Our findings could not demonstrate any involvement of POF1B, but suggest that rare mutations in the DACH2 gene may have a role in the POF phenotype.

Context:The relevance of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) as a negative prognostic factor is a subject of intense debate. This mutation has been associated with several clinicopathological features, but the lack of consistency among data does not support its usefulness as marker of tumor aggressiveness and poorer outcome. Due to the genetic heterogeneity of the tumor, both the occurrence and the allele percentage of the BRAF mutation should be considered to unravel this controversy.Objective: We aimed to evaluate the impact of the BRAF V600E mutation occurrence and the allele percentage on the metastatic process in PTCs. Study Design:The presence and allele percentage of the BRAF mutation were determined by pyrosequencing in 132 cases of well-differentiated PTCs with (n ϭ 37) or without lymph node metastases (LNMs) (n ϭ 95) and in 40 LNMs matched with 35 PTCs.Results: No significant differences were observed in either the occurrence or the allele percentage of V600E mutation between the 2 groups of PTCs with or without LNMs. The LNMs were heterogeneous for the V600E mutation as the primary lesions. Conclusions:In this study, the occurrence and percentage of the BRAF V600E mutated allele was not preferentially associated with the development of metastases and the average mutated allele percentage decreased as the tumor progresses from the primary site to the lymph node metastatic sites. These observations support the need to reevaluate the role of the BRAF V600E mutation as a negative prognostic marker in PTCs. (J Clin Endocrinol Metab 98: E934 -E942, 2013) P apillary thyroid carcinoma (PTC) accounts for approximately 90% of all thyroid cancers. Although most these tumors show an indolent behavior and favorable prognosis, a small but significant percentage behaves aggressively and results in poor clinical outcome (1). The identification of prognostic markers able to discriminate PTCs with more aggressive behavior from those with an indolent course would be of great relevance when planning therapeutic strategies. In this regard, the relevance of BRAF (v-Raf murine sarcoma viral oncogene homolog B1) mutations as marker of tumor aggressiveness and poorer outcome in thyroid cancer has been recently a subject of intense debate.The BRAF V600E mutation, resulting from the BRAFT1799A transversion, is the most common genetic mutation in PTC, with a mean frequency of 45% of mu- Abbreviations: BRAF, v-Raf murine sarcoma viral oncogene homolog B1; IHC, immunohistochemistry; LN, lymph node; LNM, lymph node metastasis; PTC, papillary thyroid carcinoma.

Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene.

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