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Maria Trovato, Alessandra Ulivieri, Roberto Dominici, Rosaria Maddalena Ruggeri, Enrica Vitarelli, Salvatore Benvenga, Gaetano Barresi, Francesco Trimarchi, Ercole Brunetti, Aldo Vecchione, Mario Andreoli, and Salvatore Sciacchitano

A careful pathological examination often reveals the presence of different lesions at various stages of tumor progression and invasion, even in those thyroid glands presenting with solitary nodules. Each thyroid lesion is composed of many different cell types, reflecting the marked heterogeneity of normal thyroid tissue. Among the different chromosome regions altered in thyroid tumors, 7q21 appears to be specifically involved in malignant tumors, especially of the follicular type. This study was conducted to analyze the loss of heterozygosity (LOH) pattern at 7q21 in pure populations of cells from each single lesion harbored in surgically removed thyroid glands, and to evaluate its clinical significance. One hundred and forty-two thyroid glands were examined, all showing, as a common trait, a goitrous appearance associated with one single lesion in 114 cases and with more than one in the remaining 28 cases. A total number of 318 lesions was analyzed, consisting of 142 goiters (TG), 48 hyperplasias (TH), 80 adenomas (TA) and 48 carcinomas (TC). Five different types of cells were isolated by laser capture microdissection from each lesion. DNA was analyzed by PCR and polyacrylamide gel electrophoresis in search of LOH affecting five microsatellite markers, D7S660, D7S630, D7S492, D7S657, and D7S689. We detected LOH at 7q21 not only in thyroid malignant tumors but also in benign lesions. Allelic loss occurred exclusively in dark nucleus and eosinophilic cytoplasm cells, commonly observed in the follicular type of lesions. In these types of lesions allelic loss frequency increases along with neoplastic transformation (9% in TG, 41% in TH, 68% in TA and 100% in TC), and is directly correlated with thyroid gland volume as well as with the presence of multiple lesions. The highest LOH rate was observed for D7S492, indicating that the recurrent region of deletion was localized at the corresponding genetic locus at 7q21.2, in the same position where the common fragile site FRA7E was previously mapped. LOH at this locus represents an early event in the development of follicular TC and is associated with intense growth of thyroid glands.

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R W Blamey

Introduction Oophorectomy has been a proven treatment for breast cancer for just 100 years (Beatson 1896) but over the last ten ovarian suppression has become available, by using luteinizing hormone-releasing hormone (LHRH) agonists. When the agent ICI 118630 (now Zoladex; Zeneca, Macclesfield, Cheshire, UK), was introduced in the early 1980s, it was up for experiment as to whether it could replace oophorectomy and ovarian ablation. An LHRH agonist, it was known from experiments to block follicular activity so as to reduce plasma oestradiol and to decrease the size of target tissues such as the hamster uterus. Initial work The drug was investigated, together with Dr Rob Nicholson at the Tenovus Institute, Cardiff, as part of the Nottingham City Hospital clinical programme. Initially, it was administered as a subcutaneous daily injection, later in a depot monthly formulation. We showed that with both the daily injection and the
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Dang Vu-Phan, Vladimir Grachtchouk, Jingcheng Yu, Lesley A Colby, Max S Wicha, and Ronald J Koenig

A chromosomal translocation results in the production of a paired box 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARG) fusion protein (PPFP) in ∼35% of follicular thyroid carcinomas. To examine the role of PPFP in thyroid oncogenesis, the fusion protein was stably expressed in the non-transformed rat thyroid cell line PCCL3. PPFP conferred on PCCL3 cells the ability to invade through Matrigel and to form colonies in anchorage-independent conditions. PPFP also increased the fraction of cells with Wnt/TCF-responsive green fluorescent protein reporter gene expression. This Wnt/TCF-activated population was enriched for colony-forming and invading cells. These actions of PPFP required a functional PPARG DNA binding domain (DBD) within PPFP and were further stimulated by PPARG agonists. These data indicate that PPFP, through its PPARG DBD, induces Wnt/TCF pathway activation in a subpopulation of cells, and these cells have properties of cellular transformation including increased invasiveness and anchorage-independent growth.

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D Bonofiglio, H Qi, S Gabriele, S Catalano, S Aquila, M Belmonte, and S Andò

Peroxisome proliferator-activated receptor γ (PPARγ) has been demonstrated to be anti-neoplastic against various human tumors. The aim of this study was to delineate the molecular mechanism underlying PPARγ ligand rosiglitazone (BRL) antiproliferative effects in follicular WRO and anaplastic FRO human thyroid carcinoma cells. BRL upregulated the p21Cip1/WAF1 levels in the two thyroid cancer cells, while did not modify the p53 protein content. Different evidences indicate that the p21Cip1/WAF1 upregulation by BRL requires a functional PPARγ, since it was reversed by silencing PPARγ and pretreatment with GW9662, an irreversible PPARγ antagonist. Transient transfection assays showed that BRL triggered the transcriptional activity of p21Cip1/WAF1 promoter gene in a p53-independent way, being a p21Cip1/WAF1 promoter construct deleted in the p53 sites still activated by BRL. The Sp1 inhibitor mithramycin silenced the p21Cip1/WAF1 promoter activity suggesting an important role of Sp1 in mediating BRL activation. The electrophoretic mobility shift and chromatin immunoprecipitation (ChIP) assays evidenced a functional interaction between PPARγ and Sp1 in regulating p21Cip1/WAF1. Intriguingly, ChIP analysis revealed in the p21Cip1/WAF1 gene promoter an increased recruitment of the RNA Pol II associated with an increased histone H3 acetylation and a reduced H3 methylation. The biological event, consistent with PPARγ-induced WRO and FRO cell growth inhibition, was reversed by p21Cip1/WAF1 antisense oligonucleotides and was confirmed by increasing the PPARγ expression, suggesting a crucial role exerted by p21Cip1/WAF1 in PPARγ action. Our results further candidate BRL as a potential agent able to inhibit tumor progression of follicular and anaplastic thyroid carcinoma.

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Natassia E Bufalo, Janaina L Leite, Ana C T Guilhen, Elaine C Morari, Fabiana Granja, Ligia V M Assumpcao, and Laura S Ward

In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P = 0.0147), reducing the risk for this type of cancer (odds ratio = 0.564; 95% confidence interval = 0.357–0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P = 0.0385) and CYP1A1 germline inheritance (P = 0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

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Federica Panebianco, Alyaksandr V Nikitski, Marina N Nikiforova, Cihan Kaya, Linwah Yip, Vincenzo Condello, Abigail I Wald, Yuri E Nikiforov, and Simion I Chiosea

ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK-translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected.

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Jaume Capdevila, Lara Iglesias, Irene Halperin, Ángel Segura, Javier Martínez-Trufero, Maria Ángeles Vaz, Jesús Corral, Gabriel Obiols, Enrique Grande, Juan Jose Grau, and Josep Tabernero

Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400 mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting.

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J D Lin, M J Liou, T C Chao, H F Weng, and Y S Ho

From 1977 through 1995, 1,013 thyroid carcinoma patients received treatment and were followed up at Chang Gung Medical Center in Taiwan. To evaluate the prognostic variables of papillary and follicular thyroid carcinomas with limited lymph node metastases, a retrospective review of these patients was performed. Of these patients, 910 had papillary or follicular thyroid carcinoma, and 119 patients were categorized as clinical stage 2 with limited neck lymph node metastases only at the time of diagnosis. The patients were categorized into two groups as no recurrence and local recurrence or distant metastasis at the end of 1997. After the operations, radioactive iodide (131I) treatments were performed in 114 patients and external radiotherapy for neck region or distant metastases in 18 patients. The median follow-up period of these patients was 5.4 years. Clinical variables were coded in our computer for statistical analysis. After the treatments, 93 patients remained disease-free; 10 were in stage 2; 5 in stage 3; and 11 aggravated to stage 4. Of the clinical variables, age, post-operative first 1311 uptake scans, and 1-month post-operative thyroglobulin levels revealed statistically significant differences between the group which improved and the group which did not. During the follow-up period, five patients died; three patients died of thyroid cancer and two died of intercurrent diseases. Patients with papillary thyroid carcinoma revealed a higher percentage of lymph node metastases. Although limited lymph node metastases did not influence survival rate, patients with poor prognostic factors need more aggressive treatment to avoid progression of the cancer.

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Stefan Karger, Carl Weidinger, Kerstin Krause, Sien-Yi Sheu, Thomas Aigner, Oliver Gimm, Kurt-Werner Schmid, Henning Dralle, and Dagmar Fuhrer

The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H2O2 exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. In vivo, we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.

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Branca M Cavaco, Pedro F Batista, Carmo Martins, Ana Banito, Francisco do Rosário, Edward Limbert, Luís G Sobrinho, and Valeriano Leite

Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N- and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.