Showing papers on "Papillary thyroid cancer published in 2018"
TL;DR: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases that found many novel genetic events previously not seen in thyroid cancer were found.
Abstract: Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer (ATC) and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.Experimental Design: The genetic profiles of 583 advanced differentiated and 196 ATCs generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed.Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared with other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated thyroid cancers and ATCs. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT, and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2, and JAK2, and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT, and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro Three genetically distinct types of ATCs are proposed.Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed. Clin Cancer Res; 24(13); 3059-68. ©2018 AACR.
286 citations
TL;DR: First-in-human testing of BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.
Abstract: The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.
273 citations
TL;DR: Although the authors fully support the de-escalation of aggressive treatment for low-risk thyroid cancers, NIFTP behaves as a low- risk thyroid cancer rather than a benign entity and ongoing surveillance is warranted.
Abstract: Renaming encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently suggested to prevent the overtreatment, cost and stigma associated with this low-risk entity. The purpose of this study is to document the incidence and further assess the clinical outcomes of reclassifying EFVPTC to NIFTP. We searched synoptic pathologic reports from a high-volume academic endocrine surgery hospital from 2004 to 2013. The standard of surgical pathology practice was based on complete submission of malignant thyroid nodules along with the nontumorous thyroid parenchyma. Rigid morphological criteria were used for the diagnosis of noninvasive EFVPTC, currently known as NIFTP. A retrospective chart review was conducted looking for evidence of malignant behavior. One hundred and two patients met the strict inclusion criteria of NIFTP. The incidence of NIFTP in our cohort was 2.1% of papillary thyroid cancer cases during the studied time period. Mean follow-up was 5.7 years (range 0–11). Five patients were identified with nodal metastasis and one patient with distant metastasis. Overall, six patients showed evidence of malignant behavior representing 6% of patients with NIFTP. Our study demonstrates that the incidence of NIFTP is significantly lower than previously thought. Furthermore, evidence of malignant behavior was seen in a significant number of NIFTP patients. Although the authors fully support the de-escalation of aggressive treatment for low-risk thyroid cancers, NIFTP behaves as a low-risk thyroid cancer rather than a benign entity and ongoing surveillance is warranted.
108 citations
TL;DR: The tumor-suppressive and oncogenic roles of various lncRNAs and their possible disease associations implicated in thyroid carcinogenesis are discussed extensively.
Abstract: Thyroid cancer continues to be the most common malignancy of endocrine glands. The incidence of thyroid cancer has risen significantly over the past 4 decades and has emerged as a major health issue. In recent years, significant progress has been achieved in our understanding of the molecular mechanisms of thyroid carcinogenesis, resulting in significant diagnostic, prognostic and therapeutic implications; yet, it has not reached a satisfactory level. Identifying novel molecular therapeutic targets and molecules for diagnosis and prognosis is expected to advance the overall management of this common malignancy. Long noncoding RNAs (lncRNAs) are implicated in the regulation of various key cellular genes involved in cell differentiation, proliferation, cell cycle, apoptosis, migration and invasion mainly through modulation of gene expression. Recent studies have established that lncRNAs are deregulated in thyroid cancer. In this review, we discuss extensively the tumor-suppressive (for example, LINC00271, MEG3, NAMA, PTCSC1/2/3, etc.) and oncogenic (for example, ANRIL, FAL1, H19, PVT1, etc.) roles of various lncRNAs and their possible disease associations implicated in thyroid carcinogenesis. We briefly summarize the strategies and mechanisms of lncRNA-targeting agents. We also describe the potential role of lncRNAs as prospective novel therapeutic targets, and diagnostic and prognostic markers in thyroid cancer.
108 citations
TL;DR: It is demonstrated that circRNA circZFR exerted oncogenic roles via regulating miR-1261/C8orf4 axis in PTC, which suggested circZ FR might be a potential therapeutic target.
87 citations
TL;DR: Sustained elevation of serum TSH levels during active surveillance is associated with PTMC progression, and maintaining a low-normal TSH range with levothyroxine treatment during active Surveillance of PTMC might be considered in future studies.
Abstract: Objective Thyroid-stimulating hormone (TSH) is a growth factor affecting initiation or progression of papillary thyroid cancer (PTC), which supports TSH suppressive therapy in patients with PTC. In patients with papillary thyroid microcarcinoma (PTMC) during active surveillance, however, the association between serum TSH level and growth of PTMC has not been demonstrated. Patients We analyzed 127 PTMCs in 126 patients under active surveillance with serial serum TSH measurement and ultrasonography. Design The patients were categorized into groups with the highest, middle, and lowest time-weighted average of TSH (TW-TSH). PTMC progression was defined as a volume increase of ≥50% compared with baseline. Kaplan-Meier survival analysis according to TW-TSH groups and Cox proportional hazard modeling was performed. We identified the cutoff point for TSH level by using maximally selected log-rank statistics. Results During a median follow-up of 26 months, PTMC progression was detected in 28 (19.8%) patients. Compared with the lowest TW-TSH group, the adjusted hazard ratio (HR) for PTMC progression in the highest TW-TSH group was significantly higher [HR 3.55; 95% confidence interval (CI), 1.22 to 10.28; P = 0.020], but that in the middle TW-TSH group was not (HR 1.52; 95% CI, 0.46 to 5.08; P = 0.489). The cutoff point for the serum TSH level for PTMC progression was 2.50 mU/L. Conclusions Sustained elevation of serum TSH levels during active surveillance is associated with PTMC progression. Maintaining a low-normal TSH range with levothyroxine treatment during active surveillance of PTMC might be considered in future studies.
81 citations
TL;DR: LncRNA NEAT1 suppression could inhibit PTC progression by upregulating miR‐129‐5p, which suppressed KLK7 expression either in vitro or vivo experiments, and their combination suppressed the progression of PTC.
Abstract: Considering the dilemma in papillary thyroid cancer treatment, this study intended to find solution in molecular respect. By probing into lncRNA-NEAT1/miR-129-5p/KLK7 interaction, this study would provide new targets for future treatment. Microarray analysis and R language package were applied to select possible lncRNA and miRNA. Luciferase reporter assay and RNA pull-down test were employed in the detection of target relationship between lncRNA and miRNA. Clone formation assay, flow cytometry analysis, wound healing assay, and transwell assay were, respectively, used to observe effects of lncRNA NEAT1/miR-129-5p/KLK7 to papillary thyroid cancer cells. Western blot and qRT-PCR were used to validate protein expressions and mRNA expressions in PTC tissues and cells. LncRNA NEAT1 was highly expressed in PTC tissues and cell lines and could deteriorate PTC by promoting proliferation, invasion, and migration accompanied by less apoptosis. Besides, miR-129-5p/lncRNA NEAT1 were found to negatively correlate with each other by direct target relationship and their combination suppressed the progression of PTC. KLK7, a highly expressed downstream protein in PTC tissues, could be directly regulated by miR-129-5p in a negative way. KLK7 accelerated the deterioration of PTC in vitro experiments which could be reversed by sh-lnc RNA NEAT1 and miR-129-5p mimics. In vivo experiments, silence of lncRNA NEAT1 restrain tumor growth in weight and volume. In conclusion, lncRNA NEAT1 suppression could inhibit PTC progression by upregulating miR-129-5p, which suppressed KLK7 expression either in vitro or vivo experiments.
70 citations
TL;DR: Preclinical results show that LAT1 inhibition is a novel therapeutic approach in the context of thyroid cancers, and more interestingly in untreatable thyroid cancers.
Abstract: The L-type amino acid transporter 1 (LAT1/SLC7A5) transports essential amino acids across the plasma membrane While LAT1 is overexpressed in a variety of human neoplasms, its expression and its role in thyroid cancer is currently unknown Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy for which no effective therapy exists The purpose of this study was to explore whether the inhibition of LAT1 in ATC would affect tumor growth both in vitro and in vivo LAT1 was pharmacologically blocked by JPH203 in human ATC and papillary thyroid cancer (PTC) cell lines The effects on proliferation and mTORC1 activity were addressed in vitro A genetically engineered mouse model of ATC was used to address the effect of blocking LAT1 on tumor growth in vivo SLC7A5 transcription was measured in patient-derived ATC samples to address the clinical relevance of the findings LAT1 block by JPH203 reduced proliferation and mTORC1 signaling in human thyroid cancer cell lines SLC7A5 transcription was upregulated in ATC tissues derived from a genetically engineered mouse model and in ATC samples recovered from patients JPH203 treatment induced thyroid tumor growth arrest in vivo in a fully immunocompetent mouse model of thyroid cancer Additionally, analysis of publicly available datasets of thyroid carcinomas revealed that high LAT1 expression is associated with potentially untreatable PTC presenting reduced NIS/SLC5A5 transcription and with ATC These preclinical results show that LAT1 inhibition is a novel therapeutic approach in the context of thyroid cancers, and more interestingly in untreatable thyroid cancers
70 citations
TL;DR: The analysis of the published CI5 data illustrates that the incidence of thyroid cancer increased between 1998–2002 and 2003–2007 in most populations worldwide, and rising rates continue in all regions of the world.
Abstract: Over the past several decades, there has been a reported increase in the incidence of thyroid cancer in many countries. We previously reported an increase in thyroid cancer incidence across continents between 1973 and 2002. Here, we provide an update on the international trends in thyroid cancer between 2003 and 2007. We examined thyroid cancer incidence data from the Cancer Incidence in Five Continents (CI5) database for the period between 1973 and 2007 from 24 populations in the Americas, Asia, Europe, Africa and Oceania, and report on the time trends as well as the distribution by histologic type and gender worldwide. The incidence of thyroid cancer increased during the period from 1998–2002 to 2003–2007 in the majority of populations examined, with the highest rates observed among women, most notably in Israel and the United States SEER registry, at over 14 per 100,000 people. This update suggests that incidence is rising in a similar fashion across all regions of the world. The histologic and gender distributions in the updated CI5 are consistent with the previous report. Our analysis of the published CI5 data illustrates that the incidence of thyroid cancer increased between 1998–2002 and 2003–2007 in most populations worldwide, and rising rates continue in all regions of the world.
63 citations
TL;DR: Many reoperations for papillary thyroid carcinoma are for management of persistent disease, which suggests strongly that improvements in the preoperative assessment and adequacy of initial operative therapy need to be made to improve the care of patients with thyroid cancer.
62 citations
TL;DR: TT + pCCND in clinically node-negative papillary thyroid cancer will detect occult lymph node metastasis in approximately half of patients, and the effect on rates of locoregional recurrence remains uncertain.
Abstract: Prophylactic central compartment neck dissection (pCCND) in addition to total thyroidectomy (TT) includes removal of central compartment lymph nodes in the absence of clinical involvement on preoperative and intraoperative evaluation. The data regarding the influence of pCCND on oncologic outcomes and surgical complication rates is mixed and, therefore, is the focus of this analysis. A systematic review of the literature on total thyroidectomy with prophylactic central compartment neck dissection (TT + pCCND) from January 1990 to October 2017 identified 221 abstracts of which 17 met inclusion criteria and were reviewed (1 randomized-control trial, 13 retrospective cohort studies, and 3 meta-analyses). TT + pCCND was found to detect occult lymph node metastasis in approximately 50% of patients who had no clinical evidence of lymph node metastasis on preoperative imaging. Permanent hypoparathyroidism occurs more frequently following TT + pCCND (TT = 1.55% vs. TT + pCCND = 3.45%), but the rates of permanent recurrent laryngeal nerve dysfunction are similar (TT = 0.89% vs. TT + pCCND = 0.96%). The locoregional recurrence rates across all 14 studies included in this analysis was 6.75% for TT alone and 4.55% for TT + pCCND. The rate of locoregional recurrence was significantly lower in patients who underwent pCCND in a few studies and one meta-analysis, but were not significantly different in the majority of studies. TT + pCCND in clinically node-negative papillary thyroid cancer will detect occult lymph node metastasis in approximately half of patients. This may change their postoperative management with regard to adjuvant radioiodine therapy. There is a higher risk of hypoparathyroidism with pCCND, and the effect on rates of locoregional recurrence remains uncertain.
TL;DR: In this updated meta-analysis, PTC patients with HT appeared to exhibit more favorable clinicopathologic characteristics and a better prognosis than those without HT.
Abstract: Background: Epidemiological studies have suggested an association between Hashimoto thyroiditis (HT) and papillary thyroid cancer (PTC) development. Other studies, however, have reported a protective role of HT against PTC progression. Through this up dated meta-analysis, we aimed to clarify the effects of HT on the progression of PTC.
Methods: We searched citation databases, including PubMed and Embase, for relevant studies from inception to September 2017. From these studies, we calculated the pooled odds ratios (ORs) of clinicopathologic features and the relative risk (RR) of PTC recur rence with 95% confidence intervals (CIs) using the Mantel-Haenszel method. Additionally, the Higgins I2 statistic was used to test for heterogeneity.
Results: The meta-analysis included 71 published studies with 44,034 participants, among whom 11,132 had HT. We observed neg ative associations between PTC with comorbid HT and extrathyroidal extension (OR, 0.74; 95% CI, 0.68 to 0.81), lymph node me tastasis (OR, 0.82; 95% CI, 0.72 to 0.94), distant metastasis (OR, 0.49; 95% CI, 0.32 to 0.76), and recurrence (RR, 0.50; 95% CI, 0.41 to 0.61).
Conclusion: In this meta-analysis, PTC patients with HT appeared to exhibit more favorable clinicopathologic characteristics and a better prognosis than those without HT.
TL;DR: Findings based on gene expression data illuminate the immune landscape of PTC and its association with TDS, immunosuppressive markers and recurrence, irrespective of clinicopathologic factors including BRAFV600E status.
Abstract: Although papillary thyroid cancer (PTC) is curable with excellent survival rate, patients with dedifferentiated PTC suffer the recurrence or death. As cancer immune escape plays a critical role in cancer progression, we aimed to investigate the relationship between differentiation and immune landscape of PTC and its implications for immunotherapy. Using The Cancer Genome Atlas data, we estimated the immune cell enrichment scores and overall immune infiltration, ImmuneScore, to characterize the immune landscape of PTC. Thyroid differentiation score (TDS) was calculated from 16 thyroid function genes. We demonstrated that ImmuneScore had a significant negative correlation with TDS, and BRAFV600E+ tumors showed significantly low TDS and high ImmuneScore. Enrichment scores of myeloid cells and B-cells were negatively correlated with TDS, while those of plasma cells were positively correlated with TDS. In addition, the association between TDS, ImmuneScore and immunosuppressive markers (CTLA-4, PD-L1, HLA-G) were evaluated according to BRAFV600E status. All immunosuppressive markers expression had a significant negative correlation with TDS, and they were significantly higher in BRAFV600E+ status. Subgroups were divided by median values of TDS and ImmuneScore, and immunosuppressive markers of these subgroups were compared. The immunosuppressive markers expression was the highest in high ImmuneScore and low TDS subgroup. Furthermore, ImmuneScore had a significant association with recurrence-free survival, irrespective of clinicopathologic factors including BRAFV600E status. These findings based on gene expression data illuminate the immune landscape of PTC and its association with TDS, immunosuppressive markers and recurrence. Our results would be extended to investigate immunotherapeutic approaches in PTC.
TL;DR: Findings suggest that recommended size thresholds to biopsy low-suspicion thyroid nodules can be increased, and that increasing tumor size does not affect survival until a threshold of 2.5 cm.
Abstract: Background: In many risk-stratification systems, the decision to biopsy thyroid nodules is determined by their sonographic features and size. Nevertheless, even low-suspicion nodules are often biop...
TL;DR: Two-thirds of distant metastases become refractory to radioiodine at some point, and when there is a significant tumor burden and documented progression on imaging, a treatment with a kinase inhibitor may provide benefits.
Abstract: Distant metastases from thyroid cancer of follicular origin are uncommon. Treatment includes levothyroxine administration, focal treatment modalities with surgery, external radiation therapy and thermal ablation, and radioiodine in patients with uptake of 131I in their metastases. Two-thirds of distant metastases become refractory to radioiodine at some point, and when there is a significant tumor burden and documented progression on imaging, a treatment with a kinase inhibitor may provide benefits.
TL;DR: In a European population of patients with DTC, the eighth edition of the AJCC/TNM staging system is a better predictor for both OS and DSS than the previous seventh edition, implying that this new edition is predicting well, regardless of DTC subtype.
Abstract: Background: Recently, the eighth edition of the American Joint Committee on Cancer (AJCC)/tumor node metastasis (TNM) staging system for differentiated thyroid cancer (DTC) was published. Studies e...
TL;DR: Serum Tg levels and the Tg/TSH ratio increased gradually after lobectomy in patients with and without recurrences, without any significant differences.
Abstract: Background: Low-risk patients with differentiated thyroid cancer can be treated with thyroid lobectomy. Serial measurements of serum thyroglobulin (Tg) are recommended for surveillance, but the cut...
TL;DR: It is reported that ERβ is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERβ decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth.
Abstract: Estrogen receptor β (ERβ) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERβ is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERβ decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERβ and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERβ expression. ERβ depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERβ is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERβ expression. Collectively, our findings reveal that ERβ-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.
TL;DR: An immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance.
Abstract: Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance.
TL;DR: The results suggest that TERT promoter mutation is an independent predictor of disease‐free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC.
Abstract: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Tumor recurrence occurs in ∼20% of PTCs and some reach advanced stages. Promoter mutation in the telomerase reverse transcriptase (TERT) gene is identified to be a prognostic marker in PTC. However, the contribution of TERT promoter mutation to cancer progression in PTC patients is still not fully understood. In this study, we investigated the incidence of TERT promoter mutations and TERT protein expression and their association with clinicopathological outcomes in a large cohort of PTC samples using direct sequencing technology and immunohistochemistry. Furthermore, two PTC cell lines were utilized to investigate role of TERT mutations in mediating metastasis. Two promoter hotspot mutations C228T and C250T were identified in 18.0% (167/927) of our cohort and were significantly associated with poor 5 years disease-free survival and distant metastasis of PTC. TERT protein overexpression was noted in 20.1% of our PTC cohort and was significantly associated with poor prognostic markers such as older age, extrathyroidal extension and Stage IV tumors. A significant association was also found between TERT overexpression and epithelial-mesenchymal transition (EMT) markers. Functional analysis showed that TERT inhibition reduced cell growth, invasion, migration and angiogenesis in PTC via suppression of EMT in PTC cells. Our results suggest that TERT promoter mutation is an independent predictor of disease-free survival and might drive the metastasis, and downregulation of TERT could potentiate antitumor and antimetastatic activities in PTC.
TL;DR: Tumor size, histologic subtype, and surgical therapy are important factors in papillary thyroid cancer survival, and total thyroidectomy was associated with improved survival in patients with 2.0‐3.9 cm conventional papillary Thyroid cancer, and should be considered for 2.3‐0.9‐cm tumors when preoperative molecular analysis is not used to distinguish conventional from follicular‐variant.
TL;DR: It is suggested that miR-222 promotes tumor invasion and metastasis in thyroid cancer by targeting PPP2R2A and could serve as a potential diagnostic biomarker, as well as an attractive therapeutic tool for thyroid cancer.
Abstract: Background: Increasing evidence indicates that microRNA dysfunction is involved in the pathogenesis and progression of cancer. MicroRNA-222 (miR-222) is upregulated in papillary thyroid carcinoma (...
Johns Hopkins University1, Qingdao University2, Johns Hopkins University School of Medicine3, University of Pisa4, University of Perugia5, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico6, Griffith University7, University of Padua8, University of Pittsburgh9, Carlos III Health Institute10, University of Sydney11
TL;DR: Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients, and the prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
Abstract: Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.
TL;DR: The results suggested that the HOXA-AS2/miR-520c-3p/S100A4 axis may play an important role in the regulation of PTC progression, which provides new insights into understanding the PTC.
Abstract: Background/aims Thyroid cancer is one of the most prevalent endocrine tumors. The present study examined the effects of lncRNA HOXA cluster antisense RNA2 (HOXA-AS2) on the progression of papillary thyroid cancer (PTC), and explored the underlying molecular mechanisms. Methods Quantitative real-time PCR was used to detect HOXA-AS2, miR-520c-3p and S100 calcium-binding protein A4 (S100A4) expression. Furthermore, the effects of HOXA-AS2 silencing and overexpression on cell proliferation, migration, and invasion were assessed in PTC in vitro by CCK8 and transwell assay. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in PTC. Results We observed that HOXA-AS2 was up-regulated in PTC tissues. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited cell growth in PTC in vitro and in vivo. Further functional assays indicated that HOXA-AS2 significantly promoted PTC cell migration and invasion by promoting EMT. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in PTC cells. MiR-520c-3p was down-regulated in PTC tissues, and S100A4 was predicted as a downstream target of miR-520c-3p, which was confirmed by luciferase reporter assay. Conclusion In summary, our results suggested that the HOXA-AS2/miR-520c-3p/S100A4 axis may play an important role in the regulation of PTC progression, which provides us with new insights into understanding the PTC.
TL;DR: Most data support that lobectomy and total thyroidectomy yield comparable oncologic outcomes for PTC measuring 1.0–4.0 cm, and the quality of the data limit the strength of the conclusions.
Abstract: The extent of surgery for low-risk papillary thyroid cancer (PTC) has been the subject of debate among experts for decades. In this paper, we aimed to systematically review whether thyroid lobectomy versus total thyroidectomy for PTC patients with tumors measuring 1.0–4.0 cm impacts tumor recurrence and survival. A systematic review of the literature from January 1990 to February 2018 yielded 13 relevant studies, including eight national cancer registry database studies, one multi-institutional thyroid cancer-specific database, three large-scale institutional series, and one meta-analysis. Data from these studies demonstrate that total thyroidectomy for the treatment of PTC measuring 1.0–4.0 cm does not confer a clinically significant improvement in disease-specific survival compared with thyroid lobectomy. Four of six studies also reported that total thyroidectomy is associated with a small but statistically significant improvement in disease-free survival, although it is argued whether this difference is clinically significant. While the quality of the data limit the strength of our conclusions, and while tumor characteristics, patient risk factors, and preferences should be considered, most data support that lobectomy and total thyroidectomy yield comparable oncologic outcomes for PTC measuring 1.0–4.0 cm.
TL;DR: Overall, autommune thyroiditis seems to contribute to the favorable prognosis of papillary thyroid microcarcinoma, and three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC.
Abstract: Although the incidence of some malignancy has decreased over the recent years, this is not the case of papillary thyroid microcarcinoma (PTMC), whose incidence has increased worldwide. Most PTMC are found incidentally after histological examination of specimens from surgery for benign thyroid disease. Hashimoto’s thyroiditis, whose incidence has also increased, coexists in about one in three PTMC patients. Three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC, namely tumor development/growth by: (i) TSH stimulation, (ii) expression of certain proto-oncogenes, (iii) chemokines and other molecules produced by the lymphocytic infiltrate. Whether Hashimoto’s thyroiditis protects against lymph node metastasis is debated. Overall, autommune thyroiditis seems to contribute to the favorable prognosis of PTMC. Major limitations of the studies so far performed include: (i) retrospective design, (ii) limited statistical power, (iii) high risk of selection bias, (iv) and predominant Asian ethnicity of patients. Full genetic profiling of both diseases and identification of environmental factors capable to trigger them, as well as well-powered prospective studies on different ethnical groups, may help understand their causal association and why their frequencies are continuing raising.
TL;DR: It is demonstrated that ZNF677 is frequently downregulated by promoter methylation in primary papillary thyroid cancers (PTC) and show that decreased expression of Z NF677 is significantly associated with poor patient survival.
Abstract: The zinc finger protein 677 (ZNF677) belongs to the zinc finger protein family, which possesses transcription factor activity by binding sequence-specific DNA. Previous studies have reported its downregulated by promoter methylation in non-small cell lung cancer. However, its biological role and exact mechanism in human cancers, including thyroid cancer, remain unknown. In this study, we demonstrate that ZNF677 is frequently downregulated by promoter methylation in primary papillary thyroid cancers (PTC) and show that decreased expression of ZNF677 is significantly associated with poor patient survival. Ectopic expression of ZNF677 in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice and induced cell-cycle arrest and apoptosis. Conversely, knockdown of ZNF677 promoted thyroid cancer cell proliferation and colony formation. ZNF677 exerted its tumor suppressor functions in thyroid cancer cells through transcriptional repression of two targets CDKN3 and HSPB1 (or HSP27), thereby inhibiting phosphorylation and activation of Akt via distinct mechanisms. Taken together, our data show that ZNF677 functions as a tumor suppressor and is frequently silenced via promoter methylation in thyroid cancer.Significance: These findings report a tumor suppressive role of the zinc-finger protein ZNF677 in primary papillary thyroid cancer through inhibition of Akt phosphorylation. Cancer Res; 78(18); 5216-28. ©2018 AACR.
TL;DR: In this narrative review, the available evidence for the management of low-risk PTC is summarized including active surveillance and minimally invasive interventions.
Abstract: The incidence of thyroid cancer has increased, mainly due to the incidental finding of low-risk papillary thyroid cancers (PTC). These malignancies grow slowly, and are unlikely to cause morbidity and mortality. New understanding about the prognosis of tumor features has led to reclassification of many tumors within the low-risk thyroid category, and to the development of a new one "very low-risk tumors." Alternative less aggressive approaches to therapy are now available including active surveillance and minimally invasive interventions. In this narrative review, we have summarized the available evidence for the management of low-risk PTC.
TL;DR: KMT5A may be a novel oncogenic factor, specifically a regulator for lipid metabolism in papillary thyroid carcinoma, and suppressed the expression of SREBP1, SCD, FASN and ACC, key molecules involved in lipid metabolism and decreased the level of malondialdehyde in Papillary thyroid cancer cells.
Abstract: KMT5A (known as PR-Set7/9, SETD8 and SET8), a member of the SET domain containing methyltransferase family specifically targeting H4K20 for methylation, has been implicated in multiple biological processes. In the present study, we identified that KMT5A was elevated in 50 pairs of papillary thyroid cancer tissue samples and in cell lines K1 and TPC-1 by qRT-PCR and western blotting, as well as by immunohistochemical staining. CCK-8 assay and flow cytometric analysis revealed that inhibition of KMT5A attenuated proliferation and induced apoptosis. Transwell assays revealed that cell migration and invasion were suppressed in KMT5A-knockdown cells. Moreover, the inhibition of KMT5A arrested the cell cycle in the G1/S phase of papillary thyroid cancer cells. The TCGA data revealed that elevated KMT5A expression was significantly correlated with extrathyroidal extension, lymph node metastasis and advanced pathological stage of papillary thyroid cancer. Furthermore, we observed that inhibition of KMT5A suppressed the expression of SREBP1, SCD, FASN and ACC, key molecules involved in lipid metabolism and decreased the level of malondialdehyde in papillary thyroid cancer cells. In conclusion, KMT5A may be a novel oncogenic factor, specifically a regulator for lipid metabolism in papillary thyroid carcinoma.
TL;DR: In the PTC cohort, the impact of tumor size on RFS was limited to patients aged ≥55 years and a single size threshold of 2 cm maximized prognostic discrimination with tumors >2”cm associated with a five times higher risk of recurrence than those ≤2’cm.
Abstract: Background: Although the importance of tumor size in papillary thyroid cancer (PTC) is well established, there is no research investigating whether age modifies the impact of tumor size, and there ...