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1.
Bull Cancer ; 107(1): 41-47, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31916995

RESUMO

A growing number of studies suggest a tumor suppressor role for the SWI/SNF complex involved in the remodeling of chromatin. Alterations of this complex have been found in many tumors of different origins, with topographic, morphologic and phenotypic diversity. Notably, they define 2 types of thoracic tumors: SMARCA4-deficient non-small cell lung carcinoma and SMARCA4-deficient sarcoma. Some clinical features appear to be common to both, such as intrathoracic localization, smoking exposure, male predominance and poor prognosis. However, the histological distinction between these two entities is sometimes difficult and it is not excluded that these entities belong to the same tumor spectrum with different degrees of differentiation. The therapy of these tumors is not yet codified. These tumors do not seem associated with oncogenic driver mutations allowing the prescription of targeted therapy, but immunotherapy has been shown to be effective in rare reported cases. More specific treatments using EZH2 inhibitors also seem promising in SMARCA4 deficient sarcomas.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Montagem e Desmontagem da Cromatina , DNA Helicases/deficiência , Proteínas de Neoplasias/deficiência , Proteínas Nucleares/deficiência , Sarcoma/genética , Neoplasias Torácicas/genética , Fatores de Transcrição/deficiência , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , DNA Helicases/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Terapia de Alvo Molecular , Complexos Multiproteicos/efeitos dos fármacos , Complexos Multiproteicos/fisiologia , Invasividade Neoplásica , Proteínas de Neoplasias/fisiologia , Proteínas Nucleares/fisiologia , Proteína SMARCB1/fisiologia , Sarcoma/patologia , Sarcoma/terapia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/terapia , Fatores de Transcrição/fisiologia
2.
Dis Markers ; 2019: 6514608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583029

RESUMO

Neuroblastoma is the most common seen solid neural tumor in children less than age one. As mutation in the miR-34b/c gene is observed in several types of human malignancies, there likely to be similar events that contribute to the pathogenesis of neuroblastoma. We hypothesize that polymorphism in the miR-34b/c gene might predispose to neuroblastoma. Here, we conducted this replication study by genotyping rs4938723 T>C from miR-34b/c in Hunan children (162 subjects with neuroblastoma and 270 control subjects) and examined its effect on the risk of neuroblastoma. We determined such association using logistic regression, adjusted for age and gender. Relative to those with TT genotype, subjects with C allele had reduced neuroblastoma risk (TC vs. TT: adjusted OR = 0.46, 95%CI = 0.30-0.71; additive model: adjusted OR = 0.64, 95%CI = 0.47-0.88; TC/CC vs. TT: adjusted OR = 0.49, 95%CI = 0.33-0.73). Stratified analysis revealed that rs4938723 TC/CC carriers were less likely to develop neuroblastoma for patients in the subgroups of age ≤ 18 months, age > 18 months, females, males, tumors in retroperitoneal, tumors in other sites, and clinical stages II, III, IV, and III+IV. Our findings verified miR-34b/c rs4938723 C variant allele as a protective factor for the risk of neuroblastoma. Further investigation of how miR-34b/c rs4938723 T>C might modify neuroblastoma risk is warranted.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias do Mediastino/genética , MicroRNAs/genética , Neuroblastoma/genética , Neoplasias Retroperitoneais/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/etnologia , Neoplasias das Glândulas Suprarrenais/patologia , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/etnologia , Neoplasias do Mediastino/patologia , Mutação , Neuroblastoma/diagnóstico , Neuroblastoma/etnologia , Neuroblastoma/patologia , Razão de Chances , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/etnologia , Neoplasias Retroperitoneais/patologia , Risco
4.
Blood ; 134(10): 802-813, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31292115

RESUMO

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.


Assuntos
Genômica/métodos , Linfoma Difuso de Grandes Células B/genética , Neoplasias do Mediastino/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Mutação , Integração de Sistemas , Adulto Jovem
5.
Int J Surg Pathol ; 27(6): 664-668, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30942102

RESUMO

In this article, we describe a case of conventional epithelioid hemangioendothelioma (EHE) arising within an extra-adrenal myelolipoma. This composite neoplasm arose in the mediastinum of a 51-year-old female. The tumor was composed of a large myelolipoma that contained nodules of EHE consisting of CD31-positive epithelioid endothelial cells that grew in solid cords and were enmeshed in a basophilic hyalinized stroma. Both EHE and myelolipoma are characterized genetically by alterations of WWTR1. We demonstrated the expression of CAMTA-1 chimeric protein by immunohistochemistry both in the neoplastic endothelial cells of EHE and some of the endothelial cells lining the blood vessels in the myelolipoma. To the best of our knowledge, this is the first report of a malignant vascular neoplasm arising in association with myelolipoma.


Assuntos
Hemangioendotelioma Epitelioide/diagnóstico , Neoplasias do Mediastino/diagnóstico , Mielolipoma/diagnóstico , Neoplasias Complexas Mistas/diagnóstico , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Humanos , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Mediastino/patologia , Pessoa de Meia-Idade , Mielolipoma/genética , Mielolipoma/patologia , Neoplasias Complexas Mistas/genética , Neoplasias Complexas Mistas/patologia , Proteínas de Fusão Oncogênica/metabolismo , Transativadores/genética , Transativadores/metabolismo
6.
In Vivo ; 33(2): 551-557, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804140

RESUMO

BACKGROUND: There are no established guidelines for the management of apocrine carcinomas of the breast; they are treated as a non-specific type of breast cancer. CASE REPORT: We report on the case of a 40-year-old man who developed primary mediastinal apocrine carcinoma overexpressing human epidermal growth factor-2 (HER2). The patient initially underwent complete resection of a mediastinal mature teratoma with a focal apocrine carcinoma component. Two years after surgery, relapse was detected in multiple mediastinal lymph nodes. He received induction chemotherapy including docetaxel, trastuzumab, and pertuzumab; consolidative concurrent chemoradiation was added after six cycles. A complete response was confirmed using computed tomography following this multimodal therapy. After chemoradiation, adjuvant trastuzumab and pertuzumab were administered for 1 year and the patient has since had no evidence of progressive disease. CONCLUSION: A multi-modal regimen that includes an anti-HER2 agent appears to be a promising treatment for patients with HER2-positive extramammary apocrine carcinoma.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Receptor ErbB-2/genética , Teratoma/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Quimioterapia Adjuvante , Terapia Combinada , Docetaxel/administração & dosagem , Feminino , Humanos , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/radioterapia , Mediastino/patologia , Terapia Neoadjuvante , Receptor ErbB-2/antagonistas & inibidores , Teratoma/genética , Teratoma/patologia , Teratoma/radioterapia
7.
Endocr Pathol ; 30(3): 237-245, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30772928

RESUMO

Neuroendocrine neoplasms (NENs) have been primarily associated with germline pathogenic variants in genes involved in chromatin remodeling (MEN1), cell cycle control (CDKN1B), PI3K/mTOR signaling (TSC1/2, PTEN) as well as pseudohypoxia (VHL, SDHx). Recent work has implicated various genes involved in DNA repair pathways in the pathophysiology of a subset of pancreatic neuroendocrine neoplasms, including BRCA2, via the homologous recombination pathway (HRD). To date, germline variants in other HRD pathway genes have not been described to contribute to NEN. PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer. Here we report three cases of NEN associated with germline pathogenic variants in PALB2 (pancreatic NEN), RAD51C (thymic NEN), and BARD1 (pancreaticoduodenal NEN) respectively, further linking the DNA repair pathway to NENs.


Assuntos
Mutação em Linhagem Germinativa , Recombinação Homóloga/genética , Tumores Neuroendócrinos/genética , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Linhagem , Transdução de Sinais/genética
8.
Pathology ; 51(1): 62-66, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30470411

RESUMO

Teratomas show diverse biologic behaviour and prognosis as well as variable histological features. Importantly, post-pubertal testicular teratomas composed of mature components have a potential for malignant behaviour, in contrast to ovarian dermoid cysts and pre-pubertal testicular teratomas which are considered almost always benign. On the other hand, the biological behaviour and histogenesis of extragonadal teratomas are still not fully elucidated. In this study of mediastinal mature teratoma (MT), we investigated clinicopathological features and chromosome 12 short arm (12p) status which constitutes a major genetic aberration in the germ cell tumours (GCT) and is indicative of malignant potential. A total of 123 cases of primary mediastinal MT were included, and clinical data were retrieved regarding demographic information, adjuvant treatment, post-operative clinical course, and level of serum tumour markers. Histopathological features were evaluated in 123 cases and 12p status was studied by FISH in 25 cases. Female predilection was identified in the post-pubertal group (38 males vs 77 females), and paediatric teratoma cases had longer follow-up (mean 62.2 months vs 26.5 months). All patients had excellent prognosis with no tumour-associated death, regardless of age and sex. None of the MT cases had cytological atypia and all 21 cases finally evaluated by fluorescence in situ hybridisation were negative for 12p over-representation. Our results support the benign nature of mediastinal MT and suggest the possibility that it may share a common histogenesis with pre-pubertal type GCTs.


Assuntos
Cromossomos Humanos Par 12 , Isocromossomos , Neoplasias do Mediastino/patologia , Teratoma/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias do Mediastino/genética , Pessoa de Meia-Idade , Prognóstico , Fatores Sexuais , Teratoma/genética , Adulto Jovem
9.
Cancer ; 124(19): 3900-3908, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30291793

RESUMO

BACKGROUND: Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases. METHODS: The authors used array genotyping data from a Children's Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth-19 years). Using Fisher's exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS-GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1-year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases. RESULTS: Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS-GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS-GCT and non-KS-GCT cases. KS-GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non-KS-GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7-30.0). CONCLUSIONS: Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one-third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.


Assuntos
Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/epidemiologia , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas/estatística & dados numéricos , Estudos de Coortes , Técnicas de Genotipagem , Homozigoto , Humanos , Lactente , Recém-Nascido , Padrões de Herança/genética , Síndrome de Klinefelter/genética , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/epidemiologia , Neoplasias do Mediastino/genética , Neoplasias Embrionárias de Células Germinativas/genética , Adulto Jovem
10.
Genes Chromosomes Cancer ; 57(12): 665-669, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30350464

RESUMO

The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.


Assuntos
Quinase do Linfoma Anaplásico/genética , Mutação em Linhagem Germinativa , Neoplasias Primárias Múltiplas/genética , Neuroblastoma/genética , Neoplasias das Glândulas Suprarrenais/genética , Pré-Escolar , Exoma , Feminino , Humanos , Lactente , Neoplasias Hepáticas/genética , Masculino , Neoplasias do Mediastino/genética , Linhagem , Fenótipo , Mutação Puntual , Neoplasias da Coluna Vertebral/genética
11.
J Cancer Res Ther ; 14(Supplement): S694-S700, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30249889

RESUMO

Objective: The objective of this paper was to reveal hub pathways in primary mediastinal B-cell lymphoma (PMBL) based on multiple pathway crosstalk networks (PCNs) and give insight for its pathological mechanism. Materials and Methods: Based on gene expression data, pathway data and protein-protein interaction data, background PCN (BPCN) and tumor PCN (TPCN) of PMBL were constructed. The rank product algorithm was implemented to identify hub pathways of BPCN and TPCN. Finally, topological properties (degree, closeness, betweenness, and transitivity) of hub pathways were analyzed. Results: For BPCN, there were three hundred nodes and 42,239 edges, and the pathway pairs had great overlaps. TPCN was composed of 281 nodes and 12,700 cross-talks. A total of five hub pathways were identified, nonalcoholic fatty liver disease (NAFLD), tuberculosis, human T-lymphotropic virus type-I (HTLV-I) infection, hepatitis B, and Epstein-Barr virus infection. The topological properties for them were different from each other, further between PMBL and normal controls. Conclusion: We have identified five hub pathways for PMBL, such as NAFLD, HTLV-I infection, and Hepatitis B, which might be potential biomarkers for target therapy for PMBL.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Células B/genética , Neoplasias do Mediastino/genética , Mapas de Interação de Proteínas/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Infecções por HTLV-I/complicações , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Hepatite B/complicações , Hepatite B/genética , Hepatite B/virologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Linfoma de Células B/complicações , Linfoma de Células B/epidemiologia , Linfoma de Células B/virologia , Neoplasias do Mediastino/complicações , Neoplasias do Mediastino/epidemiologia , Neoplasias do Mediastino/virologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/virologia , Transdução de Sinais/genética , Tuberculose/complicações , Tuberculose/genética , Tuberculose/virologia
12.
Am J Surg Pathol ; 42(12): 1662-1673, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30256256

RESUMO

Mediastinal teratomas are enigmatic; those in children and women are almost invariably benign but in men they may be benign or malignant. There are few data on the chromosome 12p status of mediastinal germ cell tumors (GCT), whereas increased 12p copy number is virtually uniform in malignant testicular GCTs. We therefore studied chromosome 12p copy number in 34 diverse mediastinal GCTs and correlated the results with morphology and follow-up to gain insight into possible pathogenesis. Four prepubertal (below 12 y) children (3 females and 1 male), 7 postpubertal females (14 to 52 y) and 6 postpubertal males (12 to 40 y old) had pure, previously untreated teratomas; 15 were mature and 2 had low-grade immaturity. All lacked 12p copy number increase and cytologic atypia, and most (14/17) showed organoid morphology. On follow-up of 16, 1 died of postoperative complications and the remaining 15 were disease free (1 to 119 mo, mean: 39 mo). Eight postpubertal males (19 to 44 y old) had pure teratomas in postchemotherapy resections; 5/8 showed 12p copy number increase. All 8 had distinct cytologic atypia, with organoid morphology in 3. On follow-up, 6 were disease free after surgical resection (1.5 to 94 mo, mean 38 mo); 1 died of disease at 14.5 months, and 1 was alive with metastases at 176 months. Two postpubertal patients, 1 male (29 y) and 1 female (31 y), had teratoma with secondary somatic-type malignancies, with positive 12p copy number increase in the former but not the latter. The man's tumor occurred after chemotherapy and was a nonorganoid teratoma with primitive neuroectodermal tumor and malignant glioma; the woman's was a previously untreated organoid teratoma with an undifferentiated carcinoma component. The man died of disease (16 mo) and the woman was alive with metastases (27 mo). Seven patients had resections for mixed GCTs (4) or pure nonteratomatous tumors, all after chemotherapy; 5/7 had positive 12p copy number increase. The teratoma component of the 2 cases having one showed distinct cytologic atypia and lacked organoid morphology. On follow-up, 1 died of disease (5 mo), 2 were alive with disease (1, 1.5 mo), 3 were disease free (1 to 43 mo; mean: 18 mo), and 1 was alive with unknown status (31 mo). Our results support that mediastinal teratomas likely develop from 2 separate pathways. Those in children, women and some men arise as pure neoplasms from a nontransformed precursor cell and, therefore, lack 12p copy number increase, show no cytologic atypia, often have organoid morphology and are benign. Common 12p copy number increase, uniform atypia, infrequent organoid structures and malignant behavior support that pure teratomas after chemotherapy in postpubertal males derive from a malignantly transformed precursor cell. Interestingly, we identified organoid pancreatic differentiation only in the benign group and neuroglia more commonly in the malignant teratomas.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 12/genética , Dosagem de Genes , Neoplasias do Mediastino/genética , Teratoma/genética , Adolescente , Adulto , Fatores Etários , Biópsia , Diferenciação Celular , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Masculino , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Fatores Sexuais , Teratoma/mortalidade , Teratoma/patologia , Teratoma/terapia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
13.
Blood ; 132(22): 2401-2405, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30257882

RESUMO

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.


Assuntos
Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Neoplasias do Mediastino/diagnóstico , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/genética , Neoplasias do Mediastino/classificação , Neoplasias do Mediastino/genética , Mediastino/patologia , Inclusão em Parafina
14.
Blood ; 132(8): 782-790, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-29976557

RESUMO

The World Health Organization now recognizes primary mediastinal B-cell lymphoma (PMBCL) as a unique clinical and biologic entity. PMBCL is distinct from other B-cell non-Hodgkin lymphoma subtypes and has features that overlap with classical Hodgkin lymphoma, including a peak incidence in the adolescent and young adult population, mediastinal presentation of disease, and molecular alterations in JAK2 and programmed death ligands. Because PMBCL is rare, there are few prospective clinical trials to guide therapy, resulting in no single standard of care. Given the long life expectancy of survivors of PMBCL, treatment approaches must balance maximizing cure while minimizing long-term toxicity. In this article, I review my approach to the treatment of PMBCL, incorporating data from adult and pediatric studies, as well as recent advances in our understanding of the molecular basis of PMBCL.


Assuntos
Linfoma de Células B/terapia , Neoplasias do Mediastino/terapia , Humanos , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/patologia
17.
Cancer ; 124(12): 2599-2606, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29603181

RESUMO

BACKGROUND: Neuroblastoma is the most frequently diagnosed extracranial solid tumor in children. Previous studies have shown that single-nucleotide polymorphisms in some genes are associated with the risk of multiple cancers, including neuroblastoma. Although Hox transcript antisense intergenic RNA (HOTAIR) gene polymorphisms have been investigated in a variety of cancers, to the authors' knowledge the relationships between HOTAIR gene polymorphisms and neuroblastoma susceptibility have not been reported to date. The objective of the current study was to evaluate the correlation between HOTAIR gene polymorphisms and neuroblastoma risk in Chinese children. METHODS: The authors genotyped 6 polymorphisms (rs920778 A>G, rs12826786 C>T, rs4759314 A>G, rs7958904 G>C, rs874945 C>T, and rs1899663 C>A) of the HOTAIR gene in 2 Chinese populations including 393 neuroblastoma cases and 812 healthy controls. The strength of the associations was evaluated using odds ratios and 95% confidence intervals. Further stratification analyses were conducted to explore the association between the HOTAIR gene polymorphisms rs12826786 C>T, rs874945 C>T, and rs1899663 C>A with neuroblastoma susceptibility in terms of age, sex, clinical stage of disease, and sites of origin. RESULTS: The authors found that the rs12826786 C>T (P =.013), rs874945 C>T (P =.020), and rs1899663 C>A (P =.029) polymorphisms were significantly associated with increased neuroblastoma risk. In stratification analyses, these associations were more predominant in females and among patients with tumor in the retroperitoneal region or mediastinum. The remaining 3 polymorphisms were not found to be related to neuroblastoma susceptibility. CONCLUSIONS: The results of the current study verified that HOTAIR gene polymorphisms are associated with increased neuroblastoma risk and suggest that HOTAIR gene polymorphisms might be a potential biomarker for neuroblastoma susceptibility. Cancer 2018;124:2599-606. © 2018 American Cancer Society.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias do Mediastino/genética , Neuroblastoma/genética , RNA Longo não Codificante/genética , Neoplasias Retroperitoneais/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Neoplasias do Mediastino/patologia , Neuroblastoma/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias Retroperitoneais/patologia
18.
Am J Surg Pathol ; 42(6): 761-766, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29543673

RESUMO

Synovial sarcoma (SS), a translocation-associated sarcoma characterized by SS18-SSX1/2 fusion, presents most often in the extremities of young adults. While SS regularly occurs in the pleuropulmonary parenchyma, the mediastinum is an exceedingly rare primary site; the literature on this subject is predominantly composed of case reports and small series, mostly without molecular confirmation. Cases of mediastinal SS were selected from our institutional and consultation archives. Diagnoses were confirmed by either SS18 fluorescence in situ hybridization (n=6) or reverse transcription polymerase chain reaction for SS18-SSX1/2 (n=15). Mediastinal SSs occurred in 21 patients (15 men; mean age, 38 y; range, 21 to 75). Only 1 patient was older than 50 years. Average tumor size was 13.5 cm (range: 6.4 to 23 cm). One tumor was biphasic and the rest were monophasic, 11 of which were poorly differentiated (52%). Of 10 cases with known fusion transcripts, 6 had SS18-SSX2 and 4 had SS18-SSX1. Follow-up was known for 16 patients (mean: 18.9 mo; range: 5 to 45): 14 had local disease progression or recurrence, and 6 had metastasis. Death from disease occurred in 11 of 16 patients (69%) at 5 to 32 months, and 5 (36%) were alive with disease at last follow-up (6 to 45 mo). Mediastinal SS is a rare and aggressive malignancy most common in patients younger than 50 years. Most are monophasic and reach large size before detection. Poorly differentiated morphology is common. SS should be included in the differential diagnosis of spindle cell, biphasic and poorly differentiated mediastinal tumors. Because of the rarity of SS at this site, molecular testing is recommended to confirm the diagnosis.


Assuntos
Biomarcadores Tumorais/genética , Diferenciação Celular , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Proteínas de Fusão Oncogênica/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/terapia , Pessoa de Meia-Idade , Fenótipo , Sistema de Registros , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma Sinovial/mortalidade , Sarcoma Sinovial/terapia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
20.
Blood ; 131(18): 2036-2046, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29467182

RESUMO

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.


Assuntos
Subunidade alfa de Receptor de Interleucina-4/genética , Janus Quinases/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/metabolismo , Mutação , Fatores de Transcrição STAT/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Camundongos , Fosforilação , Transdução de Sinais
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