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.

[Healthcare impact of introduction of thyroid ultrasound in a thyroid nodule pathology unit]. / Impacto asistencial tras la introducción de la ecografía tiroidea en una unidad monográfica de atención al nódulo tiroideo.

INTRODUCTION: Worldwide incidence of thyroid cancer has increased in recent decades. OBJECTIVE: To provide evidence of the diagnostic and care efficiency of a monographic thyroid nodule clinic integrating clinical examination, ultrasound examination, and cytology with on site evaluation. PATIENTS AND METHODS: Patients attending the monographic thyroid nodule clinic from January 2004 to June 2010. Two periods may be distinguished based on availability of ultrasound equipment at the time of the visit: a first period (P1: 01/2004-09/2007) where no ultrasound equipment was available at the clinic and FNA by palpation was performed, and a second period (P2: 10/2007-06/2010) where this equipment was available and ultrasound-guided FNA was performed. RESULTS: A total of 1036 patients [P1: 537 (52%), P2: 499 (48%)] were seen and enrolled. Diagnostic efficiency (P1 vs P2): 143 vs 181 patients were seen annually, p<0.001; FNA number/nodule: 1.68 vs 1.17, p<0.001; percent FNAs with inadequate material: 26% vs 5.3%, p<0.001; mean (SD) nodule size: 23.6 (12.4) vs 21.7 (11.7) mm, p 0.040; proportion of nodules examined less than 10mm in size: 9.9% vs 13.7%, p 0.030. Care efficiency: mean time (range) from the first visit to surgery indication: 332 (0-2177) vs 108 (0-596) days, p<0.001; proportion of patients referred for surgery due to suspect cytology/other reasons: 1.06 vs 2.21, p<0.001; and operated benign neoplasm/pathology: 0.47 vs 0.93, p=0.002. CONCLUSION: A monographic thyroid nodule clinic integrating clinical examination, ultrasound, and cytology evaluated on site increases diagnostic and care efficiency in patients with thyroid nodules.