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Dara O Kavanagh, Marie McIlroy, Eddie Myers, Fiona Bane, Thomas B Crotty, E McDermott, Arnold D Hill, and Leonie S Young

Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERα, ERβ, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERα was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERα and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan–Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.

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Rengyun Liu and Mingzhao Xing

The 2013 discovery of Telomerase reverse transcriptase (TERT) promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for E-twenty-six transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0, 11.3, 17.1, 43.2 and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g. RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer.

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Margarida M Moura, Branca M Cavaco, and Valeriano Leite

Medullary thyroid carcinoma (MTC) is a rare malignancy originating from the calcitonin-secreting parafollicular thyroid C cells. Approximately 75% of cases are sporadic. Rearranged during transfection (RET) proto-oncogene plays a crucial role in MTC development. Besides RET, other oncogenes commonly involved in the pathogenesis of human cancers have also been investigated in MTC. The family of human RAS genes includes the highly homologous HRAS, KRAS, and NRAS genes that encode three distinct proteins. Activating mutations in specific hotspots of the RAS genes are found in about 30% of all human cancers. In thyroid neoplasias, RAS gene point mutations, mainly in NRAS, are detected in benign and malignant tumors arising from the follicular epithelium. However, recent reports have also described RAS mutations in MTC, namely in HRAS and KRAS. Overall, the prevalence of RAS mutations in sporadic MTC varies between 0–43.3%, occurring usually in tumors with WT RET and rarely in those harboring a RET mutation, suggesting that activation of these proto-oncogenes represents alternative genetic events in sporadic MTC tumorigenesis. Thus, the assessment of RAS mutation status can be useful to define therapeutic strategies in RET WT MTC. MTC patients with RAS mutations have an intermediate risk for aggressive cancer, between those with RET mutations in exons 15 and 16, which are associated with the worst prognosis, and cases with other RET mutations, which have the most indolent course of the disease. Recent results from exome sequencing indicate that, besides mutations in RET, HRAS, and KRAS, no other recurrent driver mutations are present in MTC.

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Kensey Bergdorf, Donna C Ferguson, Mitra Mehrad, Kim Ely, Thomas Stricker, and Vivian L Weiss

The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4–4.5, P = 5.4 × 10−4). Increased dendritic cells (OR = 3.4, CI = 1.9–6.3, P = 5.5 × 10−5) and neutrophils (OR = 10.5, CI = 2.7–44, P = 8.7 × 10−4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6–13, P = 4.9 × 10−3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10−3, CI = 5.3 × 10−5–0.031, P = 4.1 × 10−5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.

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D Deandreis, A Al Ghuzlan, S Leboulleux, L Lacroix, J P Garsi, M Talbot, J Lumbroso, E Baudin, B Caillou, J M Bidart, and M Schlumberger

The aim of this study is to search for relationships between histology, radioiodine (131I) uptake, fluorodeoxyglucose (FDG) uptake, and disease outcome in patients with metastatic thyroid cancer. Eighty patients with metastatic thyroid cancer (34 males, 46 females, mean age at the time of the diagnosis of metastases: 55 years) were retrospectively studied. All patients were treated with radioactive iodine and evaluated by FDG-positron emission tomography (PET). Primary tumor tissue sample was available in all cases. Forty-five patients (56%) had a papillary, 12 (15%) a follicular, and 23 (29%) a poorly differentiated thyroid cancer. Cellular atypias, necrosis, mitoses, thyroid capsule infiltration, and vascular invasion were frequently detected (70, 44, 52, 60, and 71% respectively). Metastases disclosed FDG uptake in 58 patients (72%) and 131I uptake in 37 patients (45%). FDG uptake was the only significant prognostic factor for survival (P=0.02). The maximum standardized uptake value and the number of FDG avid lesions were also related to prognosis (P=0.03 and 0.009). Age at the time of the diagnosis of metastases (P=0.001) and the presence of necrosis (P=0.002) were independent predictive factors of FDG uptake. Radioiodine uptake was prognostic for stable disease (P=0.001) and necrosis for progressive disease at 1 year (P=0.001). Histological subtype was not correlated with in vivo tumor metabolism and prognosis. In conclusion, FDG uptake in metastatic thyroid cancer is highly prognostic for survival. Histological subtype alone does not correlate with 131I/FDG uptake pattern and patient outcome. Well-differentiated thyroid cancer presenting histological features such as necrosis and FDG uptake on PET scan should be considered aggressive differentiated cancers.

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J Lado-Abeal, R Celestino, S B Bravo, M E R Garcia-Rendueles, J de la Calzada, I Castro, P Castro, C Espadinha, F Palos, P Soares, C V Alvarez, M Sobrinho-Simões, and J Cameselle-Teijeiro

Our main objective was to search for mutations in candidate genes and for paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARγ) rearrangement in a well-differentiated angioinvasive follicular thyroid carcinoma (FTC) causing hyperthyroidism. DNA and RNA were extracted from the patient's thyroid tumor, as well as ‘normal’ thyroid tissue, and from peripheral blood lymphocytes (PBLs) of the patient, her daughter, and two siblings. Nuclear isolation was extracted from the patient's tumor, ’normal’ thyroid tissue, PBLs, and uterine leiomyoma tissue. TSH receptor (TSHR), RAS, and BRAF genes were sequenced. We searched for PAX8 PPAR γ in thyroid, PBL, and uterine leiomyoma samples from the patient and family members. Proliferative effects of detected mutants on non-transformed human thyrocytes cultures. An activating TSHR mutation, M453T, was detected in the tumor. PAX8 (exons 1 8 + 10) PPAR γ was found in all tested patient's tissues. A second rearrangement, PAX8 (exons 1 8) PPAR γ, was detected in the patient's normal thyroid tissue. Under deprived medium condition, co-transfection of PAX8 PPAR γ and TSHR M453T dramatically increased the number of thyrocytes, an effect that it was not observed with TSHR wild-type (WT); under complete medium conditions, co-transfection of PAX8 PPAR γ with either TSHR M453T or TSHR WT inhibited cell proliferation. We report a patient with hyperthyroidism due to a FTC bearing an activating TSHR mutation and PAX8 PPAR γ rearrangements. PAX8 PPAR γ was present as a mosaicism affecting tissues from endodermal and mesodermal origin. PAX8 PPAR γ and TSHR M453T inhibited or promoted thyrocyte proliferation depending on medium conditions. The activating TSHR mutation could promote in vivo FTC development in PAX8 PPAR γ-positive thyrocytes under poor blood supply with deprivation of growth factors but restraint the tumor growth when growth factors are supplied.

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Hai-Yan Zhang, Hua-Qin Wang, Hai-Mei Liu, Yifu Guan, and Zhen-Xian Du

DJ-1, a cancer-associated protein protects cells from multiple toxic stresses. The expression of DJ-1 and its influence on thyroid cancer cell death has not been investigated so far. We analyzed DJ-1 expression in human thyroid carcinoma cell lines and the effect of DJ-1 on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. DJ-1 was expressed in human thyroid carcinoma cell lines; small interfering RNA-mediated downregulation of its levels significantly sensitized thyroid carcinoma cells to TRAIL-induced apoptosis, whereas the forced exogenous expression of DJ-1 significantly suppressed cell death induced by TRAIL. We also report here that TRAIL-induced thyroid cancer cell apoptosis is mediated by oxidative stress and that DJ-1, a potent nutritional antioxidant, protects cancer cells from apoptosis at least in part by impeding the elevation of reactive oxygen species levels induced by TRAIL and impairing caspase-8 activation. Subsequently, we investigated DJ-1 expression in 52 normal and 74 primary thyroid carcinomas from patients of China Medical University. The protein was not detectable in the 52 specimens of normal thyroid, while 70 out of 74 analyzed carcinomas (33 out of 33 follicular, 17 out of 19 papillary, 12 out of 13 medullar, and 8 out of 9 anaplastic) were clearly positive for DJ-1 expression. Our data demonstrated that DJ-1 is specifically expressed in thyroid carcinomas and not in the normal thyroid tissue. In addition, the protein modulates the response to TRAIL-mediated apoptosis in human neoplastic thyroid cells, at least partially through its antioxidant property.

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Iñigo Landa, Cristina Montero-Conde, Donatella Malanga, Silvia De Gisi, Guillermo Pita, Luis-Javier Leandro-García, Lucía Inglada-Pérez, Rocío Letón, Carmela De Marco, Cristina Rodríguez-Antona, Giuseppe Viglietto, and Mercedes Robledo

The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27Kip1, are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (−79C>T) and rs36228499 (−838C>A)) to perform the first case–control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (−79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09–4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P value <0.001). This effect was observed in −79TT genotype control carriers, who showed a tendency towards lower CDKN1B mRNA levels in lymphocytes, as well as at the protein level. This is the first study that identifies CDKN1B as a low-penetrance gene in thyroid cancer, and specifically in FVPTC subtype. We propose a reduced CDKN1B gene transcription depending on the genotype of the −79C>T (rs34330) variant as a novel mechanism underlying p27Kip1 downregulation.

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Tae Hyuk Kim, Young-Eun Kim, Soomin Ahn, Ji-Youn Kim, Chang-Seok Ki, Young Lyun Oh, Kyunga Kim, Jae Won Yun, Woong-Yang Park, Jun-Ho Choe, Jung-Han Kim, Jee Soo Kim, Sun Wook Kim, and Jae Hoon Chung

TERT promoter mutations are emerging prognostic biomarkers in multiple cancers and are found in highly aggressive thyroid cancer. Our aim is to investigate the prognostic value of these mutations for the outcome of thyroid cancer-related mortality in a large cohort of thyroid cancer patients. This was a retrospective study of 409 patients (393 with differentiated thyroid cancer) with a median age of 44 years (range 16–81 years) and median follow-up of 13 years (interquartile range 11–16 years). Analyses of associations between mutational status and various clinicopathological variables were performed. TERT promoter mutations were identified in 32 (9.8%) papillary, 11 (16.7%) follicular and seven (43.8%) poorly differentiated/anaplastic thyroid cancer patients. The presence of TERT promoter mutations was associated with factors such as increased age (P < 0.001), extrathyroidal invasion (P = 0.01), increased stage at diagnosis (P < 0.001) and dedifferentiated histological type (P = 0.001). A TERT promoter mutation was independently associated with poorer overall survival in patients with differentiated thyroid cancer (10-year survival rate, 66.2% vs 98.3% for wild type; adjusted HR, 7.18; 95% CI: 2.77–18.59) and in patients with papillary cancer (74.2% vs 99.3%; 14.20; 3.03–66.68). Concomitant TERT and BRAF mutations worsened the survival rate of patients with papillary cancer (82.6% vs 99.4% for exclusively BRAF mutation alone; 5.62; 1.85–17.09). In conclusion, the presence of TERT promoter mutations is independently associated with increased mortality in patients with differentiated thyroid cancer. The results suggest that inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

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Kyoungjune Pak, Seong-Jang Kim, In Joo Kim, Bo Hyun Kim, Sang Soo Kim, and Yun Kyung Jeon

The incidence of thyroid cancer in both men and women is increasing faster than that of any other cancer. Although positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has received much attention, the use of FDG PET for the management of thyroid cancer is limited primarily to postoperative follow-up. However, it might have a role in selected, more aggressive pathologies, and so patients at a high risk of distant metastasis may benefit from PET before surgery. As less FDG-avid thyroid cancers may lower the diagnostic accuracy of PET in preoperative assessment, an understanding of FDG avidity is important for the evaluation of thyroid cancer. FDG avidity has been shown to be associated with tumor size, lymph node metastasis, and glucose transporter expression and differentiation. As PET is commonly used in clinical practice, the detection of incidentalomas by PET is increasing. However, incidentalomas detected by PET have a high risk of malignancy. Clinicians handling cytologically indeterminate nodules face a dilemma regarding a procedure for a definitive diagnosis, usually lobectomy. With ‘nondiagnostic (ND)’ fine-needle biopsy (FNA), PET has shown a negative predictive value (NPV) of 100%, which indicates that negative uptake in a ND FNA procedure accurately excludes malignancy. With ‘atypia of undetermined significance’ or ‘follicular neoplasm’, the sensitivity and NPV of PET are 84 and 88%. PET does not provide additional information for the preoperative assessment of thyroid cancer. However, factors associated with FDG positivity are related to a poor prognosis; therefore, FDG PET scans before surgery may facilitate the prediction of the prognosis of differentiated thyroid cancer.