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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
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
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
Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10(-22) , rs7037324: OR = 1.54, p = 1.2 × 10(-17) ). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10(-04) , OR = 1.26, p = 5.2 × 10(-04) and OR = 1.38, p = 5.9 × 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease.
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Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 6/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Femenino , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , España , Adulto JovenRESUMEN
Medullary thyroid carcinoma accounts for 2% to 5% of thyroid malignancies, of which 75% are sporadic and the remaining 25% are hereditary and related to multiple endocrine neoplasia type 2 syndrome. Despite a genotype-phenotype correlation with specific germline RET mutations, knowledge of pathways specifically associated with each mutation and with non-RET-mutated sporadic MTC remains lacking. Gene expression patterns have provided a tool for identifying molecular events related to specific tumor types and to different clinical features that could help identify novel therapeutic targets. Using transcriptional profiling of 49 frozen MTC specimens classified as RET mutation, we identified PROM1, LOXL2, GFRA1, and DKK4 as related to RET(M918T) and GAL as related to RET(634) mutation. An independent series of 19 frozen and 23 formalin-fixed, paraffin-embedded (FFPE) MTCs was used for validation by RT-qPCR. Two tissue microarrays containing 69 MTCs were available for IHC assays. According to pathway enrichment analysis and gene ontology biological processes, genes associated with the MTC(M918T) group were involved mainly in proliferative, cell adhesion, and general malignant metastatic effects and with Wnt, Notch, NFκB, JAK/Stat, and MAPK signaling pathways. Assays based on silencing of PROM1 by siRNAs performed in the MZ-CRC-1 cell line, harboring RET(M918T), caused an increase in apoptotic nuclei, suggesting that PROM1 is necessary for survival of these cells. This is the first report of PROM1 overexpression among primary tumors.
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Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Neoplasias de la Tiroides/genética , Antígeno AC133 , Antígenos CD/metabolismo , Apoptosis/genética , Carcinoma Neuroendocrino , Línea Celular Tumoral , Análisis por Conglomerados , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Glicoproteínas/metabolismo , Humanos , Inmunohistoquímica , Patrón de Herencia/genética , Péptidos/metabolismo , ARN Interferente Pequeño/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Tiroides/patologíaRESUMEN
The introduction and generalization of next-generation sequencing techniques have significantly increased the identification of mutations in thyroid tumors from multiple patient cohorts. The understanding of the association between specific mutations and clinical outcomes is gradually leading to individualizing the care of patients with thyroid cancer. BRAFV600 is the most common mutation seen in thyroid cancer patients and unequivocally predicts malignancy, but when considered in isolation, it is not recommended to be used as an independent prognostic factor. Mutations in RAS are the second most common alterations in thyroid cancer but can be found in benign and malignant lesions. Rearrangements involving receptor tyrosine kinases, primarily RET, are found in a subset of thyroid tumors without mutations in either BRAF or RAS. The assessment of additional mutations is increasingly employed in thyroid cancer prognostication. The coexistence of BRAF with alterations in genes such as PIK3CA, TERT promoter, or TP53 is associated with less favorable outcomes. Similar studies have also shown that additional oncogenic mutations in RAS-mutant thyroid carcinoma, such as those affecting the EIF1AX gene, likely predict a more aggressive clinicopathologic behavior. Overall, emerging evidence suggests that the co-occurrence of specific alterations in defined genes with BRAF or RAS mutations can become prognostic tools and useful predictors of thyroid tumor aggressiveness.
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Tumours can arise from thyroid follicular cells if they acquire driver mutations that constitutively activate the MAPK signalling pathway. In addition, a limited set of additional mutations in key genes drive tumour progression towards more aggressive and less differentiated disease. Unprecedented insights into thyroid tumour biology have come from the breadth of thyroid tumour sequencing data from patients and the wide range of mutation-specific mechanisms identified in experimental models, in combination with the genomic simplicity of thyroid cancers. This knowledge is gradually being translated into refined strategies to stratify, manage and treat patients with thyroid cancer. This Review summarizes the biological underpinnings of the genetic alterations involved in thyroid cancer initiation and progression. We also provide a rationale for and discuss specific examples of how to implement genomic information to inform both recommended and investigational approaches to improve thyroid cancer prognosis, redifferentiation strategies and targeted therapies.
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Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/terapia , Mutación , Transducción de Señal/genética , Pronóstico , GenómicaRESUMEN
CONTEXT: Active surveillance for papillary thyroid cancer (PTC) meeting criteria for surgical resection is uncommon. Which patients may prove reasonable candidates for this approach is not well defined. OBJECTIVE: This work aimed to examine the feasibility and safety of active surveillance for patients with known or suspected intrathyroidal PTC up to 4â cm in diameter. METHODS: A retrospective review was conducted of all consecutive patients who underwent nonoperative active surveillance of suspicious or malignant thyroid nodules over a 20-year period from 2001 to 2021. We included patients with an initial ultrasound-fine-needle aspiration confirming either (a) Bethesda 5 or 6 cytology or (b) a "suspicious" Afirma molecular test. The primary outcomes and measures included the rate of adverse oncologic outcomes (mortality and recurrence), as well as the cumulative incidence of size/volume growth. RESULTS: Sixty-nine patients were followed with active surveillance for 1 year or longer (average 55 months), with 26 patients (38%) having nodules 2â cm or larger. No patients were found to develop new-incident occurrence of lymph node or distant metastasis. One patient, however, demonstrated concern for progression to a dedifferentiated cancer on repeat core biopsy 17 years after initial start of nonoperative selection. A total of 21% of patients had an increase in maximum diameter more than 3 mm, while volume increase of 50% or greater was noted in 25% of patients. Thirteen patients ultimately underwent delayed (rescue) surgery, and no disease recurrence was noted after such treatment. Age and initial nodule size were not predictors of nodule growth. CONCLUSION: These data expand consideration of active surveillance of PTC in select patients with intrathyroidal suspected malignancy greater than 1â cm in diameter. Rescue surgery, if required at a later time point, appears effective.
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Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Nódulo Tiroideo , Espera Vigilante , Humanos , Nódulo Tiroideo/patología , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/epidemiología , Nódulo Tiroideo/cirugía , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugía , Espera Vigilante/estadística & datos numéricos , Adulto , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/diagnóstico , Cáncer Papilar Tiroideo/cirugía , Cáncer Papilar Tiroideo/epidemiología , Anciano , Biopsia con Aguja Fina , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/diagnóstico , Estudios de Seguimiento , Estudios de Factibilidad , UltrasonografíaRESUMEN
Thyroid cancers are often initiated by the acquisition of a BRAFV600E mutation. BRAFV600E-driven thyroid tumors display a wide range of behaviors, from the slow-growing papillary carcinomas to the highly aggressive anaplastic. Mutations in the promoter of TERT (telomerase reverse transcriptase) gene were discovered a decade ago and identified as prevalent events in thyroid cancers. Multiple studies showed that TERT promoter mutations, particularly when co-occurring with BRAFV600E, are markers of poor prognosis across thyroid cancer subtypes, and can be implemented for routine clinical stratification. Mechanistically, TERT promoter mutations reactivate telomerase expression via the differential recruitment of transcriptional complexes. Re-expression of TERT impacts tumor biology, plausibly via both the well-known function of telomerase maintaining telomeres and by affecting other cancer-relevant processes.
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Differentiated thyroid cancers (DTCs) are primarily initiated by mutations that activate the MAPK signaling cascade, typically at BRAF or RAS oncoproteins. DTCs can evolve to more aggressive forms, specifically, poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), by acquiring additional genetic alterations which deregulate key pathways. In this review, we focused on bona fide mutations involved in thyroid cancer progression for which consistent mechanistic data exist. Here we summarized the relevant literature, spanning approximately 2 decades, highlighting genetic alterations that are unquestionably enriched in PDTC/ATC. We describe the relevant functional data obtained in multiple in vitro and in vivo thyroid cancer models employed to study genetic alterations in the following genes and functional groups: TP53, effectors of the PI3K/AKT pathway, TERT promoter, members of the SWI/SNF chromatin remodeling complex, NF2, and EIF1AX. In addition, we briefly discuss other genetic alterations that are selected in aggressive thyroid tumors but for which mechanistic data is still either limited or nonexistent. Overall, we argue for the importance conveyed by preclinical studies for the clinical translation of genomic knowledge of thyroid cancers.
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Adenocarcinoma , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Fosfatidilinositol 3-Quinasas/genética , Neoplasias de la Tiroides/patología , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Mutación , Adenocarcinoma/genética , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
The genomic simplicity of differentiated cancers derived from thyroid follicular cells offers unique insights into how oncogenic drivers impact tumour phenotype. Essentially, the main oncoproteins in thyroid cancer activate nodes in the receptor tyrosine kinase-RAS-BRAF pathway, which constitutively induces MAPK signalling to varying degrees consistent with their specific biochemical mechanisms of action. The magnitude of the flux through the MAPK signalling pathway determines key elements of thyroid cancer biology, including differentiation state, invasive properties and the cellular composition of the tumour microenvironment. Progression of disease results from genomic lesions that drive immortalization, disrupt chromatin accessibility and cause cell cycle checkpoint dysfunction, in conjunction with a tumour microenvironment characterized by progressive immunosuppression. This Review charts the genomic trajectories of these common endocrine tumours, while connecting them to the biological states that they confer.
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Células Epiteliales Tiroideas , Neoplasias de la Tiroides , Humanos , Células Epiteliales Tiroideas/metabolismo , Células Epiteliales Tiroideas/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Transducción de Señal , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Microambiente Tumoral/genéticaRESUMEN
CONTEXT: The natural history of benign thyroid nodules is typically characterized by slow growth and minimal risk of malignant transformation. Available data have, to date, been unable to elucidate the diversity of benign nodule growth patterns over time nor predictive of which patients follow which pattern. OBJECTIVE: We aimed to better define the diverse patterns of benign nodule behavior and their predictors. METHODS: We prospectively studied 389 consecutive patients with solitary, solid, cytologically benign thyroid nodules ≥1 cm and follow-up ultrasound for at least 4 years. Demographic, sonographic, biochemical data were collected at initial evaluation, and subsequent growth patterns were identified over the follow-up. Predictors of growth at initial evaluation and 3 years of follow-up were defined. RESULTS: The mean (±SD) follow-up was 7.7 (±2.7) years. Three distinct growth patterns were identified: A) stagnant nodules with average growth rate < 0.2 mm/year; B) slow-growing nodules with a rate 0.2 to 1.0 mm/year; and C) fast-growing nodules increasing > 1.0 mm/year. Fast-growing nodules represented 17.2% of the cohort, and were more frequent in patients younger than 50 years (OR 2.2 [1.2-4.1], P = 0.016), and in larger nodules (2.0-2.9 cm, OR 3.5 [1.7-7.1], P = 0.001; >3.0 cm, OR 4.4 [1.8-10.4], P = 0.001 vs reference 1-1.9 cm). In a multiple regression model, nodule growth at 3 years at an average growth rate over 0.2 mm/year over 3 years since initial evaluation was an independent predictor of longer-term fast nodule growth, even after adjusting for age, biological sex, TSH level, and nodule size (P < 0.001). CONCLUSION: The natural history of benign nodule growth is diverse, with over 80% of nodules demonstrating minimal to no growth long-term. Nearly 20% of cytologically benign nodules may exhibit a fast, continued growth pattern, which can be predicted by the 3-year growth rate pattern. These findings can help inform decision making for tailored benign nodule follow-up and monitoring.
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Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Nódulo Tiroideo/diagnóstico por imagen , Nódulo Tiroideo/patología , Neoplasias de la Tiroides/patología , Estudios Retrospectivos , Biopsia con Aguja Fina , UltrasonografíaRESUMEN
Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a noncoding region. TERT promoter mutations (TPM) are biomarkers of poor prognosis in cancer, including thyroid tumors. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert-123C>T) and crossed it with thyroid-specific BrafV600E-mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all BrafV600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of BrafV600E+Tert-123C>T and BrafV600E+K5-Tert mice progressed to poorly differentiated cancers at week 20, respectively. Tert-upregulated tumors showed increased mitosis and necrosis in areas of solid growth, and older animals displayed anaplastic-like features, that is, spindle cells and macrophage infiltration. Murine TPM increased Tert transcription in vitro and in vivo, but temporal and intratumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine, and chemokine signaling, were overactivated. These models constitute useful preclinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs. IMPLICATIONS: Telomerase-driven cancer progression activates pathways that can be dissected and perhaps therapeutically exploited.
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Telomerasa , Neoplasias de la Tiroides , Animales , Ratones , Telomerasa/genética , Regulación hacia Arriba , Fosfatidilinositol 3-Quinasas/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación , Microambiente TumoralRESUMEN
Background: While the diagnosis of papillary thyroid carcinomas (PTCs) with tall cell features (PTCtcf) is often made for carcinomas with histological features intermediate between classic and tall cell subtypes of PTC (tcPTC), its comparative signature to that of either tcPTC or classic PTC is less clear. The objective of this study was to perform an integrative clinicopathologic and genomic analysis elucidating the spectrum of tcPTC, PTCtcf, and classic PTC. Methods: We analyzed all consecutive patients with tcPTC and PTCtcf evaluated at a tertiary academic referral center between 2005 and 2020, as well as a comparative cohort of classic PTC, in a retrospective observational cohort analysis. Clinicopathologic data were compared among the three groups, including progression-free survival (PFS), recurrent/persistent disease, and a negative composite outcome of death, progression, or need for advanced therapy. To specifically understand differences between tcPTC and PTCtcf, targeted next-generation sequencing was performed in a subset of these cohorts. Results: A total of 292 patients were analyzed (81 tcPTC, 65 PTCtcf, 146 classic PTC). Thirteen percent of tcPTC versus 8% of PTCtcf versus 1% of classic PTC had the advanced American Joint Committee on Cancer stage (p = 0.002). Similarly, macroscopic extrathyroidal extension was observed in 38% of tcPTC, 14% of PTCtcf, and 12% of classic PTC (p < 0.001). The 5-year PFS was 76.5%, 81.5%, and 88.3% for tcPTC, PTCtcf, and classic PTC, respectively, while the rates of the negative composite outcome 40.2% for tcPTC, 20.7% for PTCtcf, and 11.2% for classic PTC (p < 0.001). In a multivariable Cox regression analysis, the negative composite outcome was independently associated with tcPTC (HR 4.3 [confidence interval 1.1-16.1], p = 0.03). tcPTC demonstrated substantially more hotspot TERT promoter mutations than PTCtcf (44% vs. 6%, p = 0.012). Conclusions: Our study demonstrates a continuum of disease-specific risk of PTC, pointing at PTCtcf as an intermediate entity between tcPTC and classic PTC. These data provide a more refined understanding of risk at time of presentation, while better elucidating the diversity of genomic drivers.
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Carcinoma Papilar , Carcinoma , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/patología , Estudios Retrospectivos , Carcinoma Papilar/patología , Carcinoma/patología , PronósticoRESUMEN
Mutations in the promoter of the telomerase reverse transcriptase ( TERT ) gene are the paradigm of a cross-cancer alteration in a non-coding region. TERT promoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert -123C>T ) and crossed it with thyroid-specific Braf V600E -mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all Braf V600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of Braf V600E +Tert -123C>T and Braf V600E +K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. Murine Tert promoter mutation increased Tert transcription in vitro and in vivo , but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.
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PURPOSE: RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC). EXPERIMENTAL DESIGN: We performed a clinical-genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next-generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations. RESULTS: Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared with DTCs harboring a solitary RAS mutation, patients with DTC with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P < 0.001) and to have larger primary tumors (4.7 vs. 2.5 cm; P = 0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P < 0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%; P = 0.011) when additional mutations were identified. CONCLUSIONS: Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision-making.
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Adenocarcinoma , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/patología , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Pronóstico , Mutación , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.
Asunto(s)
Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad , Variación Genética , Neoplasias de la Tiroides/metabolismo , Factores Estimuladores hacia 5'/metabolismo , Adulto , Secuencia de Bases , Sitios de Unión , Estudios de Casos y Controles , Femenino , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Unión Proteica , España , Neoplasias de la Tiroides/genética , Factores Estimuladores hacia 5'/genéticaRESUMEN
Hereditary primary hyperparathyroidism (HPT) may develop as a solitary endocrinopathy (FIHP) or as part of multiple endocrine neoplasia Type 1, multiple endocrine neoplasia Type 2A, or hereditary HPT-jaw tumor syndrome. Inactivating germline mutations of the tumor suppressor gene CDC73 account for 14 and 50% of all FIHP and HPT-JT patients, respectively, and have also been found in almost 20% of apparently sporadic parathyroid carcinoma patients. Although more than 60 independent germline mutations have been described, to date no rearrangement affecting the CDC73 locus has been identified. By means of multiplex-PCR we found a large germline deletion affecting the whole gene in a two-generation HPT-JT family. Subsequently array-CGH and specific PCR analysis determined that the mutation spanned â¼ 547 kb, and included four additional genes: TROVE2, GLRX2, B3GALT2, and UCHL5. Although no clear mutation-specific phenotype was found associated to the presence of the mutation, further studies are needed to assess whether the loss of the neighboring genes could modify the phenotype of carriers. There was complete absence of nuclear staining in the two HPT-JT-related tumors available. The finding of the first rearrangement affecting the CDC73 gene warrants screening for this tumor suppressor gene inactivation mechanism not only in high-risk CDC73 point mutation-negative HPT-JT families, but also in FIHP patients.
Asunto(s)
Eliminación de Gen , Mutación de Línea Germinal , Hiperparatiroidismo Primario/genética , Neoplasias Maxilomandibulares/genética , Proteínas Supresoras de Tumor/genética , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Femenino , Humanos , Hiperparatiroidismo Primario/metabolismo , Inmunohistoquímica , Neoplasias Maxilomandibulares/metabolismo , Masculino , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/metabolismo , Reacción en Cadena de la Polimerasa , Síndrome , Proteínas Supresoras de Tumor/metabolismoRESUMEN
"Thyroid cancer" encompasses a heterogeneous group of tumors that range from the predominant papillary thyroid cancer (PTC) subtype, which shows excellent survival rates, to the poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) forms, accounting for most of the disease-related morbidity and mortality [...].
RESUMEN
DICER1 gene encodes an RNaseIII endoribonuclease essential for the cleavage of pre-microRNA to mature microRNA. Germline DICER1 mutation results in DICER syndrome, a cancer predisposition syndrome which manifests in the thyroid gland as early-onset multinodular goiter and increased risk for differentiated thyroid carcinoma. Recently, somatic DICER1 mutations were described in various thyroid neoplasms, including follicular adenoma, papillary thyroid carcinoma, follicular carcinoma, and poorly differentiated thyroid carcinoma. In this study, we identified and described 14 cases (1.7%) with somatic DICER1 mutations from a cohort of 829 patients with thyroid follicular cell-derived thyroid carcinomas which were sequenced using MSK-IMPACT targeted next-generation sequencing platform. We expanded the histologic spectrum of thyroid carcinomas with somatic DICER1 mutations to include Hurthle cell carcinoma, high-grade differentiated thyroid carcinoma, and anaplastic thyroid carcinoma. All patients were adults with a median age of diagnosis of 59 years (range: 22-82). Although rare, a subset of thyroid cancers, including the aggressive subtypes, display somatic DICER1 mutations, some of which have oncogenic potential.