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Open access

Wei Li, Qing Huang, Danyang Sun, Guizhi Zhang, and Jian Tan

RAD52 motif containing 1 (RDM1) encodes the RAD52 protein involved in DNA double-strand break repair and recombination events. However, the importance of RDM1 in papillary thyroid carcinoma (PTC) is largely unknown. In the present study, we examined the role of RDM1 in thyroid cancer. The RDM1 expression in PTC patients was examined using immunohistochemistry. The expression levels of RDM1 mRNA in thyroid cancer cells were measured by quantitative real-time PCR (qRT-PCR). Lentivirus-mediated small interfering RNAs (siRNAs) were used to knock down the RDM1 expression in the K1 and TPC1 cells. Then, changes in the RDM1 target gene expression were determined by qRT-PCR and Western blot. Cell proliferation was examined by a high content screening assay. Cell cycle distribution and apoptosis were detected by flow cytometric analysis and MTT analysis. We showed that the RDM1 expression was higher in PTC tissue compared to pericarcinous tissue. RDM1 mRNA was found to be expressed by qRT-PCR. Using a lentivirus-based RNA interference (RNAi) approach, the RDM1 expression was significantly inhibited. The inhibition of RDM1 expression by RNAi significantly impaired cell proliferation, increased apoptosis and arrested cells in the G2/M phase. These data showed that RDM1 was highly expressed in PTC tissue and thyroid cancer cell lines. Moreover, RDM1 may play an important role in cell proliferation, cell cycle distribution and apoptosis of human PTC cells.

Open access

Thomas Crezee, Mirela Petrulea, Doina Piciu, Martin Jaeger, Jan W A Smit, Theo S Plantinga, Carmen E Georgescu, and Romana Netea-Maier

The PI3K-Akt-mTOR pathway plays a central role in the development of non-medullary thyroid carcinoma (NMTC). Although somatic mutations have been identified in these genes in NMTC patients, the role of germline variants has not been investigated. Here, we selected frequently occurring genetic variants in AKT1, AKT2, AKT3, PIK3CA and MTOR and have assessed their effect on NMTC susceptibility, progression and clinical outcome in a Dutch discovery cohort (154 patients, 188 controls) and a Romanian validation cohort (159 patients, 260 controls). Significant associations with NMTC susceptibility were observed for AKT1 polymorphisms rs3803304, rs2494732 and rs2498804 in the Dutch discovery cohort, of which the AKT1 rs3803304 association was confirmed in the Romanian validation cohort. No associations were observed between PI3K-Akt-mTOR polymorphisms and clinical parameters including histology, TNM staging, treatment response and clinical outcome. Functionally, cells bearing the associated AKT1 rs3803304 risk allele exhibit increased levels of phosphorylated Akt protein, potentially leading to elevated signaling activity of the oncogenic Akt pathway. All together, germline encoded polymorphisms in the PI3K-Akt-mTOR pathway could represent important risk factors in development of NMTC.

Open access

Thomas Couronne, Paul Girot, Julien Hadoux, Thierry Lecomte, Alice Durand, Caroline Fine, Katia Vandevoorde, Catherine Lombard-Bohas, and Thomas Walter

Objective

First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment.

Material and methods

This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS).

Results

Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments.

Conclusion

LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

Open access

Joana Simões-Pereira, Daniel Macedo, and Maria João Bugalho

Introduction

Metastases to central nervous system (M1-CNS) are rarely reported in thyroid cancer (TC) patients. We aimed to characterize patients with M1-CNS from TC followed in our department.

Methods

Review of the medical records of 27 patients with TC-related M1-CNS.

Results

Mean age at TC diagnosis was 56.9 ± 19.1 years. Papillary TC (55.6%) was the commonest histological type, followed by poorly differentiated (18.5%), medullary (11.1%), follicular (7.4%) and Hürthle cell (7.4%) carcinomas. Angioinvasion and extrathyroidal extension were observed in a high number of patients. At M1-CNS diagnosis, other distant metastases were already present in 77.8% of the patients. Treatment directed to M1-CNS was offered to 20 (74%) patients: 1 was submitted to surgery, 18 to radiotherapy (either whole-brain radiotherapy or stereotaxic radiosurgery or both) and 4 to surgery and radiotherapy. Four patients received cytotoxic chemotherapy and one was submitted to 131I. Median survival since M1-CNS detection was 5.0 months. The only factor associated with better survival was surgery to brain metastases (P = 0.012).

Conclusions

The management of these patients is very challenging given the inexistence of effective treatments, except for brain surgery in selected cases.

Open access

Qi Che, Xirong Xiao, Jun Xu, Miao Liu, Yongning Lu, Suying Liu, and Xi Dong

Accumulating evidence revealed that the leading risk factor of endometrial cancer is exposure to endogenous and exogenous estrogens, while the exact mechanism underlying estrogen contribution to endometrial cancer progression has not been elucidated clearly. Interleukin (IL)-6 has been verified to be critical for tumor progression in several human cancers. In this study, we provided evidence that 17β-estradiol (E2) could significantly promote endometrial cancer cells viability, migration and invasion through activation of IL-6 pathway, which involved in its downstream pathway and target genes (p-Stat3, Bcl-2, Mcl-1, cyclin D1 and MMP2). Meanwhile, utilization of IL-6-neutralizing antibody could partially attenuate the increased cancer growth and invasion abilities in Ishikawa and RL95-2 endometrial cancer cell lines and an orthotopic endometrial cancer model. We established a causative link between estrogen and IL-6 signaling activation in the development of endometrial cancer. The molecular mechanism defined in this study provided the evidence that E2 promotes endometrial carcinoma progression via activating the IL-6 pathway, indicating that interruption of IL-6 might be an essential therapeutic strategy in estrogen-dependent endometrial cancer.

Open access

Rui M B Maciel, Cleber P Camacho, Lígia V M Assumpção, Natassia E Bufalo, André L Carvalho, Gisah A de Carvalho, Luciana A Castroneves, Francisco M de Castro Jr, Lucieli Ceolin, Janete M Cerutti, Rossana Corbo, Tânia M B L Ferraz, Carla V Ferreira, M Inez C França, Henrique C R Galvão, Fausto Germano-Neto, Hans Graf, Alexander A L Jorge, Ilda S Kunii, Márcio W Lauria, Vera L G Leal, Susan C Lindsey, Delmar M Lourenço Jr, Léa M Z Maciel, Patrícia K R Magalhães, João R M Martins, M Cecília Martins-Costa, Gláucia M F S Mazeto, Anelise I Impellizzeri, Célia R Nogueira, Edenir I Palmero, Cencita H C N Pessoa, Bibiana Prada, Débora R Siqueira, Maria Sharmila A Sousa, Rodrigo A Toledo, Flávia O F Valente, Fernanda Vaisman, Laura S Ward, Shana S Weber, Rita V Weiss, Ji H Yang, Magnus R Dias-da-Silva, Ana O Hoff, Sergio P A Toledo, and Ana L Maia

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Open access

Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Sten Schytte, Stefano Christian Londero, Henrik Baymler Pedersen, Christoffer Holst Hahn, Jens Bentzen, Sören Möller, Mette Gaustadnes, Maria Rossing, Finn Cilius Nielsen, Kim Brixen, Christian Godballe, and Danish Thyroid Cancer Group (DATHYRCA)

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38–4.57) vs 3.04 (95% CI: 1.38–6.67) for stage II, 2.06 (95% CI: 0.45–9.39) vs 3.59 (95% CI: 1.61–8.03) for stage III and 5.87 (95% CI: 2.02–17.01) vs 59.26 (20.53–171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

Open access

Huy Gia Vuong, Nguyen Phuoc Long, Nguyen Hoang Anh, Tran Diem Nghi, Mai Van Hieu, Le Phi Hung, Tadao Nakazawa, Ryohei Katoh, and Tetsuo Kondo

There are still ongoing debates as to which cut-off percentage of tall cell (TC) should be used to define tall cell variant (TCV) papillary thyroid carcinoma (PTC). In this meta-analysis, we aimed to investigate the clinicopathological significance of PTC with tall cell features (PTC-TCF, PTC with 10–50% of TCs) in comparison with classical PTC and TCVPTC (PTC with more than 50% of TCs) to clarify the controversial issue. Four electronic databases including PubMed, Web of Science, Scopus and Virtual Health Library were accessed to search for relevant articles. We extracted data from published studies and pooled into odds ratio (OR) and its corresponding 95% confidence intervals (CIs) using random-effect modeling. Nine studies comprising 403 TCVPTCs, 325 PTC-TCFs and 3552 classical PTCs were included for meta-analyses. Overall, the clinicopathological profiles of PTC-TCF including multifocality, extrathyroidal extension, lymph node metastasis, distant metastasis and patient mortality were not statistically different from those of TCVPTC. Additionally, PTC-TCF and TCVPTC were both associated with an increased risk for aggressive clinical courses as compared to classical PTC. The prevalence of BRAF mutation in PTC-TCF and TCVPTC was comparable and both were significantly higher than that in classical PTC. The present meta-analysis demonstrated that even a PTC comprising only 10% of TCs might be associated with a poor clinical outcome. Therefore, the proportions of PTC in PTC should be carefully estimated and reported even when the TC component is as little as 10%.

Open access

Weixi Wang, Rulai Han, Lei Ye, Jing Xie, Bei Tao, Fukang Sun, Ran Zhuo, Xi Chen, Xiaxing Deng, Cong Ye, Hongyan Zhao, and Shu Wang

Objective

Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1.

Design and methods

A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed.

Results

Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells.

Conclusions

ACC associated with MEN1 is rare and may occur in familial aggregates.

Open access

June Young Choi, Jin Wook Yi, Jun Hyup Lee, Ra-Yeong Song, Hyeongwon Yu, Hyungju Kwon, Young Jun Chai, Su-jin Kim, and Kyu Eun Lee

The purpose of this study was to assess the relationship between vitamin D receptor gene (VDR) expression and prognostic factors in papillary thyroid cancer (PTC). mRNA sequencing and somatic mutation data from The Cancer Genome Atlas (TCGA) were analyzed. VDR mRNA expression was compared to clinicopathologic variables by linear regression. Tree-based classification was applied to find cutoff and patients were split into low and high VDR group. Logistic regression, Kaplan–Meier analysis, differentially expressed gene (DEG) test and pathway analysis were performed to assess the differences between two VDR groups. VDR mRNA expression was elevated in PTC than that in normal thyroid tissue. VDR expressions were high in classic and tall-cell variant PTC and lateral neck node metastasis was present. High VDR group was also associated with classic and tall cell subtype, AJCC stage IV and lower recurrence-free survival. DEG test reveals that 545 genes were upregulated in high VDR group. Thyroid cancer-related pathways were enriched in high VDR group in pathway analyses. VDR mRNA overexpression was correlated with worse prognostic factors such as subtypes of papillary thyroid carcinoma that are known to be worse prognosis, lateral neck node metastasis, advanced stage and recurrence-free survival.