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BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.
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Mutación , Proteínas Proto-Oncogénicas c-ret , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Femenino , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Adulto , Pronóstico , Estudios de Seguimiento , Tasa de Supervivencia , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Anciano , Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas B-raf/genética , Genómica , Ubiquitina Tiolesterasa/genética , Adulto Joven , Complejos de Clasificación Endosomal Requeridos para el Transporte/genéticaRESUMEN
AIMS: Papillary thyroid carcinoma, tall cell subtype (PTC-TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high-grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC-TC). METHODS AND RESULTS: We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC-TC and HGDTC-TC. HGDTC-TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC-TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC-TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis-free survival (DMFS; P < 0.001). The 10-year DSS was 72 and 99%, the 10-year LRDFS was 61 and 92% and the 10-year DMFS was 53 and 97%, respectively, for HGDTC-TC and PTC-TC. On multivariate analysis, the classification (HGDTC-TC versus PTC-TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. CONCLUSIONS: Compared with PTC-TC, HGDTC-TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC-TC versus 34% in PTC-TC) and incurs a significantly worse prognosis. HGDTC-TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas.
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Fenotipo , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/patología , Persona de Mediana Edad , Femenino , Masculino , Estudios Retrospectivos , Adulto , Cáncer Papilar Tiroideo/patología , Anciano , Carcinoma Papilar/patología , Pronóstico , Adulto Joven , Anciano de 80 o más Años , Adolescente , Clasificación del TumorRESUMEN
OBJECTIVE: Exposure to therapeutic radioactive iodine (RAI) is associated with an increased relative risk of myeloid malignancies. Clonal hematopoiesis (CH) is a precursor state that can be detected in blood of healthy individuals decades before overt development of leukemia. We prospective studied the effects of RAI on CH. DESIGN: Prospective cohort study. PATIENTS AND MEASUREMENTS: We examined the effect of RAI on CH in 20 patients exposed to RAI for thyroid carcinoma and 20 age-matched unexposed controls. CH status was determined at baseline, 6, 12, 18 and 24 months. We also examined the effect of CH on structural progression of disease. RESULTS: No CH mutations were observed in the patient population that were not present at baseline. Using a variant allelic fraction (VAF) of 2% to define CH, 6/20 older patients (55-80 years old) had CH compared to 2/20 younger patients (20-40 years old) (p = 0.11). Six patients exposed to RAI had CH compared to two patients not exposed to RAI (30% vs. 10%, p = 0.11). There was no significant difference in CH VAF increase in patients treated with RAI compared to untreated age-matched controls (3.8% vs. 1.2%, p = 0.2). CH was significantly associated with somatic BRAFV600E mutations and with worse progression-free survival in the overall cohort as well as among BRAFV600E-mutant tumors. CONCLUSIONS: There was no increase in CH in patients treated with RAI over a 2-year follow-up period. Larger studies with longer follow-up periods are needed to investigate the association between RAI and clonal dynamics. The presence of CH is associated with worse structural progression in both BRAFV600E-mutant and wild-type thyroid cancers.
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Neoplasias de la Tiroides , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Adulto , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/tratamiento farmacológico , Estudios Prospectivos , Radioisótopos de Yodo/uso terapéutico , Hematopoyesis Clonal , RiesgoRESUMEN
PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.
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Adenocarcinoma , Neoplasias de la Tiroides , Humanos , Adenocarcinoma/tratamiento farmacológico , Radioisótopos de Yodo/uso terapéutico , Dosis de Radiación , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/tratamiento farmacológicoRESUMEN
BACKGROUND: Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of Hippo intermediates only identify a minority of cancers with illegitimate YAP activation. Yap has been implicated in resistance to targeted therapies, but the mechanisms by which YAP may impact adaptive resistance to MAPK inhibitors are unknown. METHODS: We screened 52 thyroid cancer cell lines for illegitimate nuclear YAP localization by immunofluorescence and fractionation of cell lysates. We engineered a doxycycline (dox)-inducible thyroid-specific mouse model expressing constitutively nuclear YAPS127A, alone or in combination with endogenous expression of either HrasG12V or BrafV600E. We also generated cell lines expressing dox-inducible sh-miR-E-YAP and/or YAPS127A. We used cell viability, invasion assays, immunofluorescence, Western blotting, qRT-PCRs, flow cytometry and cell sorting, high-throughput bulk RNA sequencing and in vivo tumorigenesis to investigate YAP dependency and response of BRAF-mutant cells to vemurafenib. RESULTS: We found that 27/52 thyroid cancer cell lines had constitutively aberrant YAP nuclear localization when cultured at high density (NU-YAP), which rendered them dependent on YAP for viability, invasiveness and sensitivity to the YAP-TEAD complex inhibitor verteporfin, whereas cells with confluency-driven nuclear exclusion of YAP (CYT-YAP) were not. Treatment of BRAF-mutant thyroid cancer cells with RAF kinase inhibitors resulted in YAP nuclear translocation and activation of its transcriptional output. Resistance to vemurafenib in BRAF-mutant thyroid cells was driven by YAP-dependent NRG1, HER2 and HER3 activation across all isogenic human and mouse thyroid cell lines tested, which was abrogated by silencing YAP and relieved by pan-HER kinase inhibitors. YAP activation induced analogous changes in BRAF melanoma, but not colorectal cells. CONCLUSIONS: YAP activation in thyroid cancer generates a dependency on this transcription factor. YAP governs adaptive resistance to RAF kinase inhibitors and induces a gene expression program in BRAFV600E-mutant cells encompassing effectors in the NRG1 signaling pathway, which play a central role in the insensitivity to MAPK inhibitors in a lineage-dependent manner. HIPPO pathway inactivation serves as a lineage-dependent rheostat controlling the magnitude of the adaptive relief of feedback responses to MAPK inhibitors in BRAF-V600E cancers.
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Neoplasias de la Tiroides , Humanos , Animales , Ratones , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Quinasas rafRESUMEN
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.
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Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/mortalidad , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/mortalidad , Adulto JovenRESUMEN
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.
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Radioterapia de Intensidad Modulada , Neoplasias de la Tiroides , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Doxorrubicina/efectos adversos , Humanos , Estudios Prospectivos , Calidad de Vida , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/etiología , Neoplasias de la Tiroides/radioterapiaRESUMEN
Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in â¼11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
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Regulación Neoplásica de la Expresión Génica/genética , Neoplasias/enzimología , Neoplasias/genética , Proteínas Tirosina Quinasas Receptoras/genética , Iniciación de la Transcripción Genética , Alelos , Quinasa de Linfoma Anaplásico , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Femenino , Células HEK293 , Histonas/química , Histonas/metabolismo , Humanos , Intrones/genética , Isoenzimas/antagonistas & inhibidores , Isoenzimas/biosíntesis , Isoenzimas/química , Isoenzimas/genética , Lisina/metabolismo , Metilación , Ratones , Datos de Secuencia Molecular , Peso Molecular , Células 3T3 NIH , Neoplasias/tratamiento farmacológico , Oncogenes/genética , Estructura Terciaria de Proteína/genética , ARN Polimerasa II/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Proteínas Tirosina Quinasas Receptoras/química , Transducción de SeñalRESUMEN
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.
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Medios de Contraste/química , Imagen por Resonancia Magnética , Cáncer Papilar Tiroideo/diagnóstico por imagen , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/patología , Adulto , Anciano , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Factores de TiempoRESUMEN
Oncogenic RAS mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with HrasG12V in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in Tpo-Cre/homozygous FR-HrasG12V mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SB-induced tumors identified 45 recurrently mutated candidate cancer genes. These mutation profiles were remarkably concordant with mutated cancer genes identified in a large series of human poorly differentiated and anaplastic thyroid cancers screened by next-generation sequencing using the MSK-IMPACT panel of cancer genes, which we modified to include all SB candidates. The disrupted genes primarily clustered in chromatin remodeling functional nodes and in the PI3K pathway. ATXN7, a component of a multiprotein complex with histone acetylase activity, scored as a significant SB hit. It was recurrently mutated in advanced human cancers and significantly co-occurred with RAS or NF1 mutations. Expression of ATXN7 mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to ATXN7 as a previously unrecognized cancer gene.
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Ataxina-7/genética , Carcinogénesis/genética , Cromatina/genética , Elementos Transponibles de ADN/genética , Genes ras/genética , Mutagénesis/genética , Glándula Tiroides/patología , Animales , Humanos , Ratones , Ratones Transgénicos , Mutación/genética , Oncogenes/genética , Fosfatidilinositol 3-Quinasas/genética , Carcinoma Anaplásico de Tiroides/genéticaRESUMEN
BACKGROUND: Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results. METHODS: In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. RESULTS: The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. CONCLUSIONS: Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society.
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Adenocarcinoma Folicular/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Sirolimus/análogos & derivados , Neoplasias de la Tiroides/tratamiento farmacológico , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Compuestos de Fenilurea/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Tolerancia a Radiación , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sorafenib , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/radioterapia , Resultado del TratamientoRESUMEN
RASopathies are syndromes caused by gain-of-function mutations in the Ras signaling pathway. One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities. We report that a majority of individuals with CS have hypo-mineralization of enamel, the outer covering of teeth, and that similar defects are present in a CS mouse model. Comprehensive analysis of the mouse model revealed that ameloblasts, the cells that generate enamel, lacked polarity, and the ameloblast progenitor cells were hyperproliferative. Ras signals through two main effector cascades, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. To determine through which pathway Ras affects enamel formation, inhibitors targeting either PI3K or MEK 1 and 2 (MEK 1/2), kinases in the MAPK pathway, were utilized. MEK1/2 inhibition rescued the hypo-mineralized enamel, normalized the ameloblast polarity defect and restored normal progenitor cell proliferation. In contrast, PI3K inhibition only corrected the progenitor cell proliferation phenotype. We demonstrate for the first time the central role of Ras signaling in enamel formation in CS individuals and present the mouse incisor as a model system to dissect the roles of the Ras effector pathways in vivo.
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Síndrome de Costello/metabolismo , Esmalte Dental/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adolescente , Adulto , Ameloblastos/metabolismo , Ameloblastos/patología , Animales , Estudios de Casos y Controles , Polaridad Celular , Niño , Preescolar , Estudios de Cohortes , Síndrome de Costello/genética , Esmalte Dental/efectos de los fármacos , Esmalte Dental/metabolismo , Esmalte Dental/ultraestructura , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Lactante , Quinasa 1 de Quinasa de Quinasa MAP/antagonistas & inhibidores , Quinasa 1 de Quinasa de Quinasa MAP/metabolismo , Masculino , Ratones , Ratones Mutantes , Microscopía Electrónica de Rastreo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/genética , Adulto JovenRESUMEN
BACKGROUND: Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS: Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
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Bencimidazoles/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Neoplasias de la Tiroides/radioterapia , Adulto , Anciano , Bencimidazoles/farmacología , Femenino , Humanos , Radioisótopos de Yodo/farmacocinética , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Imagen Multimodal , Mutación , Metástasis de la Neoplasia , Tomografía de Emisión de Positrones , Radiometría , Simportadores/efectos de los fármacos , Simportadores/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Tirotropina Alfa/farmacología , Tomografía Computarizada por Rayos XRESUMEN
ETV6-NTRK3 fusion was identified in several cancers including the recently described mammary analog secretory carcinoma (MASC) of the salivary glands and a minority of papillary thyroid carcinomas. We describe three cases of primary MASC of the thyroid gland and provide a detailed clinical and pathological characterization of the tumor morphology, immunoprofile, and genetic background. Immunohistochemistry for PAX8, TTF-1, thyroglobulin, mammaglobin, GCDFP-15, S-100 protein, and p63 was used to define the tumor immunophenotype. Fluorescence in situ hybridization for ETV6 rearrangement was performed in three, and the next-generation sequencing assay MSK-IMPACT™ (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) was performed in two cases. Primary MASC of the thyroid occurred in two women and one man, age 47-72 years. All patients presented with high T stage, infiltrative, locally aggressive tumors with extrathyroidal extension. Two cases were associated with well-differentiated papillary thyroid carcinoma. Histologically, they appeared as low-grade tumors, resembling MASC of the salivary glands and labeled positive for mammaglobin, GCDFP-15, S-100 protein, p63, weakly positive for PAX8, and negative for TTF-1 and thyroglobulin. Fluorescence in situ hybridization revealed ETV6 rearrangement in all cases. In two tested cases MSK-IMPACT™ confirmed the presence of ETV6-NTRK3 gene fusion. Two patients had at least two local recurrences, one was alive with disease, and one was alive and free of disease after 14 and 17 years, respectively. The third patient was alive and free of disease after 2 years. MASC of the thyroid is histologically, immunophenotypically, and genetically similar to its salivary gland counterpart. Thyroid MASC can be associated with a well-differentiated papillary thyroid carcinoma component, supporting follicular cell origin. Clinically, these carcinomas may show frequent recurrences but are associated with long-term survival. Patients with MASC of the thyroid may potentially benefit from Trk molecular-targeted therapy.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Fusión Génica , Carcinoma Secretor Análogo al Mamario/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Tiroides/genética , Adenocarcinoma/química , Adenocarcinoma/patología , Adenocarcinoma/terapia , Anciano , Biomarcadores de Tumor/análisis , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Carcinoma Secretor Análogo al Mamario/química , Carcinoma Secretor Análogo al Mamario/patología , Carcinoma Secretor Análogo al Mamario/terapia , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Fenotipo , Neoplasias de la Tiroides/química , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Resultado del TratamientoRESUMEN
Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.
Asunto(s)
Carcinoma Papilar/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Neoplasias de la Tiroides/metabolismo , Animales , Carcinoma Papilar/secundario , División Celular/fisiología , Línea Celular Tumoral , Receptor gp130 de Citocinas/metabolismo , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Interleucina-6/metabolismo , Quinasas Janus/metabolismo , Ratones , Ratones Transgénicos , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Factor de Transcripción STAT3/genética , Neoplasias de la Tiroides/patología , Trasplante Heterólogo , Microambiente Tumoral/fisiologíaAsunto(s)
Carcinoma , Neoplasias de la Tiroides , Carcinoma/diagnóstico , Carcinoma/genética , Carcinoma/terapia , Carcinoma Medular/diagnóstico , Carcinoma Medular/genética , Carcinoma Medular/terapia , Carcinoma Papilar , Humanos , Mutación , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/terapiaRESUMEN
BACKGROUND AND OBJECTIVES: To review clinical outcomes and toxicities in locally advanced differentiated thyroid cancer patients treated with external beam radiotherapy (EBRT) with or without concurrent chemotherapy (CCRT). METHODS: Between 1990 and 2012, 66 patients with gross residual/unresectable non-anaplastic non-medullary thyroid cancer were treated with EBRT. RESULTS: The median overall survival was 42.0 months. The overall locoregional progression-free survival (LPFS) at 3 years was 77.3%. CCRT resulted in a non-significant improvement in LPFS (90.0% vs. 73.0%, P = 0.347). Poorly differentiated histology had significantly improved LPFS (89.4% vs. 66.1%, P = 0.020), despite a significantly worse distant metastasis-free survival (43.9% vs. 82.5%, P = 0.023). Acute treatment-related toxicity included dermatitis, mucositis, and dysphagia with grade three rates of 12.1%, 19.7%, and 16.7%, respectively. The incidence of late toxicity was low. CCRT was only associated with a significant greater rate of acute grade 3 hoarseness (10.0% vs. 0.0%, P = 0.033), but with no difference in the rate of grade 2 late toxicity. CONCLUSIONS: EBRT is a safe and effective treatment modality with 90% LPFS at 3 years in patients with gross residual or unresectable non-anaplastic, non-medullary thyroid carcinoma treated with CCRT. Further incorporation of EBRT with concurrent chemotherapy may result in improved disease control.
Asunto(s)
Quimioradioterapia , Recurrencia Local de Neoplasia/terapia , Neoplasias de la Tiroides/terapia , Anciano , Quimioradioterapia/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patologíaRESUMEN
Mutations of BRAF are found in â¼45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf(V600E)/TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf(V600E) induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-Braf(V600E)/TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gsα gene in LSL-Braf(V600E)/TPO-Cre/Gnas-E1(fl/fl) mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence.