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1.
Am J Dermatopathol ; 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39141750

RESUMO

ABSTRACT: Malignant proliferating pilar tumors (MPPTs) are rare, unique cutaneous adnexal tumors. Sarcomatous transformation in MPPTs is even rarer (4 previous cases reported). Here, we report an extraordinary case of a MPPT with sarcomatous transformation occurring on the scalp of a 63-year-old man with an in-depth molecular profile along with histologic, immunohistochemical, and follow-up data. Shared mutations in the epithelial and sarcomatous components included a loss-of-function TP53 mutation. An inactivating TP53 mutation was only identified in the epithelial component, and an inactivating CDKN2A mutation was only identified in the sarcomatous component. Copy number variations previously reported in MPPT were also identified, including 6p21.1 loss, 6q arm loss, and 15q21.1-q26.3 gain [epithelial], and 6p22.2-p22.3 loss [sarcoma]. Histologically, the tumor demonstrated juxtaposed areas of proliferating pilar tumor, carcinoma with clear cell change, and sarcomatous areas that did not stain for AE1/AE3, p40, CD34, S100 protein, and smooth muscle actin  by immunohistochemistry. The patient is alive at 2 years without evidence of recurrence or metastasis.

2.
Mod Pathol ; 36(9): 100237, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37295554

RESUMO

Primary pericardial mesotheliomas are extremely rare, accounting for <1% of all mesotheliomas, and their molecular genetic features and predisposing factors remain to be determined. Here, we report the clinicopathologic, immunohistochemical, and molecular genetic findings of 3 pericardial mesotheliomas without pleural involvement. Three cases diagnosed between 2004 and 2022 were included in the study and analyzed by immunohistochemistry and targeted next-generation sequencing (NGS); corresponding nonneoplastic tissue was sequenced in all cases. Two patients were female and 1 was male, aged between 66 and 75 years. Two patients each had prior asbestos exposure and were smokers. Histologic subtypes were epithelioid in 2 cases and biphasic in 1 case. Immunohistochemical staining identified expression of cytokeratin AE1/AE3 and calretinin in all cases, D2-40 in 2 cases, and WT1 in 1 case. Staining for tumor suppressors revealed loss of p16, MTAP, and Merlin (NF2) expression in 2 cases and loss of BAP1 and p53 in 1 case. Abnormal cytoplasmic BAP1 expression was observed in an additional case. Protein expression abnormalities correlated with NGS results, which showed concurrent complete genomic inactivation of CDKN2A/p16, CDKN2B, MTAP, and NF2 in 2 mesotheliomas and of BAP1 and TP53 in 1 mesothelioma each, respectively. In addition, 1 patient harbored a pathogenic BRCA1 germline mutation, which resulted in biallelic inactivation in the mesothelioma. All mesotheliomas were mismatch repair proficient and showed several chromosomal gains and losses. All patients died from disease. Our study demonstrates that pericardial mesotheliomas share common morphologic, immunohistochemical, and molecular genetic features with pleural mesothelioma, including recurrent genomic inactivation of canonical tumor suppressors. Our study adds new insights into the genetic landscape of primary pericardial mesothelioma and highlights BRCA1 loss as a potential contributing factor in a subset of cases, thereby contributing to refined precision diagnostics for this rare cancer.


Assuntos
Neoplasias Cardíacas , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Neoplasias do Timo , Humanos , Masculino , Feminino , Idoso , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia , Mesotelioma/diagnóstico , Neoplasias Pleurais/patologia , Neoplasias Cardíacas/genética , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo
3.
Mod Pathol ; 36(10): 100252, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37355153

RESUMO

Lipoblastoma-like tumor (LLT) is a rare adipocytic neoplasm with a predilection for the vulva. Since 2002, <30 cases have been reported, characterizing it as an indolent tumor that may sometimes recur locally. Diagnosis can be challenging due to its rarity and morphologic overlap with other adipocytic tumors. Thus far, there are no specific molecular or immunohistochemical features to aid in the diagnosis of LLT. Recent case reports have described LLT arising at other sites, including the spermatic cord and gluteal region, suggesting wider anatomical distribution. We present a large series of LLT to further characterize its clinicopathologic and molecular features. Twenty-eight cases of LLT were retrieved from departmental and consult archives (including 8 from a prior series). The cohort comprised 28 patients (8 males, 20 females) with a median age of 28 years (range: 1-80 years). There were 17 primary LLT of the vulva. Other anatomical sites included the scrotum (n = 3), spermatic cord (n = 2), inguinal region (n = 2), limbs (n = 2), pelvis (n = 1), and retroperitoneum (n = 1). Median tumor size was 6.0 cm (range: 1.8-30.0 cm). The tumors had a lobulated architecture and were typically composed of adipocytes, lipoblasts, and spindle cells in a myxoid stroma with prominent thin-walled vessels. Using immunohistochemistry, a subset showed loss of Rb expression (12/23 of samples). Follow-up in 15 patients (median: 56 months) revealed 8 patients with local recurrence and 1 patient with metastases to the lung/pleura and breasts. Targeted DNA sequencing revealed a simple genomic profile with limited copy number alterations and low mutational burden. No alterations in RB1 were identified. The metastatic LLT showed concurrent pathogenic PIK3CA and MTOR activating mutations, both in the primary and in the lung/pleural metastasis; the latter also harbored TERT promoter mutation. One tumor had a pathogenic TSC1 mutation, and one tumor showed 2-copy deletion of CDKN2A, CDKN2B, and MTAP. No biologically significant variants were identified in 8 tumors. No gene fusions were identified by RNA sequencing in 4 tumors successfully sequenced. This study expands the clinicopathologic spectrum of LLT, highlighting its wider anatomical distribution and potential for occasional metastasis. Molecularly, we identified activating mutations in the PI3K-MTOR signaling pathway in 2 tumors, which may contribute to exceptional aggressive behavior.

4.
Histopathology ; 83(4): 569-581, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37679051

RESUMO

AIMS: Although TSC1 or TSC2 inactivating mutations that lead to mTORC1 hyperactivation have been reported in hepatic angiomyolipomas (hAML), the role of other somatic genetic events that may contribute to hAML development is unknown. There are also limited data regarding the tumour microenvironment (TME) of hAML. The aim of the present study was to identify other somatic events in genomic level and changes in TME that contribute to tumorigenesis in hAML. METHODS AND RESULTS: In this study, we performed exome sequencing in nine sporadic hAML tumours and deep-coverage targeted sequencing for TSC2 in three additional hAML. Immunohistochemistry and multiplex immunofluorescence were carried out for 15 proteins to characterise the tumour microenvironment and assess immune cell infiltration. Inactivating somatic variants in TSC2 were identified in 10 of 12 (83%) cases, with a median allele frequency of 13.6%. Five to 18 somatic variants (median number: nine, median allele frequency 21%) not in TSC1 or TSC2 were also identified, mostly of uncertain clinical significance. Copy number changes were rare, but detection was impaired by low tumour purity. Immunohistochemistry demonstrated numerous CD68+ macrophages of distinct appearance from Küpffer cells. Multiplex immunofluorescence revealed low numbers of exhausted PD-1+/PD-L1+, FOXP3+ and CD8+ T cells. CONCLUSION: hAML tumours have consistent inactivating mutations in TSC2 and have a low somatic mutation rate, similar to other TSC-associated tumours. Careful histological review, standard IHC and multiplex immunofluorescence demonstrated marked infiltration by non-neoplastic inflammatory cells, mostly macrophages.


Assuntos
Angiomiolipoma , Neoplasias Gastrointestinais , Neoplasias Hepáticas , Proteína 2 do Complexo Esclerose Tuberosa , Humanos , Angiomiolipoma/genética , Neoplasias Hepáticas/genética , Macrófagos , Mutação , Microambiente Tumoral , Proteína 2 do Complexo Esclerose Tuberosa/genética
5.
Cancer Treat Res ; 186: 299-312, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37978142

RESUMO

This chapter explores the multifaceted roles of DNA-PK with particular focus on its functions in non-homologous end-joining (NHEJ) DNA repair. DNA-PK is the primary orchestrator of NHEJ but also regulates other biologic processes. The growing understanding of varied DNA-PK biologic roles highlights new avenues for cancer treatment. However, these multiple roles also imply challenges, particularly in combination therapies, with perhaps a higher risk of clinical toxicities than was previously envisioned. These considerations underscore the need for compelling and innovative strategies to accomplish effective clinical translation.


Assuntos
Produtos Biológicos , Proteínas de Ligação a DNA , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , DNA/genética , Reparo do DNA , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo
6.
Br J Cancer ; 127(11): 2072-2085, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36175617

RESUMO

BACKGROUND: Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition. METHODS: Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure. RESULTS: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST. CONCLUSIONS: These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.


Assuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Humanos , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Quinase 6 Dependente de Ciclina , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética
7.
Cancer ; 127(15): 2666-2673, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33788262

RESUMO

BACKGROUND: Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases. METHODS: TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization. RESULTS: Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients. CONCLUSIONS: These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.


Assuntos
Genes p53 , Leiomiossarcoma , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Neoplasias Uterinas , Feminino , Genes p16 , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , PTEN Fosfo-Hidrolase/genética , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
8.
Mod Pathol ; 34(9): 1763-1779, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33986460

RESUMO

Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. In this study, we used next-generation DNA and RNA sequencing to profile 25 primary prostatic mesenchymal neoplasms of possible specialized prostatic stromal origin, including cases originally diagnosed as PSS (11) and STUMP (14). Morphologically, the series comprised 20 cases with solid architecture (11 PSS and 9 STUMP) and 5 cases with phyllodes-like growth pattern (all STUMP). Combined DNA and RNA sequencing results demonstrated that 19/22 (86%) cases that underwent successful sequencing (either DNA or RNA) harbored pathogenic somatic variants. Except for TP53 alterations (6 cases), ATRX mutations (2 cases), and a few copy number variants (-13q, -14q, -16q and +8/8p), the findings were largely nonrecurrent. Eight gene rearrangements were found, and 4 (NAB2-STAT6, JAZF1-SUZ12, TPM3-NTRK1 and BCOR-MAML3) were useful for reclassification of the cases as specific entities. The present study shows that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous and include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, including soft tissue and the uterus. These data suggest that tumors of purported specialized prostatic stromal origin may perhaps not represent a single diagnostic entity or specific disease group and that alternative diagnoses should be carefully considered.


Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Adolescente , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Adulto Jovem
9.
Mod Pathol ; 34(1): 95-103, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32669612

RESUMO

Mesenchymal tumors driven by NTRK fusions are clinically and morphologically heterogeneous. With an increasing number of clinicopathological entities being associated with NTRK fusions, the diagnostic and predictive value of the identification of NTRK fusions is uncertain. Recently, mesenchymal tumors in the gastrointestinal tract with NTRK fusions were described as gastrointestinal stromal tumors (GIST), but the nosology of such neoplasms remains controversial. We report eight mesenchymal tumors involving the gastrointestinal tract with NTRK1 or NTRK3 rearrangements. The tumors occurred in six children and two adults, five males and three females (age range 2 months-55 years; median 3.5 years), and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1), and mesentery (n = 1). Clinical outcomes were variable, ranging from relatively indolent (n = 2) to aggressive diseases (n = 2). Morphologically, the tumors were heterogeneous and could be classified in the following three groups: (1) infantile fibrosarcoma involving the gastrointestinal tract (n = 4), enriched for NTRK3 fusions; (2) low-grade CD34-positive, S100 protein-positive spindle-cell tumors, associated with NTRK1 fusions (n = 2); and (3) unclassified high-grade spindle-cell sarcomas, with NTRK1 fusions (n = 2). By immunohistochemistry, the tumors demonstrated diffuse pan-TRK expression, of variable intensity, and lacked a specific line of differentiation. Four cases expressed CD34, which was coexpressed with S100 protein in three cases. Expression of SOX10, KIT, and DOG1 was consistently absent. Molecular genetic testing identified TPM3-NTRK1 (n = 3), TPR-NTRK1, LMNA-NTRK1, and ETV6-NTRK3 (n = 2), and SPECC1L-NTRK3 in-frame gene fusions. We conclude that the evaluation of mesenchymal spindle-cell neoplasms of the gastrointestinal tract without a definitive line of differentiation should include interrogation of NTRK alterations, particularly in pediatric patients. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements are clinically and morphologically heterogeneous, and few, if any, seem related to GIST.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Adulto , Criança , Pré-Escolar , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Receptor trkA/genética , Estudos Retrospectivos
10.
Br J Cancer ; 122(3): 372-381, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31776458

RESUMO

BACKGROUND: Most gastrointestinal stromal tumours (GIST) are driven by activating oncogenic mutations of KIT/PDGFRA, which provide a compelling therapeutic target. Our previous studies showed that CDC37, regulated by casein kinase 2 (CK2), is a crucial HSP90 cofactor for KIT oncogenic function and a promising and more selective therapeutic target in GIST. METHODS: Biologic mechanisms of CK2-mediated CDC37 regulation were assessed in GISTs by immunoblotting, immunoprecipitations, knockdown and inactivation assays. The effects of a combination of KIT and CK2 inhibition were assessed by immunoblotting, cell viability, colony growth, cell cycle analysis, apoptosis, migration and invasiveness. RESULTS: CK2 overexpression was demonstrated by immunoblotting in GIST cell lines and patient biopsies. Treatment with a specific CK2 inhibitor, CX4945, leads to CDC37 dephosphorylation and inhibits KIT signalling in imatinib-sensitive and in imatinib-resistant GIST cell lines. Immunoprecipitation demonstrated that CK2 inhibition blocks KIT:HSP90:CDC37 interaction in GIST cells. Coordinated inhibition of CK2 and KIT by CX4945 (or CK2 shRNA) and imatinib, respectively, leads to increased apoptosis, anti-proliferative effects and cell cycle arrest and decreased p-AKT and p-S6 expression, migration and invasiveness in all GIST cell lines compared with either intervention alone, indicating additive effects of inhibiting these two important regulators of GIST biology. CONCLUSION: Our findings suggest that combinatorial inhibition of CK2 and KIT warrants evaluation as a novel therapeutic strategy in GIST, especially in imatinib-resistant GIST.


Assuntos
Caseína Quinase II/genética , Proteínas de Ciclo Celular/metabolismo , Chaperoninas/metabolismo , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Naftiridinas/farmacologia , Fenazinas , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
11.
Br J Cancer ; 120(6): 612-620, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30792533

RESUMO

BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Animais , Células CHO , Ensaios Clínicos Fase II como Assunto , Cricetulus , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Camundongos Nus , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/farmacologia , Sunitinibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Br J Cancer ; 121(3): 281, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31123346

RESUMO

The additional information of this manuscript originally stated that the authors declare no competing interests. This statement was incorrect, and should instead have stated the following:M.C.H. has the following competing interests to declare: Equity interest at Molecular MD; Consulting at Molecular MD, Blueprint Medicines, Deciphera Pharmaceuticals; Expert Testimony at Novartis; Licensed patent with royalty payments at Novartis. The remaining authors have no competing interests to declare.The authors apologise for any convenience this may have caused.

13.
Mod Pathol ; 32(11): 1688-1697, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31189997

RESUMO

Uterine myxoid smooth muscle tumors, including myxoid leiomyosarcoma, are rare and their genomic profile has not been fully characterized. With the discovery of uterine sarcomas with ZC3H7B-BCOR fusion and BCOR internal tandem duplications, the differential diagnosis of myxoid smooth muscle lesions is expanding to include molecularly-defined tumors. Thus, we aimed to explore the genomic landscape of myxoid smooth muscle tumor using comprehensive tools. We performed whole exome next-generation sequencing and a pan-sarcoma RNA fusion assay in tumoral paraffin-embedded tissue from nine well-characterized uterine myxoid smooth muscle tumors (seven myxoid leiomyosarcomas and two myxoid smooth muscle tumors of unknown malignant potential). By immunohistochemistry, all tumors were strongly positive for smooth muscle markers and negative for BCOR staining; 4/6 expressed PLAG1. None of the tumors harbored known fusions including ZC3H7B-BCOR, TRPS1-PLAG1, and RAD51B-PLAG1. None harbored exon 15 BCOR internal tandem duplications; however, four tumors contained BCOR internal tandem duplications of unknown significance (mostly intronic). Mutational burden was low (median 3.8 mutations/megabase). DNA damage repair pathway gene mutations, including TP53 and BRCA2, were found. Copy number variation load, inferred from sequencing data, was variable with genomic indexes ranging from 2.2 to 74.7 (median 25.7), with higher indexes in myxoid leiomyosarcomas than myxoid smooth muscle tumors of unknown malignant potential. The absence of clear driver mutations suggests myxoid smooth muscle tumors to be genetically heterogeneous group of tumours and that other genetic (eg., undiscovered translocation) or epigenetic events drive the pathogenesis of uterine myxoid smooth muscle neoplasia.


Assuntos
Tumor de Músculo Liso/genética , Transcriptoma , Neoplasias Uterinas/genética , Adulto , Idoso , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico/métodos
14.
J Pathol ; 241(3): 316-323, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27874193

RESUMO

ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Proteínas de Transporte/genética , Inflamação/metabolismo , Miofibroblastos/metabolismo , Proteínas Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Sarcoma/genética , Quinase do Linfoma Anaplásico , Humanos , Sarcoma/patologia
15.
N Engl J Med ; 370(14): 1327-34, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24693892

RESUMO

Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.


Assuntos
Neoplasias Gastrointestinais/enzimologia , Tumores do Estroma Gastrointestinal/enzimologia , Hipotireoidismo/enzimologia , Hipotireoidismo/etiologia , Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/deficiência , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Humanos , Iodeto Peroxidase/genética , Masculino , Pessoa de Meia-Idade , Radiografia Abdominal
16.
Adv Anat Pathol ; 24(5): 259-267, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28632504

RESUMO

The classification "gastrointestinal stromal tumor" (GIST) became commonplace in the 1990s and since that time various advances have characterized the GIST lineage of origin, tyrosine kinase mutations, and mechanisms of response and resistance to targeted therapies. In addition to tyrosine kinase mutations and their constitutive activation of downstream signaling pathways, GISTs acquire a sequence of chromosomal aberrations. These include deletions of chromosomes 14q, 22q, 1p, and 15q, which harbor putative tumor suppressor genes required for stepwise progression from microscopic, preclinical forms of GIST (microGIST) to clinically relevant tumors with malignant potential. Recent advances extend our understanding of GIST biology beyond that of the oncogenic KIT/PDGFRA tyrosine kinases and beyond mechanisms of KIT/PDGFRA-inhibitor treatment response and resistance. These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of succinate dehydrogenase deficient GIST, which are particularly common in young adults. Also, recent discoveries of MAX and dystrophin genomic inactivation have expanded our understanding of GIST development and progression, showing that MAX inactivation is an early event fostering cell cycle activity, whereas dystrophin inactivation promotes invasion and metastasis.


Assuntos
Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mutação/genética , Invasividade Neoplásica/genética , Aberrações Cromossômicas , Tumores do Estroma Gastrointestinal/diagnóstico , Humanos , Transdução de Sinais/genética , Fatores de Transcrição/genética
17.
Genes Chromosomes Cancer ; 55(1): 25-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26355893

RESUMO

Biphenotypic sinonasal sarcoma (SNS) is a low grade spindle cell sarcoma that affects middle-aged adults, in which the PAX3-MAML3 chimeric transcription factor induces an aberrant dual myogenic and neuroectodermal phenotype. We report an alternate PAX3-FOXO1 oncogenic fusion in SNS, confirming the crucial role of PAX3 in SNS oncogenesis. The presence of PAX3-FOXO1 in SNS and alveolar rhabdomyosarcoma suggests that these two entities are genetically similar lesions arising from distinct progenitor cell pools. This finding has important implications for the molecular diagnosis of SNS and alveolar rhabdomyosarcoma, and underscores the critical contribution of the cell of origin to the phenotype induced by oncogenic transcription factor reprogramming.


Assuntos
Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Neoplasias dos Seios Paranasais/patologia , Sarcoma/genética , Adulto , Humanos , Hibridização in Situ Fluorescente , Masculino , Neoplasias dos Seios Paranasais/genética , Translocação Genética
18.
Genes Chromosomes Cancer ; 55(5): 442-51, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26773439

RESUMO

Knowledge of the clinicopathological and molecular spectrum of pediatric renal cell carcinomas (RCC) remains limited, and approximately 16%-24% of these neoplasms cannot be classified into specific subtypes. In this review of 168 pediatric RCC prospectively registered on Children's Oncology Group AREN03B2 protocol, six RCC (3.5%) that demonstrated a unique epithelioid morphology and a peculiar immunophenotypic profile that includes expression of ALK, TFE3, and retention of INI1 was identified. Further investigation revealed ALK rearrangements in all cases, manifested molecularly by fusion transcripts of either VCL-ALK (3 patients all with sickle cell trait which had been previously reported) or TPM3-ALK (3 patients, none with sickle cell trait). Based on the shared unique morphologic, immunophenotypic, and genetic features, it was proposed that these neoplasms belonged to a distinct subgroup of RCC frequently occurring in pediatric patients, which they have termed as ALK-rearranged RCC. Importantly, additional therapeutic options may be available for these patients.


Assuntos
Carcinoma de Células Renais/genética , Ordem dos Genes , Neoplasias Renais/genética , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Criança , Humanos , Hibridização in Situ Fluorescente
19.
Lab Invest ; 96(10): 1128-37, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27617402

RESUMO

Mesenchymal chondrosarcomas are rare and highly aggressive sarcomas occurring in bone and soft tissue, with poor overall survival. Bcl-2 expression was previously shown to be upregulated in mesenchymal chondrosarcomas. We here report on a newly derived mesenchymal chondrosarcoma cell line, MCS170, in which we investigated treatment with the BH3 mimetic ABT-737 alone or in combination with conventional chemotherapy as a possible new therapeutic strategy. The presence of the characteristic HEY1-NCOA2 fusion was confirmed in the MCS170 cell line using FISH, RT-PCR, and sequencing. The MCS170 cell line was treated with ABT-737 alone or in combination with doxorubicin or cisplatin. Cell viability and proliferation was determined using WST-1 viability assays and the xCELLigence system. Expression of Bcl-2 family members was studied using immunohistochemistry. Apoptosis was determined using the caspase-glo 3/7 assay and western blot for PARP cleavage. The MCS170 cell line was sensitive to doxorubicin treatment with an IC50 of 0.09 µM after 72 h, but more resistant to cisplatin treatment with an IC50 of 4.5 µM after 72 h. Cells showed little sensitivity toward ABT-737 with an IC50 of 1.8 µM after 72 h. Combination treatments demonstrated ABT-737 synergism with cisplatin as well as doxorubicin as shown by induction of apoptosis and reduction in cell proliferation. Restoration of the apoptotic machinery by inhibition of Bcl-2 family members sensitizes MCS170 mesenchymal chondrosarcoma cells to conventional chemotherapy. This indicates that combining the inhibition of Bcl-2 family members with conventional chemotherapy can be a possible therapeutic strategy for patients with mesenchymal chondrosarcoma.


Assuntos
Linhagem Celular Tumoral/efeitos dos fármacos , Condrossarcoma Mesenquimal , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Adulto , Antineoplásicos , Compostos de Bifenilo , Cisplatino , Doxorrubicina , Humanos , Masculino , Nitrofenóis , Piperazinas , Sulfonamidas
20.
Br J Cancer ; 114(11): 1219-26, 2016 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-27140314

RESUMO

BACKGROUND: Leiomyosarcoma is an aggressive soft tissue sarcoma with a 5-year survival rate of 15 to 60%. Treatment options for inoperable or metastatic patients are limited owing to frequent resistance of tumours to chemotherapy and radiation. In this study, we hypothesised that antiapoptotic Bcl-2 family proteins might contribute to leiomyosarcoma chemoresistance and therefore inhibition of Bcl-2 family proteins might sensitise leiomyosarcomas to conventional chemotherapy. METHODS: Expression of the Bcl-2 family proteins Bcl-xL, Bcl-w and Bcl-2 was investigated using immunohistochemistry on a tissue microarray containing 43 leiomyosarcomas. Furthermore, we investigated whether ABT-737, a potent BH3 mimetic, sensitises leiomyosarcoma cells to doxorubicin treatment in vitro. RESULTS: Seventy-seven per cent, 84% and 42% of leiomyosarcomas demonstrated high expression of Bcl-2, Bcl-xL and Bcl-w, respectively. Single-agent treatment with ABT-737 resulted in a minor reduction of cell viability. However, combination treatment of ABT-737 and doxorubicin revealed synergism in all four cell lines, by inducing apoptosis. CONCLUSIONS: In conclusion, Bcl-2 family proteins contribute to soft tissue leiomyosarcoma chemoresistance. Antiapoptotic proteins are highly expressed in leiomyosarcoma of soft tissue, and inhibition of these proteins using a BH3 mimetic increases leiomyosarcoma sensitivity to doxorubicin.


Assuntos
Compostos de Bifenilo/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leiomiossarcoma/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Nitrofenóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/fisiologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Leiomiossarcoma/secundário , Proteínas de Neoplasias/fisiologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Neoplasias Retroperitoneais/secundário , Neoplasias de Tecidos Moles/patologia , Neoplasias Uterinas/patologia , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/fisiologia
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