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1.
PLoS One ; 14(7): e0219064, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315131

RESUMO

PURPOSE: Deep infiltrating endometriosis (DIE) is defined as an endometriotic lesion penetrating to a depth of >5 mm and is associated with pelvic pain, but the underlying mechanisms are unclear. Our objective is to investigate whether plasminogen activator inhibitor-1 expression (PAI-1) in endometriotic tissues is increased in women with DIE. METHODS: In this blinded in vitro study, immunohistochemistry and Histoscore were used to examine the expression of PAI-1 in glandular epithelium (GECs) and stroma (SCs) in a total of 62 women: deep infiltrating uterosacral/rectovaginal endometriosis (DIE; n = 13), ovarian endometrioma (OMA; n = 14), superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP; n = 23), uterine (eutopic) endometrium from women with endometriosis (UE; n = 6), and non-endometriosis eutopic endometrium (UC; n = 6). The following patient characteristics were also collected: age, American Fertility Society stage, hormonal suppression, phase of menstrual cycle, dysmenorrhea score and deep dyspareunia score. RESULTS: PAI-1 expression in GECs and SCs of the DIE group was significantly higher than that of SUP group (p = 0.01, p = 0.01, respectively) and UE group (p = 0.03, p = 0.04, respectively). Interestingly, increased PAI-1 expression in GECs and SCs was also significantly correlated with increased dysmenorrhea (r = 0.38, p = 0.01; r = 0.34, p = 0.02, respectively). CONCLUSIONS: We found higher expression of PAI-1 in DIE, and an association between PAI-1 and worse dysmenorrhea.

3.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

4.
Artigo em Inglês | MEDLINE | ID: mdl-29610391

RESUMO

Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole-genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding. Identification of oncogenic drivers in recurrent pediatric PTC may facilitate targeted therapy while avoiding repeated RAI.

5.
J Pediatr Hematol Oncol ; 39(5): e263-e266, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27841828

RESUMO

The programmed death-1 (PD-1) pathway of immune evasion is exploited by many malignancies to limit host T-cell-mediated immune responses. Nivolumab is a PD-1-blocking monoclonal antibody that disrupts this pathway and is FDA approved for the treatment of metastatic melanoma, renal cell carcinoma, and squamous non-small cell lung cancer. In this case report, we describe the first published pediatric experience of nivolumab in refractory classic Hodgkin lymphoma. In this patient with primary refractory disease and high disease burden, cytokine release syndrome requiring inotropic support developed following the first infusion of nivolumab. The patient subsequently demonstrated a dramatic clinical response with resolution of fevers, transfusion independence, improvement in functional status, and very good partial response on PET/CT following a single dose. Nivolumab was continued with corticosteroid and antihistamine premedication without further adverse events and clinical benefit was sustained at 11 months after therapy initiation, despite evidence of slow radiographic disease progression.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Antineoplásicos/uso terapêutico , Cardiotônicos/uso terapêutico , Criança , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/diagnóstico por imagem , Humanos , Masculino , Nivolumabe , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Terapia de Salvação/métodos , Resultado do Tratamento
6.
Am J Med Genet A ; 170(9): 2440-4, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27374786

RESUMO

Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Pulmão/anormalidades , Mutação , Fenótipo , Proteínas com Domínio T/genética , Alelos , Autopsia , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Evolução Fatal , Feminino , Genótipo , Heterozigoto , Humanos , Recém-Nascido , Cariótipo , Pulmão/patologia , Linhagem , Radiografia Torácica
7.
Am J Med Genet A ; 170(3): 559-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26572961

RESUMO

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57(Kip2) protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith-Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Hiperinsulinismo Congênito/genética , Síndrome de Costello/genética , Impressão Genômica , Hipoglicemia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Dissomia Uniparental/genética , Substituição de Aminoácidos , Sequência de Bases , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/patologia , Cromossomos Humanos Par 11/química , Células Clonais , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/patologia , Síndrome de Costello/diagnóstico , Síndrome de Costello/patologia , Evolução Fatal , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/patologia , Lactente , Padrões de Herança , Fator de Crescimento Insulin-Like II/genética , Perda de Heterozigosidade , Masculino , Dados de Sequência Molecular , Pâncreas/metabolismo , Pâncreas/patologia , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/patologia
8.
Reprod Sci ; 23(7): 892-901, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26711313

RESUMO

The etiology of deep dyspareunia in endometriosis is unclear. Our objective was to determine whether nerve bundle density in the cul-de-sac/uterosacrals (zone II) is associated with deep dyspareunia in women with endometriosis. We conducted a blinded retrospective immunohistochemistry study (n = 58) at a tertiary referral center (2011-2013). Patients were stringently phenotyped into a study group and 2 control groups. The study group (tender endometriosis, n = 29) consisted of patients with deep dyspareunia, a tender zone II on examination, and an endometriosis lesion in zone II excised at surgery. Control group 1 (nontender endometriosis, n = 17) consisted of patients without deep dyspareunia, a nontender zone II on examination, and an endometriosis lesion in zone II excised at surgery. Control group 2 (tender nonendometriosis, n = 12) consisted of patients with deep dyspareunia, a tender zone II on examination, and a nonendometriosis lesion (eg, normal histology) in zone II excised at surgery. Protein gene product 9.5 (PGP9.5) immunohistochemistry was performed to identify nerve bundles (nerve fibers surrounded by perineurium) in the excised zone II lesion. PGP9.5 nerve bundle density (bundles/high powered field [HPF]) was then scored by a pathologist blinded to the group. We found a significant difference in PGP9.5 nerve bundle density between the 3 groups (analysis of variance, F2,55 = 6.39, P = .003). Mean PGP9.5 nerve bundle density was significantly higher in the study group (1.16 ± 0.56 bundles/HPF [±standard deviation]) compared to control group 1 (0.65 ± 0.36, Tukey test, P = .005) and control group 2 (0.72 ± 0.56, Tukey test, P = .044). This study provides evidence that neurogenesis in the cul-de-sac/uterosacrals may be an etiological factor for deep dyspareunia in endometriosis.


Assuntos
Dispareunia/etiologia , Dispareunia/patologia , Endometriose/complicações , Fibras Nervosas/patologia , Útero/inervação , Adolescente , Adulto , Dispareunia/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Dor Pélvica/complicações , Estudos Retrospectivos , Ubiquitina Tiolesterase/metabolismo , Útero/metabolismo , Útero/patologia , Adulto Jovem
9.
Pediatr Dev Pathol ; 18(3): 237-44, 2015 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25668678

RESUMO

Costello syndrome is characterized by constitutional mutations in the proto-oncogene HRAS, causing dysmorphic features, multiple cardiac problems, intellectual disability, and an increased risk of neoplasia. We report a male infant with dysmorphic features, born prematurely at 32 weeks, who, during his 3-month life span, had an unusually severe and ultimately fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia. Molecular studies in this patient demonstrated the uncommon Q22K mutation in the HRAS gene, diagnostic of Costello syndrome. The major autopsy findings revealed hypertrophic cardiomyopathy, congenital myopathy, and a 1.4-cm pancreatic nodule that was positive for insulin expression and morphologically identical to a focal lesion of congenital hyperinsulinism. Sequencing of KCNJ11 and ABCC8, the 2 most commonly mutated genes in focal lesion of congenital hyperinsulinism, revealed no mutations. While hyperinsulinism is a recognized feature of RASopathies, a focal proliferation of endocrine cells similar to a focal lesion of hyperinsulinism is a novel pathologic finding in Costello syndrome.


Assuntos
Cardiomiopatia Hipertrófica/congênito , Hiperinsulinismo Congênito/etiologia , Síndrome de Costello/complicações , Cardiomiopatia Hipertrófica/patologia , Hiperinsulinismo Congênito/patologia , Síndrome de Costello/genética , Síndrome de Costello/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Pâncreas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
10.
Am J Surg Pathol ; 39(7): 977-82, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25634745

RESUMO

A variety of immunohistochemical (IHC) stains have been proposed to mark either benign or malignant mesothelial proliferations. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions of 9p21, is a good marker of mesotheliomas but lacks sensitivity. Recent reports indicate that some mesotheliomas are associated with loss of BRCA-associated protein 1 (BAP1) expression. Here we investigate BAP1 and p16 as potential markers of malignancy and compare test characteristics with previously proposed markers using a well-characterized tissue microarray. BAP1 protein expression was interrogated by IHC. The p16 locus was examined by fluorescence in situ hybridization (FISH) directed toward chromosome 9p21. Loss of BAP1 was identified in 7/26 mesotheliomas and 0/49 benign proliferations. Loss of p16 was identified in 14/27 mesotheliomas and 0/40 benign proliferations, yielding 100% specificity and positive predictive value for each marker. Together, BAP1 IHC and p16 FISH were 58% sensitive for detecting malignancy. Various combinations of p53, EMA, IMP3, and GLUT1 showed reasonably high specificity (96% to 98%) but poor to extremely poor sensitivity. Combined BAP1 IHC/p16 FISH testing is a highly specific method of diagnosing malignant mesotheliomas when the question is whether a mesothelial proliferation is benign or malignant and is particularly useful when tissue invasion by mesothelial cells cannot be demonstrated. However, combined BAP1/p16 FISH testing is not highly sensitive, and negative results do not rule out a mesothelioma. The test characteristics of previously proposed markers EMA, p53, GLUT1, IMP3 suggest that, even in combination, these markers are not useful tools in this clinical setting.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/análise , Epitélio/patologia , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , Mesotelioma/química , Mesotelioma/patologia , Proteínas Supressoras de Tumor/análise , Ubiquitina Tiolesterase/análise , Proliferação de Células , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Sensibilidade e Especificidade
11.
Pediatr Dev Pathol ; 17(4): 278-85, 2014 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24856811

RESUMO

Survival rates have plateaued at 70% for osteosarcoma. Proteins ectopically produced by malignant tumors may provide insight into new therapeutic targets. Osteosarcomas secreting human chorionic gonadotropin (hCG) have been suggested to have a worse prognosis. We examined the frequency of expression of ß-subunit of hCG (ß-hCG) in pretreatment osteosarcoma biopsies, and asked if it was associated with various clinical prognostic parameters, and the development of metastases. We subjected 51 pretreatment biopsies of high-grade osteosarcoma, from 51 patients, to ß-hCG immunohistochemistry. In 19 of these patients, postchemotherapy metastatic biopsies also were examined for ß-hCG expression. Clinical information (patient age, sex, survival status, and serum hCG in females only), and tumor characteristics (site, size, and presence of metastases) were recorded. The ß-hCG positive and negative biopsies were separated and compared. Of 49 interpretable pretreatment biopsies, 28 (57%) showed positive cytoplasmic ß-hCG expression: 27 with sparse positivity (1% of tumor cells) and 1 with frequent positivity (10% of tumor cells). The patient with frequent ß-hCG positivity in her pretreatment biopsy had elevated serum hCG (88.2 mIU/mL) at diagnosis, decreasing to undetectable following chemotherapy and definitive resection. There was no difference in clinical parameters or rate of metastasis between ß-hCG positive versus negative groups. Expression of ß-hCG may be seen in high-grade osteosarcoma, but frequent ß-hCG immunohistochemical expression by tumor cells, associated with clinically elevated serum ß-hCG, is rare. Recognition that some nongerm cell tumors may produce ß-hCG can prevent confusion with malignancies containing neoplastic syncytiotrophoblast cells, including germ cell and trophoblastic tumors.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , Neoplasias Ósseas/química , Gonadotropina Coriônica Humana Subunidade beta/sangue , Imuno-Histoquímica , Osteossarcoma/sangue , Osteossarcoma/química , Adolescente , Biomarcadores Tumorais/urina , Biópsia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/urina , Criança , Gonadotropina Coriônica Humana Subunidade beta/urina , Feminino , Humanos , Masculino , Gradação de Tumores , Osteossarcoma/secundário , Osteossarcoma/urina , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Regulação para Cima
12.
Am J Surg Pathol ; 37(3): 421-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23108021

RESUMO

Distinguishing malignant mesotheliomas from benign mesothelial proliferations on hematoxylin and eosin-stained sections can be extremely challenging. Various immunohistochemical stains have been suggested to help in making this distinction, but all are controversial. Recently, IMP3 (insulin-like growth factor II mRNA binding protein 3) and GLUT-1 (glucose transporter protein 1) have been proposed as immunohistochemical markers that are positive in mesotheliomas but not in benign proliferations. We evaluated the performance of these markers on a tissue microarray containing 30 malignant mesotheliomas and 48 benign thoracic or abdominal mesothelial proliferations. IMP3 was positive in 53% of malignant and 27% of benign cases (P=0.03), whereas GLUT-1 was positive in 60% of malignant and 13% of benign cases (P=0.0003). Forty-three percent of malignant cases, but only 4% of benign cases, were positive for both IMP3 and GLUT-1 (P=0.00003). We conclude that, statistically, both IMP3 and GLUT-1 are more frequently positive in malignant compared with benign mesothelial processes; however, the frequency of positive staining in benign cases is too high to allow their diagnostic use as single stains. The combination of both markers may be of greater diagnostic value, but this hypothesis should be confirmed in further studies.


Assuntos
Biomarcadores Tumorais/análise , Transportador de Glucose Tipo 1/análise , Mesotelioma/diagnóstico , Neoplasias de Tecido Fibroso/diagnóstico , Proteínas de Ligação a RNA/análise , Proliferação de Células , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Mesotelioma/metabolismo , Neoplasias de Tecido Fibroso/metabolismo , Sensibilidade e Especificidade , Análise Serial de Tecidos
13.
N Engl J Med ; 366(3): 234-42, 2012 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-22187960

RESUMO

BACKGROUND: Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors. METHODS: We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays. RESULTS: DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity. CONCLUSIONS: Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).


Assuntos
RNA Helicases DEAD-box/genética , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Tumor de Células de Sertoli-Leydig/genética , Carcinossarcoma/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , MicroRNAs/metabolismo , Neoplasias Embrionárias de Células Germinativas/genética , Rabdomiossarcoma/genética , Análise de Sequência de DNA
14.
Hum Pathol ; 42(11): 1804-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21658743

RESUMO

Low-grade fibromyxoid sarcoma was first described more than 20 years ago. Subsequently, it was discovered to carry the recurrent chromosomal translocation t(7;16)(q33;p11) encoding a FUS-CREB3L2 fusion oncoprotein. Molecular tests for this pathognomonic gene fusion can confirm the identity of histologic variants (such as hyalinizing spindle cell tumor with giant rosettes) and suggest that some cases of sclerosing epithelioid fibrosarcoma may represent a high-grade version of this entity. We present a case of an ossifying tumor of the perineum that required an open biopsy and fluorescent in situ hybridization testing for FUS and CREB3L2 for diagnosis as a variant of low-grade fibromyxoid sarcoma. Subsequent excision revealed characteristic areas with collagen rosettes as well as foci of heterotopic ossification. Significant ossification, which is well documented in entities such as synovial sarcoma, ossifying fibromyxoid tumor, and extraskeletal osteosarcoma, has not been reported previously in low-grade fibromyxoid sarcoma. This case demonstrates the value of having a distinctive confirmatory molecular pathology test for diagnosis and expands our knowledge of the histologic variants possible in low-grade fibromyxoid sarcoma.


Assuntos
Fibrossarcoma/patologia , Ossificação Heterotópica/etiologia , Períneo/patologia , Neoplasias de Tecidos Moles/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fibrossarcoma/cirurgia , Humanos , Hibridização in Situ Fluorescente , Masculino , Ossificação Heterotópica/patologia , Proteína FUS de Ligação a RNA/genética , Neoplasias de Tecidos Moles/cirurgia , Translocação Genética
15.
J Pathol ; 224(3): 328-33, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21590771

RESUMO

Mutation of the ARID1A gene and loss of the corresponding protein BAF250a has recently been described as a frequent event in clear cell and endometrioid carcinomas of the ovary. To determine whether BAF250a loss is common in other malignancies, immunohistochemistry (IHC) for BAF250a was performed on tissue microarrays (TMAs) in more than 3000 cancers, including carcinomas of breast, lung, thyroid, endometrium, kidney, stomach, oral cavity, cervix, pancreas, colon and rectum, as well as endometrial stromal sarcomas, gastrointestinal stromal tumours, sex cord-stromal tumours and four major types of lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma and follicular lymphoma). We found that BAF250a loss is frequent in endometrial carcinomas but infrequent in other types of malignancies, with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium, 18% (17/95) of uterine serous carcinomas and 26% (6/23) of uterine clear cell carcinomas. Since endometrial cancers showed BAF250a loss, we stained whole tissue sections for BAF250a expression in nine cases of atypical hyperplasia and 10 cases of atypical endometriosis. Of the nine cases of complex atypical endometrial hyperplasia, all showed BAF250a expression; however, of 10 cases of atypical endometriosis (the putative precursor lesion for ovarian clear cell and endometrioid carcinoma), one case showed loss of staining for BAF250a in the atypical areas, with retention of staining in areas of non-atypical endometriosis. This was the sole case that recurred as an endometrioid carcinoma, indicating that BAF250a loss may be an early event in carcinogenesis. Since BAF250a loss is seen in endometrial carcinomas at a rate similar to that seen in ovarian carcinomas of clear cell and endometrioid type, and is uncommon in other malignancies, we conclude that loss of BAF250a is a particular feature of carcinomas arising from endometrial glandular epithelium.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Endométrio/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais/genética , Montagem e Desmontagem da Cromatina , Neoplasias do Endométrio/genética , Feminino , Humanos , Mutação , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Estudos Prospectivos , Análise Serial de Tecidos/métodos , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
16.
Appl Immunohistochem Mol Morphol ; 19(3): 233-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21084965

RESUMO

Small cell osteosarcoma and mesenchymal chondrosarcoma are 2 primary bone tumors with a small round blue cell component, which can mimic the appearance of Ewing sarcoma. Distinguishing these tumors from each other on biopsy material is important clinically, as optimal therapy differs according to the tumor type. However, separating these entities on morphology alone can be challenging. FLI-1 has been described to be a useful marker for Ewing sarcoma, particularly when hematolymphoid markers are negative. In small cell osteosarcoma and mesenchymal chondrosarcoma, the FLI-1 staining pattern has not been adequately characterized. Using a monoclonal FLI-1 antibody, nuclear immunoreactivity in tumor cells was evaluated in 10 small cell osteosarcomas, 10 mesenchymal chondrosarcomas, and 8 Ewing sarcomas, together with a number of other small, round, blue cell tumors. None of the small cell osteosarcomas or mesenchymal chondrosarcomas exhibited FLI-1 staining in the tumor cells, in contrast to the positive nuclear FLI-1 staining in the stromal endothelial cells. In comparison, 6 of the 8 Ewing sarcomas showed moderate-to-strong nuclear FLI-1 staining of the tumor cells in addition to strong staining of the stromal endothelial cell nuclei. With the exception of lymphoblastic lymphomas, FLI-1 positivity was not seen in the other small round blue cell tumors examined. These findings show that, in contrast to Ewing sarcoma, small cell osteosarcoma and mesenchymal chondrosarcoma lack FLI-1 immunoreactivity. FLI-1 is therefore useful in the differential diagnosis of small round blue cell tumors of the bone.


Assuntos
Núcleo Celular/metabolismo , Condrossarcoma Mesenquimal/diagnóstico , Proteína Proto-Oncogênica c-fli-1/metabolismo , Sarcoma de Ewing/diagnóstico , Sarcoma de Células Pequenas/diagnóstico , Biomarcadores Tumorais/metabolismo , Biópsia , Condrossarcoma Mesenquimal/patologia , Condrossarcoma Mesenquimal/fisiopatologia , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Seleção de Pacientes , Proteína Proto-Oncogênica c-fli-1/genética , Sarcoma de Ewing/patologia , Sarcoma de Ewing/fisiopatologia , Sarcoma de Células Pequenas/patologia , Sarcoma de Células Pequenas/fisiopatologia
17.
Am J Surg Pathol ; 34(7): 1007-13, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20534996

RESUMO

Hereditary diffuse gastric cancer (HDGC), an autosomal dominant cancer susceptibility syndrome, is largely attributable to germline mutations and deletions in the gene encoding E-cadherin, CDH1. Asymptomatic, mutation-positive individuals often choose prophylactic gastrectomy for cancer risk reduction. Examination of the entire mucosa of prophylactic gastrectomy specimens is essential and shows occult gastric cancers in most cases. We hypothesized that primary screening entire cases stained with periodic acid-Schiff (PAS) instead of hematoxylin and eosin (H&E) could improve diagnostic accuracy and speed of detecting invasive signet-ring adenocarcinoma. Serial sections from 6 prophylactic gastrectomy specimens with molecularly confirmed CDH1 mutations were stained with PAS and H&E, respectively (108 to 164 blocks per case). PAS-stained and H&E-stained slides were randomized for each case and examined microscopically for the presence of invasive signet-ring cells. The time to examine each slide was recorded. Our results showed that significantly fewer lesions were missed (ie, the lesion was initially identified on only 1 section, but present on both sections) on PAS-stained slides (6 missed lesions) than on H&E-stained slides (23 missed lesions); (P<0.05). Furthermore, it took significantly less time to screen a PAS-stained case (3 h 05+/-41 min) than an H&E-stained case (4 h 59+/-1 h 2 min) (P<0.05). Selected lesions were confirmed as epithelial by pan-keratin-positive immunohistochemistry. Thus, doing PAS staining instead of H&E on CDH1 mutation-positive prophylactic gastrectomy specimens may increase the detection rate of adenocarcinoma while reducing screening time.


Assuntos
Adenocarcinoma/diagnóstico , Caderinas/genética , Triagem de Portadores Genéticos/métodos , Mutação , Reação do Ácido Periódico de Schiff/métodos , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Adulto , Antígenos CD , Corantes , Feminino , Gastrectomia , Predisposição Genética para Doença , Hematoxilina , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirurgia , Fatores de Tempo
18.
J Neurosci ; 24(41): 9174-84, 2004 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-15483136

RESUMO

The p53 family member, p73, is essential for the survival of sympathetic neurons during the developmental period of naturally occurring neuronal death. Here, we have asked whether DeltaNp73, which is the only p73 isoform expressed in sympathetic neurons, mediates this survival by p53-dependent and/or p53-independent mechanisms. Initially, we used a genetic approach and crossed p53+/- and p73+/- mice. Quantitation of neurons in the sympathetic superior cervical ganglion during the period of naturally occurring cell death revealed that the loss of p53 partially rescued the death of neurons seen in p73-/- animals. Moreover, exogenous expression of DeltaNp73 in cultured p53-/- sympathetic neurons rescued these neurons from apoptosis after NGF withdrawal. Biochemical studies asking how DeltaNp73 inhibited NGF withdrawal-induced apoptosis in wild-type neurons demonstrated that it prevented the upregulation of the direct p53 targets p21 and Apaf-1 as well as cleavage of caspase-3. It also inhibited events at the mitochondrial apoptotic checkpoint, suppressing the induction of BimEL and the release of mitochondrial cytochrome c. Interestingly, DeltaNp73 expression also inhibited one very early event in the apoptotic cascade, the activation of c-Jun N-terminal protein kinase (JNK), likely by binding directly to JNK. Finally, we show that neuronal cell size is decreased in p73-/- mice, and that this decrease is not rescued by the lack of p53, suggesting a role for p73 in regulating cell size that does not involve interactions with p53. Thus, DeltaNp73 promotes neuronal survival via p53-dependent and -independent mechanisms, and it does so at multiple points, including some of the most proximal events that occur after NGF withdrawal.


Assuntos
Neurônios/metabolismo , Proteínas Nucleares/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/fisiologia , Fator Apoptótico 1 Ativador de Proteases , Proteínas de Ciclo Celular/metabolismo , Tamanho Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21 , Citocromos c/metabolismo , Proteínas de Ligação a DNA/genética , Técnicas de Transferência de Genes , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor
19.
J Neurosci ; 22(22): 9800-9, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12427836

RESUMO

Here, we show that the p53 family member, p73, is necessary for survival and long-term maintenance of CNS neurons, including postnatal cortical neurons. In p73-/- animals, cortical neuron number is normal at birth but decreases significantly by postnatal day 14 (P14)-P16 because of enhanced apoptosis. This decrease continues into adulthood, when p73-/- animals have approximately one-half as many cortical cells as their wild-type littermates. Cortical neurons express the DeltaNp73alpha protein, and overexpression of DeltaNp73 isoforms rescues cortical neurons from diverse apoptotic stimuli. Thus, DeltaNp73 isoforms are survival proteins in cortical neurons, and their deletion causes a gradual loss of cortical neurons in the weeks and months after birth. This decrease in CNS neuron number in p73-/- animals is not limited to the cortex; facial motor neuron number is decreased, and postnatal development of the olfactory bulb is greatly perturbed. These findings, together with our previous work showing that DeltaNp73 is essential for survival of peripheral sympathetic neurons (Pozniak et al., 2000), indicate that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons.


Assuntos
Sistema Nervoso Central/patologia , Proteínas de Ligação a DNA/deficiência , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Proteínas Nucleares/deficiência , Animais , Apoptose , Tronco Encefálico/patologia , Caspase 3 , Caspases/metabolismo , Contagem de Células , Sobrevivência Celular/genética , Sistema Nervoso Central/metabolismo , Cerebelo/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Genes Supressores de Tumor , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/classificação , Neurônios/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Tumoral p73 , Proteínas Supressoras de Tumor
20.
Genes Chromosomes Cancer ; 35(3): 219-31, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12353264

RESUMO

Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer-derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome-wide level. Eighty-four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24-qter (53%), 20q13-qter (48%), 1p32-p36 (42%), 22q12-qter (27%), 17p13-pter (24%), 16p13-pter (21%), 6p21-pter (19%), 20p12-pter (19%), 7p21-pter (18%), 3q28-qter (8%), and 13q13-q14 (8%), and losses at 18q12-qter (11%), 3p12 (8%), 3p25-pter (8%), 5q14-q23 (8%), and 9p21-p23 (5%), are associated with unique patient or tumor-related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy.


Assuntos
Adenocarcinoma/genética , Aberrações Cromossômicas , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Deleção Cromossômica , DNA de Neoplasias/genética , Feminino , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente/métodos , Interfase/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Hibridização de Ácido Nucleico , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas
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