9-9.6] and median 3.0 [IQR 1.8-5.6] in TGFBR3L negative and positive tumours respectively, p = 0.008) and P-LH (median 2.8 IU/L [IQR 1.9-3.7] and median 1.8 [IQR 1.1-3.0] in TGFBR3L negative and positive tumours respectively, p = 0.03). TGFBR3 stained positive in 22% (n = 25) of gonadotroph tumours with no correlation to TGFBR3L. CONCLUSION: TGFBR3L was selectively detected in half (52%) of gonadotroph NF-PitNETs. The association to LHß staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs.
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Gonadotrofos , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Masculino , Animais , Camundongos , Gonadotrofos/metabolismo , Neoplasias Hipofisárias/patologia , Gonadotropinas , Fatores de Crescimento Transformadores/metabolismo , Hormônio FoliculoestimulanteRESUMO
SARS-coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic has posed to be a global challenge. An increasing number of neurological symptoms have been linked to the COVID-19 disease, but the underlying mechanisms of such symptoms and which patients could be at risk are not yet established. The suggested key receptor for host cell entry is angiotensin I converting enzyme 2 (ACE2). Previous studies on limited tissue material have shown no or low protein expression of ACE2 in the normal brain. Here, we used stringently validated antibodies and immunohistochemistry to examine the protein expression of ACE2 in all major regions of the normal brain. The expression pattern was compared with the COVID-19-affected brain of patients with a varying degree of neurological symptoms. In the normal brain, the expression was restricted to the choroid plexus and ependymal cells with no expression in any other brain cell types. Interestingly, in the COVID-19-affected brain, an upregulation of ACE2 was observed in endothelial cells of certain patients, most prominently in the white matter and with the highest expression observed in the patient with the most severe neurological symptoms. The data shows differential expression of ACE2 in the diseased brain and highlights the need to further study the role of endothelial cells in COVID-19 disease in relation to neurological symptoms.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Enzima de Conversão de Angiotensina 2/genética , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Humanos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2RESUMO
Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant, is a histopathological distinct low-grade lesion encountered in older children and young adults that shows epigenetic similarity with ATRT-MYC and has the potential for malignant progression.
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Tumor Rabdoide , Teratoma , Criança , Epigênese Genética , Humanos , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Adulto JovemRESUMO
The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.
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Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/patologia , HumanosRESUMO
OBJECTIVES: Somatostatin receptors (SSTRs) are potential targets for detecting pituitary neuroendocrine tumours (PitNETs) that can be visualized effectively with 68 Ga-labelled PET tracers. With this study, we have evaluated the diagnostic properties of such a tracer, 68 Ga-DOTATOC, in patients with hormone-producing PitNETs before and after surgery. DESIGN/METHODS: This prospective case-control study presents preoperative positron emission tomography (PET) and histopathological data in 18 patients with somatotroph (n = 8), corticotroph (n = 7) and thyrotroph (n = 3) PitNETs. Patients were scanned pre- and postoperatively with 68 Ga-DOTATOC PET. For the postoperative part of the study, patients with gonadotroph tumours (n = 7) were also included. Fifteen pituitary healthy controls underwent the same protocol once. The maximum standard uptake value (SUVmax ) was analysed in manually outlined regions around the tumour in patients and around the pituitary gland in controls. specimens were collected during surgery in subjects for assessment of adenohypophyseal tumour cell type and the SSTR expression. RESULTS: Thyrotroph tumours showed higher uptake (median SUVmax 41.1; IQR 37.4-60.0) and corticotroph tumours lower uptake (SUVmax 6.8; 2.6-9.3) than normal pituitary gland (SUVmax 13.8; 12.1-15.5). The uptake in somatotroph tumours (SUVmax 15.9; 11.6-19.7) was similar to the uptake in the pituitary gland. There was a strong correlation between SUVmax and SSTR2 expression (r = .75 (P < .01)). In the postoperative evaluation, PET was able to correlate tracer uptake with biochemical cure and noncure in patients with an abnormal postoperative magnetic resonance image and a preoperative tumour uptake SUVmax > 13.8. CONCLUSIONS: 68 Ga-DOTATOC PET can be used to detect thyrotroph tumours in the pre- and postoperative imaging assessment. Corticotroph tumours had a significantly lower uptake compared to the pituitary gland but without a distinct increased tumour uptake the clinical postoperative value is limited.
Assuntos
Tumores Neuroendócrinos , Compostos Organometálicos , Estudos de Casos e Controles , Hormônios , Humanos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/cirurgia , Octreotida/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de PósitronsRESUMO
PURPOSE: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. METHODS: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). RESULTS: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364). CONCLUSION: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Hipotonia Muscular , Criança , Conectina/genética , Estudos de Associação Genética , Humanos , Mutação , FenótipoRESUMO
OBJECTIVES: 68 Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga-DOTATOC PET in the most common PitNET, ie non-functioning (NF)-PitNET. DESIGN/PATIENTS: NF-PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68 Ga-DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROI) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression. RESULTS: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P < .01]. In ROC analysis, the area under the curve was 0.87 (P < .01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5. CONCLUSIONS: This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET.
Assuntos
Radioisótopos de Gálio/farmacocinética , Tumores Neuroendócrinos/metabolismo , Octreotida/análogos & derivados , Hipófise/metabolismo , Neoplasias Hipofisárias/metabolismo , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Octreotida/farmacocinética , Hipófise/diagnóstico por imagem , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/patologia , Tomografia por Emissão de Pósitrons/métodos , Estudo de Prova de Conceito , Estudos ProspectivosRESUMO
The anatomical and histological complexity of the parasellar region as well as the presence of embryonic remnants determine the huge diversity of parasellar neoplasms. Some of them are only located in the parasellar region, whereas others can occur elsewhere, within or outside the central nervous system. Their spectrum ranges from histologically benign and low-grade malignant to high-grade malignant tumours. Although rare, metastases can pose differential diagnostic dilemmas. The severity of the clinical picture, the challenges of surgery and the risk of adverse sequelae related to surgery or radiotherapy make parasellar tumours interesting entities for the clinicians irrespective of their histological malignancy grade. Due to the different cell origins of parasellar tumours, the World Health Organization classification system does not categorise them as a distinct group. Detailed criteria for classification and malignancy grading are presented in the classification systems covering central nervous system tumours, haematological malignancies and tumours of the soft tissue and bone. In the last few years, molecular genetic features have been integrated into the diagnosis of several types of the parasellar tumours enhancing diagnostic accuracy and providing information of the value for targeting therapies. In this review, we will present histopathological and molecular genetic features, updated classification criteria and recent advances in the diagnostics and rationale for novel pharmacological therapies of selected types of parasellar neoplasms.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Sela Túrcica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , HumanosRESUMO
Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify "high-risk adenomas." A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification.
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Neoplasias Hipofisárias/diagnóstico , Animais , Humanos , Imuno-Histoquímica , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Fatores de Transcrição/metabolismoRESUMO
AIM: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre- and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome. METHODS: During a fifteen-year period (1995-2009), all patients (age 0-17.99years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re-evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study. RESULTS: A total of 25 out of 28 (89%) eligible patients were included. The M:F ratio was 1.5:1. Mean follow-up time after surgery was 12.1years (range 5.0-19.3). Twenty patients were adults (>18years) at follow-up. Seizure freedom was achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p=0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free. CONCLUSION: Long-term outcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedom seems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable.
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Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/cirurgia , Epilepsia/fisiopatologia , Epilepsia/cirurgia , Adolescente , Adulto , Neoplasias Encefálicas/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Eletroencefalografia/tendências , Epilepsia/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Prospectivos , Sistema de Registros , Resultado do Tratamento , Adulto JovemRESUMO
Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.
Assuntos
Craniofaringioma/tratamento farmacológico , Imidazóis/uso terapêutico , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Oximas/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Idoso , Craniofaringioma/diagnóstico por imagem , Craniofaringioma/genética , Humanos , Masculino , Terapia de Alvo Molecular , Mutação , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Sela Túrcica/diagnóstico por imagemRESUMO
PURPOSE: Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas. METHODS: We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses. RESULTS: In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses. CONCLUSION: IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1.
Assuntos
Adenoma/metabolismo , Isocitrato Desidrogenase/metabolismo , Neoplasias Hipofisárias/metabolismo , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Síndrome de Nelson/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Prolactinoma/metabolismo , Estudos Retrospectivos , Análise Serial de TecidosRESUMO
BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS. METHODS AND RESULTS: We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17â weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency. CONCLUSIONS: To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.
Assuntos
Anormalidades Múltiplas/genética , Artrogripose/genética , Junção Neuromuscular/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genética , Anormalidades Múltiplas/fisiopatologia , Artrogripose/fisiopatologia , Exoma/genética , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/fisiopatologia , Feto/fisiopatologia , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Mutação , Junção Neuromuscular/crescimento & desenvolvimento , Junção Neuromuscular/fisiopatologia , Linhagem , Transdução de SinaisAssuntos
Adenoma , Tumores Neuroendócrinos , Doenças da Hipófise , Neoplasias Hipofisárias , Humanos , HipófiseRESUMO
Background: Cells with stem cell features have been described in pituitary neuroendocrine tumours (PitNETs). Transcription factors SOX2 and SOX9 are stem cell-associated markers while the pituitary progenitor marker PROP1 is involved in anterior pituitary development. We characterised the presence of these markers known to be present in the human pituitary in non-functioning (NF) PitNETs. Methods: We investigated the pituitary transcription factors SOX2, SOX9 and PROP1 by immunohistochemistry (IHC) (N = 125) and RT-qPCR (N = 78) in a retrospective cohort of clinically NF-PitNETs. The markers were scored based on the percentage of immunolabeled cells. IHC staining scores were compared to reintervention rates for the whole cohort, and to expression of FSH, LH or ER in gonadotroph NF-PitNETs. Results: Most tumours showed no or few cells positive for SOX2, SOX9 and PROP1. More patients with SOX2-negative tumours went through reintervention (40 % vs 19 %, p = 0.03). SOX2, SOX9 and PROP1 staining correlated positively to each other (SOX2 and SOX9 rs = 0.666, SOX2 and PROP1 rs = 0.704, SOX9 and PROP1 rs = 0.570, and p < 0.001 for all). In gonadotroph NF-PitNETs, staining for SOX2 and PROP1 was positively associated to FSHß staining (p < 0.001 for both). Staining for SOX2, SOX9 and PROP1 was positively associated with gene expression of Estrogen Receptor 1 (ESR1) (p < 0.001, p = 0.004 and p < 0.001) and IHC staining for ERα (p = 0.001, p = 0.03 and p = 0.05, respectively). Conclusion: SOX2, SOX9 and PROP1 were present at low levels in NF-PitNETs. Absence of SOX2 staining was associated with a higher reintervention rate. The stem cell markers correlated positively with markers of gonadotroph differentiation in gonadotroph NF-PitNETs. SOX2 and SOX9 were frequently coexpressed and showed positivity in intratumoural cells with epithelial features, however without coexpression of pituitary transcription factors.
RESUMO
Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown. We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization. Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs. Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.
RESUMO
Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole exome sequencing. Within the conserved haplotype, we identified a single heterozygous mutation c.1150G>A (p.E384K) in T-cell intracellular antigen-1 (TIA1) in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing, and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7, and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1,050 years, which coincides with the epoch of early seafaring across the Baltic Sea.
Assuntos
Miopatias Distais/genética , Efeito Fundador , Mutação , Proteínas de Ligação a Poli(A)/genética , Splicing de RNA , Processamento Alternativo , Sequência de Aminoácidos , Sequência de Bases , Miopatias Distais/metabolismo , Exoma , Éxons , Expressão Gênica , Haplótipos , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas de Ligação a Poli(A)/metabolismo , Alinhamento de Sequência , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Antígeno-1 Intracelular de Células TRESUMO
Aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs) are heterogeneous with regard to clinical presentation, proliferative markers, clinical course, and response to therapy. Half of them show an aggressive course only many years after the first apparently benign presentation. APTs and PCs share several properties, but a Ki67 index greater than or equal to 10% and extensive p53 expression are more prevalent in PCs. Mutations in TP53 and ATRX are the most common genetic alterations; their detection might be of value for early identification of aggressiveness. Treatment requires a multimodal approach including surgery, radiotherapy, and drugs. Temozolomide is the recommended first-line chemotherapy, with response rates of about 40%. Immune checkpoint inhibitors have emerged as second-line treatment in PCs, with currently no evidence for a superior effect of dual therapy compared to monotherapy with PD-1 blockers. Bevacizumab has resulted in partial response (PR) in few patients; tyrosine kinase inhibitors and everolimus have generally not been useful. The effect of peptide receptor radionuclide therapy is limited as well. Management of APT/PC is challenging and should be discussed within an expert team with consideration of clinical and pathological findings, age, and general condition of the patient. Considering that APT/PCs are rare, new therapies should preferably be evaluated in shared standardized protocols. Prognostic and predictive markers to guide treatment decisions are needed and are the scope of ongoing research.
Assuntos
Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/terapia , Temozolomida/uso terapêutico , Bevacizumab/uso terapêuticoRESUMO
We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291-13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD.