Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 160
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Cancer Sci ; 115(3): 894-904, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38178783

RESUMO

Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.


Assuntos
Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genética
2.
Cancer Sci ; 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39351646

RESUMO

Accurate estimation of tumor mutational burden (TMB) as a predictor of responsiveness to immune checkpoint inhibitors in gene panel assays requires an adequate panel size. The current calculations of TMB only consider coding regions, while most of gene panel assays interrogate non-coding regions. Leveraging the non-coding regions is a potential solution to address this panel size limitation. However, the impact of including non-coding regions on the accuracy of TMB estimates remains unclear. This study investigated the validity of leveraging non-coding regions to supplement panel size using the OncoGuide NCC Oncopanel System (NOP). The aim of this study was to evaluate test performance against orthogonal assays and the association with responsiveness to immune checkpoint inhibitors was not included in the evaluation. We compared TMB status and values between TMB calculated only from coding regions (NOP-coding) and from both coding and non-coding regions (NOP-overall) using whole exome sequencing (WES) and FoundationOne®CDx (F1CDx) assay. Our findings revealed that NOP-overall significantly improved the overall percent agreement (OPA) with TMB status compared with NOP-coding for both WES (OPA: 96.7% vs. 73.3%, n = 30) and F1CDx (OPA: 90.0% vs. 73.3%). Additionally, the mean difference in TMB values compared with WES was lower for NOP-overall (3.55 [95% CI: 0.98-6.13]) than for NOP-coding (6.22 [95% CI: 3.73-8.70]). These results exemplify the utility of incorporating non-coding regions to maintain accurate TMB estimates in small-sized panels.

3.
N Engl J Med ; 384(1): 42-50, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33406329

RESUMO

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).


Assuntos
Adenocarcinoma Mucinoso/etiologia , Carcinoma Neuroendócrino/etiologia , Neoplasias Pulmonares/etiologia , Complicações Neoplásicas na Gravidez , Neoplasias do Colo do Útero , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/genética , Adulto , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/genética , Carcinoma de Células Escamosas/patologia , Criança , Evolução Fatal , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mães , Gravidez , Vagina , Sequenciamento do Exoma
4.
Mod Pathol ; 37(1): 100359, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37871654

RESUMO

Inflammatory rhabdomyoblastic tumors (IRMTs) are newly recognized skeletal muscle tumors with uncertain malignant potential. We investigated 13 IRMTs using clinicopathologic, genetic, and epigenetic methods. The cohort included 7 men and 6 women, aged 23 to 80 years (median, 50 years), of whom 2 had neurofibromatosis type 1. Most tumors occurred in the deep soft tissues of the lower limbs, head/neck, trunk wall, and retroperitoneum/pelvis. Two tumors involved the hypopharyngeal submucosa as polypoid masses. Eight tumors showed conventional histology of predominantly spindled cells with nuclear atypia, low mitotic activity, and massive inflammatory infiltrates. Three tumors showed atypical histology, including uniform epithelioid or plump cells and mitotically active histiocytes. The remaining 2 tumors demonstrated malignant progression to rhabdomyosarcoma; one had additional IRMT histology and the other was a pure sarcoma. All 11 IRMTs without malignant progression exhibited indolent behavior at a median follow-up of 43 months. One of the 2 patients with IRMTs with malignant progression died of lung metastases. All IRMTs were positive for desmin and PAX7, whereas myogenin and MyoD1 were expressed in a subset of cases. Targeted next-generation sequencing identified pathogenic mutations in NF1 (5/8) and TP53 (4/8). All TP53 mutations co-occurred with NF1 mutations. TP53 variant allele frequency was much lower than that of NF1 in 2 cases. These tumors showed geographic (subclonal) strong p53 immunoreactivity, suggesting the secondary emergence of a TP53-mutant clone. DNA methylation-based copy number analysis conducted in 11 tumors revealed characteristic flat patterns with relative gains, including chromosomes 5, 18, 20, 21, and/or 22 in most cases. Widespread loss of heterozygosity with retained biparental copies of these chromosomes was confirmed in 4 tumors analyzed via allele-specific profiling. Based on unsupervised DNA methylation analysis, none of the 11 tumors tested clustered with existing reference entities but formed a coherent group, although its specificity warrants further study.


Assuntos
Neoplasias Musculares , Neurofibromatose 1 , Rabdomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Masculino , Humanos , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética
5.
Cell ; 136(3): 535-50, 2009 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-19203586

RESUMO

p53 And Akt are critical players regulating tumorigenesis with opposite effects: whereas p53 transactivates target genes to exert its function as a tumor suppressor, Akt phosphorylates its substrates and transduces downstream survival signals. In addition, p53 and Akt negatively regulate each other to balance survival and death signals within a cell. We now identify PHLDA3 as a p53 target gene that encodes a PH domain-only protein. We find that PHLDA3 competes with the PH domain of Akt for binding of membrane lipids, thereby inhibiting Akt translocation to the cellular membrane and activation. Ablation of endogenous PHLDA3 results in enhanced Akt activity and decrease of p53-dependent apoptosis. We also demonstrate the suppression of anchorage-independent cell growth by PHLDA3. Loss of the PHLDA3 genomic locus was frequently observed in primary lung cancers, suggesting a role of PHLDA3 in tumor suppression. Our results reveal a new mode of coordination between the p53 and Akt pathways.


Assuntos
Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Proteína Oncogênica v-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Humanos , Camundongos , Camundongos Knockout , Proteínas Nucleares/química , Proteínas Nucleares/genética , Fosfatos de Fosfatidilinositol/metabolismo , Fosforilação , Estrutura Terciária de Proteína , Transdução de Sinais
6.
Genes Chromosomes Cancer ; 62(12): 755-760, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37732625

RESUMO

Dedifferentiated chondrosarcoma is a subtype of chondrosarcoma with a biphasic histological appearance of a chondrosarcoma component transitioning to a high-grade, noncartilaginous sarcoma. It is particularly difficult to confirm the diagnosis when a sarcoma lacking cartilaginous component occurs at a distant location from the primary lesion. The patient was a 72-year-old woman with multiple lesions in the pelvis, lungs, and liver, 18 months after resection of grade 2 central chondrosarcoma of the sternum. Imaging showed no cartilage component in any location. Although a needle biopsy from the pelvic region confirmed the diagnosis as high-grade sarcoma without a cartilage component, it was difficult to distinguish between a new primary sarcoma and metachronous metastatic lesions from patient's known prior dedifferentiated chondrosarcoma. We therefore performed a comparative molecular analysis by whole-exome sequencing of the biopsy sample and the resected sternal central chondrosarcoma. Both lesions had no IDH1/2 mutations but shared 19 somatic mutations and wide-range chromosomal losses, indicating similar origin. This case illustrates the challenge is coupling a diagnosis of metastatic dedifferentiated chondrosarcoma when no chondroid component is evident. Our study also highlights the benefit of genomic analysis in this differential diagnosis, especially in the context of dedifferentiated chondrosarcoma lacking IDH1/2 mutations.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Feminino , Humanos , Idoso , Condrossarcoma/diagnóstico , Condrossarcoma/genética , Condrossarcoma/patologia , Mutação , Aberrações Cromossômicas , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia
7.
Breast Cancer Res Treat ; 197(3): 593-602, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36494460

RESUMO

PURPOSE: Male breast cancer (MBC) is a rare cancer accounting for only 1% of all male cancers and is, therefore, poorly studied. We aimed to characterize the subtypes of MBC in Japanese patients based on genetic profiling, the presence of tumor-infiltrating cells, and the expression of immunohistochemical markers. METHODS: This retrospective study included 103 patients with MBC diagnosed between January 2009 and December 2019 at various hospitals in Japan. Clinicopathological patient characteristics were obtained from medical records, and formalin-fixed paraffin-embedded tissue specimens were analyzed for histological markers, mutations of 126 genes, BRCA1 methylation, and stromal tumor-infiltrating lymphocytes. RESULTS: The median patient age was 71 (range 31-92) years. T1-stage tumors were the most frequent (47.6%), and most were node negative (77.7%). The majority of tumors were positive for estrogen receptor (98.1%), progesterone receptor (95.1%), and androgen receptor (96.1%), and BRCA2 was the most frequently mutated gene (12.6%). The most common treatment was surgery (99.0%), either total mastectomy (91.1%) or partial mastectomy (7.0%). Survival analysis showed a 5-year recurrence-free survival rate of 64.4% (95% confidence interval [CI] 46.7-88.8) and a 5-year overall survival rate of 54.3% (95% CI 24.1-100.0). CONCLUSION: Japanese MBC is characterized by a high rate of hormonal receptor positivity and BRCA2 somatic mutation. Due to the observed clinicopathological differences in MBC between the Western countries and Japan, further prospective studies are needed to evaluate the most suitable treatment strategies.


Assuntos
Neoplasias da Mama Masculina , Neoplasias da Mama , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/patologia , População do Leste Asiático , Mastectomia , Metilação , Mutação , Estudos Retrospectivos
8.
Mod Pathol ; 36(4): 100083, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36788089

RESUMO

Neurotrophic tyrosine receptor kinase (NTRK) fusions define infantile fibrosarcomas in young children and NTRK-rearranged spindle-cell tumors in older children and adults, which share characteristic spindle-cell histology and CD34 or S100 protein expression. Similar phenotypes were identified in tumors with BRAF, RAF1, or RET fusions, suggesting a unifying concept of "spindle-cell tumors with kinase gene fusions." In this study, we investigated CD30 expression in 38 mesenchymal tumors with kinase gene fusions using immunohistochemistry. CD30 was expressed in 15 of 22 NTRK-rearranged tumors and 12 of 16 tumors with BRAF, RAF1, or RET fusions. In total, CD30 was expressed in 27 of the 38 tumors (71%), with >50% CD30-positive cells in 21 tumors and predominantly moderate or strong staining in 24 tumors. CD34 and S100 protein were also expressed in 71% and 69% of the tumors, respectively. In contrast, CD30 was significantly less frequently expressed in other mesenchymal tumor types that histologically mimic kinase fusion-positive tumors (9 of 150 tumors, 6%), of which none showed >50% or predominantly strong staining. Among these mimicking tumors, malignant peripheral nerve sheath tumors occasionally (30%) expressed CD30, albeit in a weak focal manner in most positive cases. CD30 was also expressed in 3 of 15 separately analyzed ALK- or ROS1-positive inflammatory myofibroblastic tumors. Frequent expression of CD30 enhances the shared phenotype of spindle-cell tumors with NTRK and other kinase gene fusions, and its sensitivity seems similar to that of CD34 and S100 protein. Although moderate sensitivity hampers its use as a screening tool, CD30 expression could be valuable to rapidly identify high-yield candidates for molecular workup, particularly in communities that lack routine genetic analysis and/or for tumors with BRAF, RAF1, or RET fusions.


Assuntos
Fibrossarcoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Fibrossarcoma/genética , Proteínas de Fusão Oncogênica , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores Proteína Tirosina Quinases , Receptor trkA/genética , Proteínas S100 , Antígenos CD/metabolismo
9.
Mod Pathol ; 36(2): 100011, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36853784

RESUMO

Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5 cases identified genetic fusions between COL1A2 and LINC-PINT in 3 cases and COL1A1::MIR29B2CHG fusion in 1, both validated using fluorescence in situ hybridization and reverse transcription (RT)-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole-exome sequencing and confirmed using Sanger sequencing. All these genetic alterations were predicted to cause frameshift and/or truncation of COL1A1/2. The chromosomal locations of COL1A2 (7q21.3), LINC-PINT (7q32.3), COL1A1 (17q21.33), and MIR29B2CHG (1q32.2) were consistent with the breakpoints identified in the previous cytogenetic studies. Subsequent screening of 3 BPOPs using fluorescence in situ hybridization identified 1 additional case each with COL1A1 or COL1A2 rearrangement. Our findings are consistent with reported chromosomal abnormalities and implicate the disruption of type I collagen, and perhaps of either noncoding RNA gene as a tumor suppressor, in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.


Assuntos
Neoplasias Ósseas , Neoplasias de Tecido Conjuntivo , Neoplasias de Tecidos Moles , Feminino , Humanos , Masculino , Proliferação de Células , Aberrações Cromossômicas , Hibridização in Situ Fluorescente , Mutação , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso
10.
Genes Chromosomes Cancer ; 61(11): 683-688, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35715887

RESUMO

CIC-rearranged sarcoma is a high-grade sarcoma, most often harboring CIC::DUX4 fusion, and is characterized by a distinct round cell histology, co-expression of ETV4 and WT1, and a specific DNA methylation class. Herein, we report a brain tumor with ATXN1::DUX4 that had an indistinguishable phenotype and DNA methylation profile from CIC-rearranged sarcoma. A 40-year-old man presented with a 5 cm hemorrhagic mass in the right frontal lobe of the cerebrum. The tumor was resected and histologically showed a dense proliferation of relatively monomorphic round cells with multifocal myxoid changes. Immunohistochemically, the tumor was diffusely positive for ETV4, WT1, and DUX4. Through classic histomorphology and immunoprofile, the tumor was provisionally diagnosed as CIC-rearranged sarcoma. However, no CIC fusions or mutations were identified using CIC break-apart fluorescence in situ hybridization (FISH) or FoundationOne CDx. Despite multiple surgeries and adjuvant chemoradiation therapy, the patient succumbed 16 months after presentation. RNA exome sequencing detected an in-frame intraexonic ATXN1 (exon 9)::DUX4 (exon 1) fusion, which was validated by reverse transcription-polymerase chain reaction and ATXN1 FISH assay. Upon DNA methylation analysis, the tumor matched with CIC-rearranged sarcoma both by the Deutsche Krebsforschungszentrum classifier and t-distributed stochastic neighbor embedding. Along with a recent report of a similar pediatric brain tumor, the present case suggests that ATXN1::DUX4 is a recurrent alternative molecular event in the sarcoma type that is presently defined by CIC rearrangement, which prompts an expansion of the tumor concept.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Sarcoma de Células Pequenas , Sarcoma , Neoplasias de Tecidos Moles , Ataxina-1/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Sistema Nervoso Central/química , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Humanos , Hibridização in Situ Fluorescente , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Sarcoma/genética , Sarcoma/patologia , Sarcoma de Células Pequenas/genética , Neoplasias de Tecidos Moles/genética
11.
Cancer Sci ; 113(1): 170-181, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34714577

RESUMO

The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient-derived colorectal cancer spheroids and identified high levels of kynurenine and TDO2 that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR-mediated PD-L1 transactivation, and dampened immune responses; these changes were all abolished by PD-L1 knockout. In patient-derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of PD-L1, but also for cancer stem cell (CSC)-related characteristics and Wnt signaling. TDO2 was coexpressed with both PD-L1 and nuclear ß-catenin in colon xenograft tumors, and the coexpression of TDO2 and PD-L1 was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2-kynurenine-AHR pathway facilitates liver metastasis of colon cancer via PD-L1-mediated immune evasion and maintenance of stemness.


Assuntos
Antígeno B7-H1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias do Colo/patologia , Dioxigenases/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Células-Tronco Neoplásicas/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Humanos , Cinurenina , Neoplasias Hepáticas/metabolismo , Camundongos , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Evasão Tumoral , Regulação para Cima , Via de Sinalização Wnt
12.
Mod Pathol ; 35(10): 1439-1448, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35440765

RESUMO

CIC-rearranged sarcoma is characterized by round cell undifferentiated histology, frequent expression of ETV4 and WT1, and aggressive behavior. A clinical encounter of a case with CIC-DUX4 fusion and ERG/CD31 co-expression prompted us to systematically investigate ERG and CD31 expression status in 30 archival cases of CIC-rearranged sarcoma. Half (15) of them showed moderate or strong ERG expression in <5-100% of tumor cells, among which nine showed heterogeneous membranous CD31 reactivity, including four cases each showing diffuse or strong expression. None of them showed uniformly strong and diffuse ERG/CD31 co-expression; however, three cases were initially interpreted and treated as angiosarcoma without response. Except for smaller superficial tumor enrichment, the clinicopathological characteristics of these nine cases of ERG+/CD31+ CIC-rearranged sarcoma did not differ from those of remaining 21 cases. Five showed focal hemorrhagic clefts/cysts, mimicking vascular spaces. All tumors expressed ETV4 and/or nuclear WT1, and fusion to DUX4 was confirmed in seven cases. Four tumors examined by next-generation sequencing harbored no CIC missense mutations. Using DNA methylation profiling, one CD31+ CIC-rearranged sarcoma was clustered with CD31- CIC-rearranged sarcomas, but distant from angiosarcomas. When compared with epithelioid angiosarcomas lacking CIC rearrangements, ERG+/CD31+ CIC-rearranged sarcomas were distinguished by focal myxoid change and the entire lack of vasoformative architecture. The angiosarcomas were characterized by uniform strong expression of ERG and CD31, but none of them were found positive for ETV4 or nuclear WT1. Heterogeneous ERG/CD31 co-expression in a subset of CIC-rearranged sarcoma is a clinically relevant pitfall for angiosarcoma, as these two diseases are treated differently.


Assuntos
Hemangiossarcoma , Sarcoma de Células Pequenas , Biomarcadores Tumorais/genética , Fusão Gênica , Rearranjo Gênico , Hemangiossarcoma/genética , Humanos , Proteínas de Fusão Oncogênica/genética , Sarcoma de Células Pequenas/diagnóstico , Regulador Transcricional ERG/genética
13.
Mod Pathol ; 35(2): 228-239, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34504309

RESUMO

Synovial sarcoma is characterized by variable epithelial differentiation and specific SS18-SSX gene fusions. The diagnosis is primarily based on phenotype, but fusion gene detection is increasingly being considered indispensable, with SS18 break-apart fluorescence in situ hybridization (FISH) being favored in many laboratories. However, SS18 FISH assay produces negative or atypical results in a minority of cases, leaving uncertainties in diagnosis and management. Here, we analyzed this challenging subset of SS18 FISH-negative/atypical synovial sarcoma using RNA sequencing and monoclonal antibodies that recognize SS18-SSX and the SSX C-terminus. Among 99 synovial sarcoma cases that were previously subjected to SS18 break-apart FISH, eight cases were reported as negative and three cases were indeterminate, owing to atypical signal patterns. Three of these 11 tumors (two monophasic and one biphasic) harbored novel EWSR1-SSX1 fusions, were negative for SS18-SSX staining, and were positive for SSX C-terminus staining. One monophasic tumor harbored a novel MN1-SSX1 fusion, and showed negative SS18-SSX expression and positive SSX C-terminus staining. Another monophasic tumor carried an SS18L1-SSX1 fusion, and was weakly positive for SS18-SSX, while SMARCB1 expression was reduced. The presence of these novel and/or rare fusions was confirmed using RT-PCR and Sanger sequencing. EWSR1-SSX1 was further validated by EWSR1 FISH assay. The remaining six tumors (five monophasic and one biphasic) showed strong SS18-SSX expression, and RNA sequencing successfully performed in three cases identified canonical SS18-SSX2 fusions. Based on a DNA methylation-based unsupervised clustering, the tumors with EWSR1-SSX1 and SS18L1-SSX1 clustered with synovial sarcoma, while the MN1-SSX1-positive tumor was not co-clustered despite classic histology and immunoprofile. In summary, we discovered novel and rare SSX1 fusions to non-SS18 genes in synovial sarcoma. The expanded genetic landscape carries significant diagnostic implications and advances our understanding of the oncogenic mechanism.


Assuntos
Sarcoma Sinovial , Humanos , Hibridização in Situ Fluorescente , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma Sinovial/patologia
14.
Pathobiology ; 89(4): 222-232, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35272288

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is associated with very poor prognoses. Therefore, new therapies and preclinical models are urgently needed. In the present study, we sought to develop more realistic experimental models for use in PDA research. METHODS: We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), which we integrated to create 13 matched "trios" - i.e., patient-derived tumor models of PDA. We then compared and contrasted histological and molecular alterations between these three model systems. RESULTS: Orthotopic implantation (OI) of the PDCLs resulted in tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDXs and OI-PDXs with passaged tumors revealed that the histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. When gene expression levels in the PDCLs, ectopic tumors, and OI tumors were compared, the distant metastasis-promoting gene CXCR4 was specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. CONCLUSION: These patient-derived tumor models provide useful tools for monitoring responses to antineoplastic agents and for studying PDA biology.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Humanos , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Pancreáticas
15.
J Orthop Sci ; 27(6): 1315-1322, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34531086

RESUMO

BACKGROUND: Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations. METHODS RESULTS: The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P < 0.0001). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Humanos , Isocitrato Desidrogenase/genética , Prognóstico , Condrossarcoma/genética , Condrossarcoma/patologia , Mutação , Inibidores Enzimáticos/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia
16.
Pathol Int ; 71(11): 725-740, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34614280

RESUMO

Clinical cancer genomic testing based on next-generation sequencing can help select genotype-matched therapy and provide diagnostic and prognostic information. Pathological tissue from malignant tumors obtained during routine practice are frequently used for genomic testing. This article is aimed to standardize the proper handling of pathological specimens in practice for genomic medicine based on the findings established in "Guidelines on the handling of pathological tissue samples for genomic medicine (in Japanese)" published by The Japanese Society of Pathology (JSP) in 2018. The two-part practical guidelines are based on empirical data analyses; Part 1 describes the standard preanalytic operating procedures for tissue collection, processing, and storage of formalin-fixed paraffin-embedded (FFPE) samples, while Part 2 describes the assessment and selection of FFPE samples appropriate for genomic testing, typically conducted by a pathologist. The guidelines recommend that FFPE sample blocks be used within 3 years from preparation, and the tumor content should be ≥30% (minimum 20%). The empirical data were obtained from clinical studies performed by the JSP in collaboration with leading Japanese cancer genome research projects. The Japanese Ministry of Health, Labour, and Welfare (MHLW) recommended to comply with the JSP practical guidelines in implementing cancer genomic testing under the national health insurance system in over 200 MHLW-designated core and cooperative cancer genome medicine hospitals in Japan.


Assuntos
Testes Genéticos/normas , Genômica/normas , Neoplasias/genética , Neoplasias/patologia , Manejo de Espécimes/normas , Testes Genéticos/métodos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Manejo de Espécimes/métodos , Preservação de Tecido/métodos , Preservação de Tecido/normas
17.
Clin Gastroenterol Hepatol ; 18(5): 1102-1111.e5, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394288

RESUMO

BACKGROUND & AIMS: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). METHODS: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. RESULTS: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). CONCLUSION: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).


Assuntos
Colite Ulcerativa , Biomarcadores/análise , Colite Ulcerativa/diagnóstico , Colonoscopia , Fezes/química , Humanos , Mucosa Intestinal , Complexo Antígeno L1 Leucocitário , Sangue Oculto , Índice de Gravidade de Doença
18.
Mod Pathol ; 33(9): 1660-1668, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32238877

RESUMO

Synovial sarcoma (SS) is an aggressive tumor that most often affects the deep soft tissues in young adults. Intrathoracic SS is rare and is associated with poor outcome, highlighting the urgent need for a novel therapeutic strategy. In the process of clinical sequencing, we identified two patients with intrathoracic SS harboring the BRAF V600E mutation. The patients were women aged 32 and 23 years, and both presented with SS18-SSX2-positive monophasic SS in the thoracic cavity. BRAF V600E mutations were detected by next generation sequencing, and validated immunohistochemically by diffuse intense positivity to BRAF V600E mutation-specific antibodies. The phosphorylated ERK (pERK) immunohistochemistry result was also positive. One patient received a combination therapy of dabrafenib and trametinib, which led to tumor shrinkage. However, the tumor growth progressed 7.5 months later with an additional NRAS Q61K mutation. Immunohistochemical screening of 67 archival SS tumor samples failed to identify additional samples with BRAF V600E mutation. However, 32% of BRAF V600E-negative cases was positive for pERK, and one of the six tumors showing the highest pERK expression harbored an FGFR2-activating mutation. This is the first report of targetable BRAF mutation in a small subset of SS. Our study suggests involvement of the mitogen-activated protein kinase pathway and the potential clinical implication of BRAF mutation screening in SS.


Assuntos
Neoplasias do Mediastino/genética , Proteínas Proto-Oncogênicas B-raf/genética , Sarcoma Sinovial/genética , Adulto , Biomarcadores Tumorais/genética , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Mutação , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Adulto Jovem
19.
Pancreatology ; 20(3): 551-557, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31917123

RESUMO

BACKGROUND: Yolk sac tumors (YSTs) of the pancreas are extremely rare, and no drug responsiveness data are available regarding YSTs. METHODS: We report a pancreatic YST in a 70-year-old woman, and its chemotherapeutic responsiveness based on clinical records and evaluation of a patient-derived xenograft (PDX) line of the YST. RESULTS: The YST was an 11-cm, solid mass located in the pancreatic tail. Histologically, the tumor showed medullary proliferation of tumor cells, with a variety of growth patterns including microcystic/reticular, endodermal sinus, and hepatoid patterns. Immunohistochemically, the tumor cells were positive for Sall4, glypican-3, and alpha-fetoprotein. We administered VIP (etoposide, ifosfamide, cisplatin) chemotherapy for a recurrent liver tumor, and obtained complete pathological remission. A drug-response assay using the PDX line from this YST revealed that both VIP and gemcitabine effectively inhibit tumor growth. CONCLUSIONS: These results suggest that differential diagnosis of YST from adenocarcinoma is important for selecting appropriate chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumor do Seio Endodérmico/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Idoso , Animais , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Diagnóstico Diferencial , Feminino , Humanos , Ifosfamida/uso terapêutico , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Vindesina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Genes Chromosomes Cancer ; 58(6): 373-380, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30597645

RESUMO

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H+ -ATPase (V-ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs. ATP6AP1 and ATP6AP2 mutations were found in 23 (45%) and 2 (4%) samples, respectively, and all were truncating or splice site mutations. In addition, seven other genes encoding V-ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136). These V-ATPase component gene mutations were mutually exclusive, with one exception. These results suggest that V-ATPase function is impaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits. Our findings provide additional support for the hypothesis that V-ATPase dysfunction promotes GCT tumorigenesis.


Assuntos
Tumor de Células Granulares/genética , Taxa de Mutação , Receptores de Superfície Celular/genética , ATPases Vacuolares Próton-Translocadoras/genética , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA