The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

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.

[Usefulness of galectin-3 expression in the clinical behavior of differentiated thyroid carcinoma]. / Utilidad de la expresión de galectina-3 en el comportamiento clínico del cáncer diferenciado de tiroides.

BACKGROUND AND OBJECTIVE: Our objective was to quantify the galectin-3 (gal-3) expression in differentiated thyroid carcinoma and study its relation with the clinical behavior of these tumors. PATIENTS AND METHOD: We investigated the immunohistochemical reaction of gal-3 in patients with papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) and performed a retrospective study in order to find correlations with clinical features. Gal-3 expression was studied in 53 differentiated tyroid carcinomas (42 PTC and 11 FTC), and was related with clinical features: metastases, extrathyroid invasion and initial stage in the diagnosis and persistence disease and relapses in the follow up. RESULTS: Gal-3 expression positivity in PTC had a median of 60% (percentil 25 [p25], 17.5%; percentil 75 [p75], 100%), and was significantly higher (p < 0.0001) than in FTC (median, 0%; p25, 0%; p75, 15%). In PTC, gal-3 expression was significantly higher in advanced stages at the time of initial diagnosis (p = 0.014), persistent disease (p = 0.012) and relapses (p = 0.012) during the follow up. We did not find any significant association between gal-3 expression and clinical features of FTC. CONCLUSIONS: Gal-3 is a negative prognosis marker in PTC but not in FTC.

Cost of clinical management of acromegaly in Spain.

INTRODUCTION AND BACKGROUND: The cost of the therapeutic management of acromegaly depends on the selection of resources used, surgery and/or pharmacological treatment, by the specialist responsible for treatment, related to the characteristics of the patient and tumour. The objective of this work is to evaluate these costs for an illness that is rare but that is associated with a high morbidity in the context of routine clinical practice. METHODS: This was an epidemiological, prospective, naturalistic, multicentre study in Spain, in which 38 endocrinologists participated. Adult patients with acromegaly and a pituitary microadenoma or macroadenoma were included in the study. Patients were assigned, according to first-line treatment, to the following two groups: surgery first-line group (surgery in the 6 months before inclusion or during the follow-up period) and pharmaceutical first-line group (treatment with somatostatin analogues [SAs] for at least 6 months and with or without surgery after starting treatment with SAs). Data were collected during routine visits made during a follow-up period of 2 years. All resources were estimated at 2009 prices (€) and adjusted according to the Spanish consumer price index in 2010. RESULTS: Seventy-four patients were included, the majority of them with macroadenoma (70%). Eighty-eight percent of patients were treated surgically (76% as a first-line treatment), while 12% of patients received only SAs. Treatment with SAs was used at some point in the study by 85% of patients. The mean annual total cost of acromegaly is €9668 per patient (€9223 for the surgery group and €11,054 for the pharmaceutical group). Seventy-one percent of the direct cost of the disease corresponds to treatment with SAs. The cost of a patient treated only with surgery is €2501 on an annual basis, versus €9745 for a patient receiving only pharmacological treatment. In cases where a combination of both types of treatment is required, the annual total cost ranges from €10,866 to €12,364. CONCLUSION: The annual direct cost per patients of acromegaly in Spain is €9668. Even though surgery is the preferred option for treatment for a great number of patients, SAs must be added to the treatment regimen of the majority of such patients. The costs associated with this treatment are greater than the cost of treatment with SAs alone.

Utilidad de la expresión de galectina-3 en el comportamiento clínico del cáncer diferenciado de tiroides / Usefulness of galectin-3 expression in the clinical behavior of differentiated thyroid carcinoma

Fundamento y objetivo: Identificar la expresión de galectina-3 (gal-3) en el cáncer diferenciado de tiroides y estudiar su relación con el comportamiento clínico de estos tumores. Pacientes y método: Se cuantificó de forma retrospectiva la expresión inmunohistoquímica de gal-3 en 42 pacientes con cáncer papilar de tiroides (CPT) y 11 pacientes con cáncer folicular de tiroides (CFT), y se relacionó esta expresión con diversas características clínicas: metástasis a distancia, invasión extratiroidea, estadio inicial en el momento del diagnóstico y presencia de enfermedad activa y recurrencias durante la evolución. Resultados: La positividad de gal-3 en el CPT presentó una mediana del 60% (percentil 25 [p25], 17,5%; percentil 75 [p75], 100%), significativamente mayor que en el CFT (p < 0,0001) (mediana, 0%; p25, 0%; p75, 15%). En el CPT la expresión de gal-3 fue significativamente mayor en estadios iniciales elevados en el momento del diagnóstico (p = 0,014), en los casos con persistencia de enfermedad activa (p = 0,012) y con recurrencias (p = 0,012) durante la evolución. No encontramos diferencias significativas entre la expresión de gal-3 y las características clínicas del CFT. Conclusiones: La gal-3 es un marcador pronóstico negativo en el CPT, pero no en el CFT

Background and objective: Our objective was to quantify the galectin-3 (gal-3) expression in differentiated thyroid carcinoma and study its relation with the clinical behavior of these tumors. Patients and method: We investigated the immunohistochemical reaction of gal-3 in patients with papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) and performed a retrospective study in order to find correlations with clinical features. Gal-3 expression was studied in 53 differentiated tyroid carcinomas (42 PTC and 11 FTC), and was related with clinical features: metastases, extrathyroid invasion and initial stage in the diagnosis and persistence disease and relapses in the follow up. Results: Gal-3 expression positivity in PTC had a median of 60% (percentil 25 [p25], 17.5%; percentil 75 [p75], 100%), and was significantly higher (p < 0.0001) than in FTC (median, 0%; p25, 0%; p75, 15%). In PTC, gal-3 expression was significantly higher in advanced stages at the time of initial diagnosis (p = 0.014), persistent disease (p = 0.012) and relapses (p = 0.012) during the follow up. We did not find any significant association between gal-3 expression and clinical features of FTC. Conclusions: Gal-3 is a negative prognosis marker in PTC but not in FTC