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1.
Artigo em Inglês | MEDLINE | ID: mdl-34897468

RESUMO

CONTEXT: The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis. OBJECTIVE: To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes. DESIGN: 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared. RESULTS: Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor ß (TGFß)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors. CONCLUSION: Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFß-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis.

2.
Mol Cancer Ther ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789562

RESUMO

Hurthle cell carcinomas (HCC) are refractory to radioactive iodine and unresponsive to chemotherapeutic agents, with a fatality rate that is the highest among all types of thyroid cancer after anaplastic thyroid cancer. Our previous study on the genomic landscape of HCCs identified a high incidence of disruptions of mTOR pathway effectors. Here, we report a detailed analysis of mTOR signaling in cell line and patient-derived xenograft (PDX) mouse models of HCCs. We show that mTOR signaling is upregulated and that targeting mTOR signaling using mTOR inhibitors suppresses tumor growth in primary tumors and distant metastasis. Mechanistically, ablation of mTOR signaling impaired the expression of p-S6 and cyclin A2, resulting in the decrease of S phase and blocking of cancer cell proliferation. Strikingly, mTOR inhibitor treatment significantly reduced lung metastatic lesions, with the decreased expression of Snail in xenograft tumors. Our data demonstrates that mTOR pathway blockade represents a novel treatment strategy for HCC.

3.
J Clin Oncol ; : JCO2101329, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34731032

RESUMO

PURPOSE: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. PATIENTS AND METHODS: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. RESULTS: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. CONCLUSION: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.

4.
Mol Cancer Res ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635506

RESUMO

Targeted inhibition of BRAF V600E achieves tumor control in a subset of advanced thyroid tumors. Nearly all tumors develop resistance, and some have been observed to subsequently undergo dedifferentiation. The molecular alterations associated with thyroid cancer dedifferentiation in the setting of BRAF inhibition are unknown. We analyzed targeted next-generation sequencing data from 639 advanced, recurrent and/or metastatic thyroid carcinomas, including 15 tumors that were treated with BRAF inhibitor drugs and had tissue sampled during or posttreatment, 8 of which had matched pretherapy samples. Pre- and posttherapy tissues from one additional patient were profiled with whole-exome sequencing and RNA expression profiling. Mutations in genes comprising the SWI/SNF chromatin remodeling complex and the PI3K-AKT-mTOR, MAPK, and JAK-STAT pathways all increased in prevalence across more dedifferentiated thyroid cancer histologies. Of 7 thyroid cancers that dedifferentiated after BRAF inhibition, 6 had mutations in these pathways. These mutations were mostly absent from matched pretreatment samples and were rarely detected in tumors that did not dedifferentiate. Additional analyses in one of the vemurafenib-treated tumors before and after anaplastic transformation revealed the emergence of an oncogenic PIK3CA mutation, activation of ERK signaling, dedifferentiation, and development of an immunosuppressive tumor microenvironment. These findings validate earlier preclinical data implicating these genetic pathways in resistance to BRAF inhibitors, and suggest that genetic alterations mediating acquired drug resistance may also promote thyroid tumor dedifferentiation. IMPLICATIONS: The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor-targeted therapy should be investigated further.

5.
Histopathology ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449926

RESUMO

AIMS: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma. METHODS AND RESULTS: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year disease-specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC-nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. CONCLUSIONS: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC.

6.
Cardiovasc Intervent Radiol ; 44(11): 1798-1806, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34254175

RESUMO

BACKGROUND: To compare laser ablation (LA) zone dimensions at two predetermined energy parameters to cover a theoretical 10 mm zone + 2 mm margin in a thyroid swine model. METHODS: Approval of the Institutional Animal Care and Use Committee was obtained. After hydrodissection, an ultrasound-guided LA (Elesta Echolaser X4 with Orblaze technology, 1064 nm) was performed in the periphery of the thyroid in 10 swine. Two cohorts were established to ablate a region of 10mm diameter with 2mm margin based on manufacturer's ex vivo data (n= 5 at 3W/1400J and n= 5 at 3W/1800J). The ablation zone was measured on contrast-enhanced computed tomography (CT) and compared to the pathological specimen. Euthanasia was performed 48 hours following ablation. RESULTS: All ablations in the 3W/1800J group achieved a diameter of 12 mm ± 1 mm in three dimensions. In the 3W/1400J group, 1 ablation reached 12 mm ± 1 mm in 2 dimensions and 4 ablations reached this size in one dimension. Maximum diameter was higher in the 3W/1800J compared to the 3W/1400J group, both on histology (1.46 cm ± 0.05 vs. 1.1 cm ± 0.0, p< 0.01) and CT (1.52 cm ± 0.04 vs. 1.18 cm ± 0.04, p< 0.01). Similar results were obtained regarding volumes, both on histology (1.12 mL ± 0.13 vs. 0.57 mL ± 0.06, p< 0.01) and CT (1.24 mL ± 0.13 vs. 0.59 mL ± 0.07, p< 0.01). Histology showed coagulation necrosis and correlated well with CT measurements. CONCLUSION: Optimal parameters to obtain a LA zone of 10 mm with 2 mm margin utilizing a single needle are 3W/1800J.


Assuntos
Técnicas de Ablação , Ablação por Cateter , Terapia a Laser , Animais , Suínos , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/cirurgia , Ultrassonografia , Ultrassonografia de Intervenção
7.
Cancer ; 127(22): 4161-4170, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34293201

RESUMO

BACKGROUND: The use of external-beam radiotherapy for locally advanced nonanaplastic thyroid cancer remains controversial. This prospective study evaluated the efficacy and tolerability of intensity-modulated radiation therapy (IMRT) with or without concurrent chemotherapy in patients with locally advanced thyroid cancer. METHODS: The authors conducted a nonrandomized phase 2 trial of IMRT with or without concurrent doxorubicin in patients with gross residual or unresectable nonanaplastic thyroid carcinoma (ClinicalTrials.gov identifier NCT01882816). The primary end point was 2-year locoregional progression-free survival (PFS). Secondary end points included overall survival (OS), safety, patient-reported outcomes, and functional outcomes. RESULTS: Twenty-seven patients were enrolled: 12 (44.4%) with unresectable disease and 15 (55.6%) with gross residual disease. The median follow-up was 45.6 months (interquartile range, 42.0-51.6 months); the 2-year cumulative incidences of locoregional PFS and OS were 79.7% and 77.3%, respectively. The rate of grade 3 or higher acute and late toxicities was 33.4%. There were no significant functional differences 12 months after treatment (assessed objectively by the modified barium swallow study). Patient-reported quality of life in the experimental group was initially lower but returned to the baseline after 6 months and improved thereafter. In a post hoc analysis, concurrent chemotherapy with intensity-modulated radiation therapy (CC-IMRT) resulted in significantly less locoregional failure at 2 years (no failure vs 50%; P = .001), with higher rates of grade 2 or higher acute dermatitis, mucositis, and dysphagia but no difference in long-term toxicity, functionality, or patient-reported quality of life. CONCLUSIONS: In light of the excellent locoregional control rates achieved with CC-IMRT and its acceptable toxicity profile as confirmed by functional assessments and patient-reported outcomes, CC-IMRT may be preferred over IMRT alone.

8.
Oncogene ; 40(31): 4955-4966, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34172934

RESUMO

A prototypic pediatric cancer that frequently shows activation of RAS signaling is embryonal rhabdomyosarcoma (ERMS). ERMS also show aberrant Hedgehog (HH)/GLI signaling activity and can be driven by germline mutations in this pathway. We show, that in ERMS cell lines derived from sporadic tumors i.e. from tumors not caused by an inherited genetic variant, HH/GLI signaling plays a subordinate role, because oncogenic mutations in HRAS, KRAS, or NRAS (collectively named oncRAS) inhibit the main HH target GLI1 via the MEK/ERK-axis, but simultaneously increase proliferation and tumorigenicity. oncRAS also modulate expression of stem cell markers in an isoform- and context-dependent manner. In Hh-driven murine ERMS that are caused by a Patched mutation, oncHRAS and mainly oncKRAS accelerate tumor development, whereas oncNRAS induces a more differentiated phenotype. These features occur when the oncRAS mutations are induced at the ERMS precursor stage, but not when induced in already established tumors. Moreover, in contrast to what is seen in human cell lines, oncRAS mutations do not alter Hh signaling activity and marginally affect expression of stem cell markers. Together, all three oncRAS mutations seem to be advantageous for ERMS cell lines despite inhibition of HH signaling and isoform-specific modulation of stem cell markers. In contrast, oncRAS mutations do not inhibit Hh-signaling in Hh-driven ERMS. In this model, oncRAS mutations seem to be advantageous for specific ERMS populations that occur within a specific time window during ERMS development. In addition, this window may be different for individual oncRAS isoforms, at least in the mouse.

9.
Endocr Relat Cancer ; 28(6): 391-402, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33890869

RESUMO

Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid-differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFB1 also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of BRAFV600E-PTC with thyroid-specific knockout of the Tgfbr1 gene to investigate the role of TGFB1 on thyroid-differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of Tgfbr1, pSMAD levels remained high, indicating that ligands other than TGFB1 were engaging in this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BRAFV600E-mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFBR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BRAFV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BRAFV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting TGFß/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.

10.
Cancer Discov ; 11(5): 1158-1175, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33318036

RESUMO

Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAFV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAFV600E-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies. SIGNIFICANCE: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.This article is highlighted in the In This Issue feature, p. 995.

11.
J Clin Invest ; 130(11): 5668-5670, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32986019

RESUMO

Growth hormone-secreting (GH-secreting) pituitary tumors are driven by oncogenes that induce cAMP signaling. In this issue of the JCI, Ben-Shlomo et al. performed a whole-exome study of pituitary adenomas. GH-secreting tumors had a high frequency of whole chromosome or chromosome arm copy number alterations and were associated with an increase in the tumor protein p53 and the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which are findings consistent with induction of a response to DNA damage. Further, treatment of mouse pituitary cells with cAMP pathway agonists in vitro and in vivo elicited biomarkers of DNA replication stress or double-strand breaks. The findings of Ben Shlomo et al. indicate that oncoproteins that drive constitutively high cAMP signaling pathway output in susceptible cell types can elicit DNA replication stress and may promote genomic instability.


Assuntos
Adenoma , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasias Hipofisárias , Adenoma/genética , Animais , AMP Cíclico , Dano ao DNA , Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Camundongos , Oncogenes/genética , Neoplasias Hipofisárias/genética
12.
Thyroid ; 30(10): 1505-1517, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32284020

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is nearly always fatal. Large studies on ATC are exceedingly rare. We aimed to study the clinical, genotypic, and histologic characteristics of ATC in the largest retrospective cohort of ATC to date. Methods: Three hundred sixty patients with ATC from two tertiary centers were studied. Molecular testing was performed in 126 cases including 107 using next-generation sequencing. Results: The median patients' age was 68 years. Differentiated thyroid carcinoma (DTC) was present in 208 cases (58%), the most common being papillary carcinoma (n = 150). The 1-, 2-, 3-, and 5-year overall survival (OS) was 36%, 17%, 13%, and 11%, respectively. On univariate analysis, age, resectability, chemotherapy, radiotherapy, margin status, encapsulation, gross residual disease, gross extrathyroidal extension, percentage, and size of ATC in the primary tumor predicted OS (p < 0.05). Age, resectability, chemotherapy, and gross residual disease were independent prognostic factors in the entire cohort, while gross residual disease was the only independent predictor of OS in patients who had resection of their tumor. BRAF, RAS, TERT promoter, TP53, PIK3CA, E1F1AX, and PTEN mutations were detected in 45%, 24%, 75%, 63%, 18%, 14%, and 14% of ATC, respectively. Concomitant BRAF/RAS and TERT mutations were associated with worse outcome than mutation in only one of the genes. BRAF-mutated and RAS-mutated ATCs had similar frequency of nodal and distant metastasis. Twelve cases were pure squamous cell carcinoma, 60% of which carried BRAFV600E mutation and showed a similar OS to other ATCs. Conclusions: (i) Gross residual disease remains the most crucial indicator of outcome in ATC. (ii) Encapsulation, margin status, percentage, and size of ATC in the primary were prognostically relevant. (iii) Pure thyroid squamous cell carcinoma may be considered as ATC given a BRAFV600E genotype and similar outcome. (iv) In contrast to DTC, BRAF-mutated and RAS-mutated ATCs have similar metastatic spread. (v) Concomitant mutations of BRAF or RAS with TERT confer a worse prognosis.


Assuntos
Imunofenotipagem/métodos , Carcinoma Anaplásico da Tireoide/diagnóstico , Carcinoma Anaplásico da Tireoide/imunologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , GTP Fosfo-Hidrolases/genética , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mitose , Mutação , Necrose , Metástase Neoplásica , Fenótipo , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Telomerase/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Resultado do Tratamento
13.
NMR Biomed ; 33(1): e4166, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31680360

RESUMO

The purpose of this study was to identify the optimal tracer kinetic model from T1 -weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data and evaluate whether parameters estimated from the optimal model predict tumor aggressiveness determined from histopathology in patients with papillary thyroid carcinoma (PTC) prior to surgery. In this prospective study, 18 PTC patients underwent pretreatment DCE-MRI on a 3 T MR scanner prior to thyroidectomy. This study was approved by the institutional review board and informed consent was obtained from all patients. The two-compartment exchange model, compartmental tissue uptake model, extended Tofts model (ETM) and standard Tofts model were compared on a voxel-wise basis to determine the optimal model using the corrected Akaike information criterion (AICc) for PTC. The optimal model is the one with the lowest AICc. Statistical analysis included paired and unpaired t-tests and a one-way analysis of variance. Bonferroni correction was applied for multiple comparisons. Receiver operating characteristic (ROC) curves were generated from the optimal model parameters to differentiate PTC with and without aggressive features, and AUCs were compared. ETM performed best with the lowest AICc and the highest Akaike weight (0.44) among the four models. ETM was preferred in 44% of all 3419 voxels. The ETM estimates of Ktrans in PTCs with the aggressive feature extrathyroidal extension (ETE) were significantly higher than those without ETE (0.78 ± 0.29 vs. 0.34 ± 0.18 min-1 , P = 0.005). From ROC analysis, cut-off values of Ktrans , ve and vp , which discriminated between PTCs with and without ETE, were determined at 0.45 min-1 , 0.28 and 0.014 respectively. The sensitivities and specificities were 86 and 82% (Ktrans ), 71 and 82% (ve ), and 86 and 55% (vp ), respectively. Their respective AUCs were 0.90, 0.71 and 0.71. We conclude that ETM Ktrans has shown potential to classify tumors with and without aggressive ETE in patients with PTC.


Assuntos
Meios de Contraste/química , Imageamento por Ressonância Magnética , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Fatores de Tempo
14.
Cancer Res ; 80(1): 102-115, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672844

RESUMO

The sodium iodide symporter (NIS) is required for iodide uptake, which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we used tandem mass spectrometry followed by coimmunoprecipitation and proximity ligation assays to identify and validate two key nodes-ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP)-controlling NIS trafficking. Using cell-surface biotinylation assays and highly inclined and laminated optical sheet microscopy, we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP-a principal component of endoplasmic reticulum (ER)-associated degradation-governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two repurposed FDA-approved VCP inhibitors abrogated VCP-mediated repression of NIS function, resulting in significantly increased NIS at the cell-surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs. SIGNIFICANCE: These findings show that ARF4 and VCP are involved in NIS trafficking to the plasma membrane and highlight the possible therapeutic role of VCP inhibitors in enhancing radioiodine effectiveness in radioiodine-refractory thyroid cancer.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Complexo de Golgi/metabolismo , Radioisótopos do Iodo/farmacologia , Simportadores/metabolismo , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Proteína com Valosina/metabolismo , Adulto , Animais , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Quimiorradioterapia/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Radioisótopos do Iodo/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Camundongos , Pessoa de Meia-Idade , Cultura Primária de Células , Prognóstico , Intervalo Livre de Progressão , Proteólise , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Glândula Tireoide/efeitos da radiação , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Distribuição Tecidual , Proteína com Valosina/antagonistas & inibidores
17.
J Clin Endocrinol Metab ; 104(10): 4889-4899, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237614

RESUMO

CONTEXT: Most papillary microcarcinomas (PMCs) are indolent and subclinical. However, as many as 10% can present with clinically significant nodal metastases. OBJECTIVE AND DESIGN: Characterization of the genomic and transcriptomic landscape of PMCs presenting with or without clinically important lymph node metastases. SUBJECTS AND SAMPLES: Formalin-fixed paraffin-embedded PMC samples from 40 patients with lateral neck nodal metastases (pN1b) and 71 patients with PMC with documented absence of nodal disease (pN0). OUTCOME MEASURES: To interrogate DNA alterations in 410 genes commonly mutated in cancer and test for differential gene expression using a custom NanoString panel of 248 genes selected primarily based on their association with tumor size and nodal disease in the papillary thyroid cancer TCGA project. RESULTS: The genomic landscapes of PMC with or without pN1b were similar. Mutations in TERT promoter (3%) and TP53 (1%) were exclusive to N1b cases. Transcriptomic analysis revealed differential expression of 43 genes in PMCs with pN1b compared with pN0. A random forest machine learning-based molecular classifier developed to predict regional lymph node metastasis demonstrated a negative predictive value of 0.98 and a positive predictive value of 0.72 at a prevalence of 10% pN1b disease. CONCLUSIONS: The genomic landscape of tumors with pN1b and pN0 disease was similar, whereas 43 genes selected primarily by mining the TCGA RNAseq data were differentially expressed. This bioinformatics-driven approach to the development of a custom transcriptomic assay provides a basis for a molecular classifier for pN1b risk stratification in PMC.


Assuntos
Genômica/métodos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Hibridização Genômica Comparativa , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Pescoço , Transcriptoma
18.
Mol Cancer Res ; 17(5): 1036-1048, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30733375

RESUMO

Cancer cell lines are critical models to study tumor progression and response to therapy. In 2008, we showed that approximately 50% of thyroid cancer cell lines were redundant or not of thyroid cancer origin. We therefore generated new authenticated thyroid cancer cell lines and patient-derived xenograft (PDX) models using in vitro and feeder cell approaches, and characterized these models in vitro and in vivo. We developed four thyroid cancer cell lines, two derived from 2 different patients with papillary thyroid cancer (PTC) pleural effusions, CUTC5, and CUTC48; one derived from a patient with anaplastic thyroid cancer (ATC), CUTC60; and one derived from a patient with follicular thyroid cancer (FTC), CUTC61. One PDX model (CUTC60-PDX) was also developed. Short tandem repeat (STR) genotyping showed that each cell line and PDX is unique and match the original patient tissue. The CUTC5 and CUTC60 cells harbor the BRAF (V600E) mutation, the CUTC48 cell line expresses the RET/PTC1 rearrangement, and the CUTC61 cells have the HRAS (Q61R) mutation. Moderate to high levels of PAX8 and variable levels of NKX2-1 were detected in each cell line and PDX. The CUTC5 and CUTC60 cell lines form tumors in orthotopic and flank xenograft mouse models. IMPLICATIONS: We have developed the second RET/PTC1-expressing PTC-derived cell line in existence, which is a major advance in studying RET signaling. We have further linked all cell lines to the originating patients, providing a set of novel, authenticated thyroid cancer cell lines and PDX models to study advanced thyroid cancer.


Assuntos
Adenocarcinoma Folicular/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/genética , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Mutação , Transplante de Neoplasias , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
19.
Clin Cancer Res ; 25(10): 3141-3151, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737244

RESUMO

PURPOSE: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. EXPERIMENTAL DESIGN: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. RESULTS: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. CONCLUSIONS: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.


Assuntos
Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Neoplasias da Glândula Tireoide/genética , Proteína Supressora de Tumor p53/genética , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/patologia , Estudos de Validação como Assunto
20.
Endocrine ; 64(1): 97-108, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30689169

RESUMO

PURPOSE: In 2016, non-invasive encapsulated follicular variant of papillary thyroid carcinoma (NI-EFVPTC) was renamed as noninvasive thyroid follicular neoplasm with papillary-like nuclear features (NIFTP). However, as the study cohort did not mention tumors with oncocytic features, such lesions are still labeled by some as FVPTC. It is therefore crucial to evaluate the outcome and molecular profile of oncocytic NI-EFVPTC. METHODS: A multi-institutional clinico-pathologic review was conducted to select 61 patients having oncocytic NI-EFVPTC. A detailed molecular profile was carried out in 15 patients. RESULTS: Oncocytic NI-EFVPTCs predominantly affected women in their 50s. There was no distant metastasis, lymph node metastases, or structural recurrence in the entire cohort. Among patients with ≥5 years of FU, all 33 individuals did not recur with a median FU of 10.2 years. Oncocytic NI-EFVPTC commonly had RAS (33%) mutations, a high frequency of mitochondrial DNA mutations (67%) and multiple chromosomal gains/losses (53%). No fusion genes were detected. CONCLUSIONS: Oncocytic NI-EFVPTC, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively with lobectomy alone without RAI therapy. These tumors share a similar mutational profile as NIFTP, FVPTC, and follicular neoplasm and are predominantly RAS-related. Like Hurthle cell neoplasms, they harbor a high frequency of mitochondrial DNA mutations, which contribute to the oncocytic cytomorphology. However, they lack the widespread chromosomal alterations observed in Hurthle cell carcinoma. Consideration should be given to include oncocytic NI-EFVPTCs as NIFTP in order to avoid overtreatment of these highly indolent tumors.


Assuntos
Carcinoma Papilar, Variante Folicular/patologia , DNA Mitocondrial , Mutação , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar, Variante Folicular/genética , Carcinoma Papilar, Variante Folicular/cirurgia , Criança , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Resultado do Tratamento , Adulto Jovem
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