RESUMEN
Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies.
Asunto(s)
Aberraciones Cromosómicas , ADN Mitocondrial/genética , Mutación , Neoplasias de la Tiroides/genética , Variaciones en el Número de Copia de ADN , Haploidia , Humanos , Metástasis de la Neoplasia , Telomerasa/genética , Neoplasias de la Tiroides/patología , Secuenciación del ExomaRESUMEN
BRAF(V600E) is a common mutation in papillary thyroid carcinoma (PTC) correlated with aggressive features. Our objective was to assess the feasibility and accuracy of a novel RNA-based blood assay to identify individuals with a high-risk tumor mutation in patients with PTC. Patients with benign or malignant thyroid disorders were included between September 2013 and July 2014 before either thyroidectomy (n = 62) or treatment of recurrent or metastatic PTC (n = 8). RNA was isolated from peripheral blood lymphocytes and reverse transcribed and followed by two rounds of nested PCR amplification with a restriction digest specific for wild-type BRAF. BRAF(V600E) levels were quantified with standardization curves. Circulating BRAF(V600E) levels were compared with BRAF mutation status from surgical pathologic DNA-based tissue assays. Testing characteristics and receiving-operator curve using tissue results as the gold standard were assessed. Matched blood and tissue assays for BRAF(V600E) were performed on 70 patients with PTC (stages I to IV, n = 48) or other (n = 22) thyroid tumors. Sixty-three percent of PTC patients tested positive for BRAF(V600E) with conventional tissue assays on surgical specimens. The correlation between the RNA-based blood assay and tissue BRAF status was 0.71. PTC patients harbor detectable BRAF(V600E) circulating tumor cells. This blood assay is feasible and has potential as a biomarker for prognosis, surveillance, clinical decision making, and assessment of treatment response to BRAF-targeted therapies.
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Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma/sangre , Carcinoma/genética , Proteínas Proto-Oncogénicas B-raf/sangre , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/genética , Carcinoma/cirugía , Carcinoma Papilar , Femenino , Humanos , Linfocitos/citología , Masculino , Persona de Mediana Edad , Mutación/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
In rural Ethiopia, environmental degradation and a shortage of arable land impose a major toll on the population. Population, health, and environment (PHE) programs, such as that of the Ethio-Wetlands and Natural Resources Association (EWNRA), have evolved to address these issues. This article examines the community-based distribution (CBD) of family planning commodities in rural Ethiopia through EWNRA's large, multisectoral PHE program. Participants indicated that the integrated program encouraged acceptance of family planning and reduced geographic barriers to access. Through peer education and collaboration across government ministries, EWNRA leveraged integrated population-environment messages to garner support for its network of CBD providers. These integration strategies are a model for PHE programs worldwide, especially amid the global response to climate change. Because of the complex nature of PHE organizations, researchers often find it difficult to effectively document and evaluate their programs. With this in mind, we propose a framework to assess PHE integration.
Asunto(s)
Anticoncepción/métodos , Servicios de Planificación Familiar/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Servicios de Salud Rural/organización & administración , Factores de Edad , Agentes Comunitarios de Salud/organización & administración , Conducta Cooperativa , Etiopía , Educación en Salud/organización & administración , Humanos , Entrevistas como Asunto , Factores Sexuales , Factores SocioeconómicosRESUMEN
BACKGROUND: The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics. OBJECTIVES: The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype. MATERIALS AND METHODS: We performed SNaPshot genotyping on a panel of 129 FVPTCs of ≥1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes. RESULTS: We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARγ. BRAF mutation was significantly associated with unencapsulated tumor status. CONCLUSIONS: These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARγ. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes.