Publications by authors named "Matthew D Ringel"

120 Publications

Facilitators and Barriers to Nursing Implementation of Continuous Glucose Monitoring (CGM) in Critically Ill Patients With COVID-19.

Endocr Pract 2021 Apr 27;27(4):354-361. Epub 2021 Jan 27.

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Medical Center, Columbus, Ohio.

Objective: We describe our implementation of a continuous glucose monitoring (CGM) guideline to support intravenous insulin administration and reduce point of care (POC) glucose monitoring frequency in the coronavirus disease 2019 medical intensive care unit (MICU) and evaluate nurses' experience with implementation of CGM and hybrid POC + CGM protocol using the Promoting Action on Research in Health Services framework.

Methods: A multidisciplinary team created a guideline providing criteria for establishing initial sensor-meter agreement within each individual patient followed by hybrid use of CGM and POC. POC measures were obtained hourly during initial validation, then every 6 hours. We conducted a focus group among MICU nurses to evaluate initial implementation efforts with content areas focused on initial assessment of evidence, context, and facilitation to identify barriers and facilitators. The focus group was analyzed using a qualitative descriptive approach.

Results: The protocol was integrated through a rapid cycle review process and ultimately disseminated nationally. The Diabetes Consult Service performed device set-up and nurses received just-in-time training. The majority of barriers centered on contextual factors, including limitations of the physical environment, complex device set-up, hospital firewalls, need for training, and CGM documentation. Nurses' perceived device accuracy and utility were exceptionally high. Solutions were devised to maximize facilitation and sustainability for nurses while maintaining patient safety.

Conclusion: Outpatient CGM systems can be implemented in the MICU using a hybrid protocol implementation science approach. These efforts hold tremendous potential to reduce healthcare worker exposure while maintaining glucose control during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.eprac.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839794PMC
April 2021

Prevalence of cancer and the benign call rate of afirma gene classifier in F-Fluorodeoxyglucose positron emission tomography positive cytologically indeterminate thyroid nodules.

Cancer Med 2021 Feb 15;10(3):1084-1090. Epub 2021 Jan 15.

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Cancer Center, Columbus, Ohio, USA.

Background: F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) positive (PET+) cytologically indeterminate thyroid nodules (ITNs) have variable cancer risk in the literature. The benign call rate (BCR) of Afirma Gene Classifier (Gene Expression Classifier, GEC, or Genome Sequence Classifier, GSC) in (PET +) ITNs is unknown.

Methods: This is a retrospective study at our institution of all patients with (PET+) ITNs (Bethesda III/IV) from 1 January 2010 to 21 May 2019 who underwent Afirma testing and/or surgery or repeat FNA with benign cytology.

Results: Forty-five (PET+) ITNs were identified: 31 Afirma-tested (GEC = 20, GSC = 11) and 14 either underwent surgery (n = 13) or repeat FNA (Benign cytology) (n = 1) without Afirma. The prevalence of cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) including only resected nodules and ITN with repeat benign FNA (n = 33) was 36.4% (12/33). Excluding all Afirma "suspicious" non-resected ITNs and assuming all Afirma "benign" ITNs were truly benign, that prevalence was 28.6% (12/42). The BCR with GSC was 64% compared to 25% with GEC (p = 0.056). Combining GSC/GEC-tested ITNs, the BCR was higher in ITNs demonstrating low/very low-risk sonographic pattern by the American Thyroid Association (ATA) classification and ITNs scoring <4 by the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR-TI-RADS) than ITNs with higher sonographic pattern/score (p = 0.025).

Conclusions: The prevalence of cancer/NIFTP in (PET+) ITNs was 28.6-36.4% depending on the method of calculation. The BCR of Afirma GSC was 64%. Combining Afirma GEC/GSC-tested ITNs, BCR was higher in ITNs with a lower risk sonographic pattern.
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http://dx.doi.org/10.1002/cam4.3704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897903PMC
February 2021

Building on strength.

Authors:
Matthew D Ringel

Endocr Relat Cancer 2021 Jan;28(1):E1-E2

Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA.

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http://dx.doi.org/10.1530/ERC-20-0427DOI Listing
January 2021

Akt isoform-specific effects on thyroid cancer development and progression in a murine thyroid cancer model.

Sci Rep 2020 10 27;10(1):18316. Epub 2020 Oct 27.

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 506 Biomedical Research Tower, 560 West 12th Avenue, Columbus, OH, 43210, USA.

The Akt family is comprised of three unique homologous proteins with isoform-specific effects, but isoform-specific in vivo data are limited in follicular thyroid cancer (FTC), a PI3 kinase-driven tumor. Prior studies demonstrated that PI3K/Akt signaling is important in thyroid hormone receptor β knock-in (PV) mice that develop metastatic thyroid cancer that most closely resembles FTC. To determine the roles of Akt isoforms in this model we crossed Akt1, Akt2, and Akt3 mice with PV mice. Over 12 months, thyroid size was reduced for the Akt null crosses (p < 0.001). Thyroid cancer development and local invasion were delayed in only the PVPV-Akt1 knock out (KO) mice in association with increased apoptosis with no change in proliferation. Primary-cultured PVPV-Akt1KO thyrocytes uniquely displayed a reduced cell motility. In contrast, loss of any Akt isoform reduced lung metastasis while vascular invasion was reduced with Akt1 or 3 loss. Microarray of thyroid RNA displayed incomplete overlap between the Akt KO models. The most upregulated gene was the dendritic cell (DC) marker CD209a only in PVPV-Akt1KO thyroids. Immunohistochemistry demonstrated an increase in CD209a-expressing cells in the PVPV-Akt1KO thyroids. In summary, Akt isoforms exhibit common and differential functions that regulate local and metastatic progression in this model of thyroid cancer.
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http://dx.doi.org/10.1038/s41598-020-75529-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591514PMC
October 2020

New Horizons: Emerging Therapies and Targets in Thyroid Cancer.

Authors:
Matthew D Ringel

J Clin Endocrinol Metab 2021 Jan;106(1):e382-e388

Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio.

The treatment of patients with progressive metastatic follicular cell-derived and medullary thyroid cancers that do not respond to standard therapeutic modalities presents a therapeutic challenge. As a deeper understanding of the molecular drivers for these tumors has occurred and more potent and specific compounds are developed, the number of Food and Drug Administration (FDA)-approved treatments for thyroid cancer has expanded. In addition, with the advent of disease-agnostic target-directed FDA approvals an ever-broadening number of therapeutic options are available for clinicians and patients. However, to date, complete remissions are rare, the average durations of response are relatively modest, and toxicities are common. These factors accentuate the need for further understanding of the mechanisms of resistance that result in treatment failures, the development of biomarkers that can improve patient selection for treatment earlier in the disease process, and the continued need for new therapeutic strategies. In this article, recent approvals relevant to thyroid cancer will be discussed along with selected new potential avenues that might be exploited for future therapies.
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http://dx.doi.org/10.1210/clinem/dgaa687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765632PMC
January 2021

Progression and dormancy in metastatic thyroid cancer: concepts and clinical implications.

Endocrine 2020 10 11;70(1):24-35. Epub 2020 Aug 11.

Division of Endocrinology, Diabetes, and Metabolism, Arthur G. James Comprehensive Center, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.

Distant metastasis classically has been defined as a late-stage event in cancer progression. However, it has become clear that metastases also may occur early in the "lifetime" of a cancer and that they may remain stable at distant sites. This stability of metastatic cancer deposits has been termed "metastatic dormancy" or, as we term it, "metastatic progression dormancy" as the progression either may reflect growth of already existing metastases or new cancer spread. Biologically, dormancy is the presence of nongrowing, static metastatic cells that survive over time. Clinically, dormancy is defined by stability in tumor markers, imaging, and clinical course. Metastatic well-differentiated thyroid cancer offers an excellent tumor type to understand these processes for several reasons: (1) primary therapy often includes removal of the entire gland with ablation of residual normal tissue thereby removing one source for new metastases; (2) the presence of a sensitive biochemical and radiographic monitoring tests enabling monitoring of metastasis throughout the progression process; and (3) its tendency toward prolonged clinical dormancy that can last for years or decades be followed by progression. This latter factor provides opportunities to define therapeutic targets and/or markers of progression. In this review, we will discuss concepts of metastatic progression dormancy and the factors that drive both long-term stability and loss of dormancy with a focus on thyroid cancer.
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http://dx.doi.org/10.1007/s12020-020-02453-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530083PMC
October 2020

Features of Cytologically Indeterminate Molecularly Benign Nodules Treated With Surgery.

J Clin Endocrinol Metab 2020 11;105(11)

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University and Arthur G. James Cancer Center, Columbus, Ohio.

Background: Most cytologically indeterminate thyroid nodules (ITNs) with benign molecular testing are not surgically removed. The data on clinical outcomes of these nodules are limited.

Methods: We retrospectively analyzed all ITNs where molecular testing was performed either with the Afirma gene expression classifier or Afirma gene sequencing classifier between 2011 and 2018 at a single institution.

Results: Thirty-eight out of 289 molecularly benign ITNs were ultimately resected. The most common reason for surgery was compressive symptoms (39%). In multivariable modeling, patients aged <40 years, nodules ≥3 cm, presence of an Afirma suspicious nodule other than the index nodule, and compressive symptoms were associated with higher surgery rates with hazard ratios for surgery of 3.5 (P < 0.001), 3.2 (P < 0.001), 16.8 (P < 0.001), and 7.31 (P < 0.001), respectively. Of resected nodules, 5 were malignant. False-negative rate (FNR) was 1.7%, presuming all unresected nodules were truly benign and 13.2% restricting analysis to resected cases. The FNR was significantly higher in nodules with a high-risk sonographic appearance for cancer (American Thyroid Association high-risk classification and American College of Radiology Thyroid Imaging Reporting and Data Systems score of 5) compared with nodules with all other sonographic categories (11.8% vs 1.1%; P = 0.03 and 11.1% vs 1.1%; P = 0.02, respectively).

Conclusions: Younger age, larger nodule size, presence of an Afirma suspicious nodule other than the index nodule, and compressive symptoms were associated with a higher rate of surgery. The FNR of benign Afirma was significantly higher in nodules with high-risk sonographic features.
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http://dx.doi.org/10.1210/clinem/dgaa506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497819PMC
November 2020

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Nat Commun 2020 08 7;11(1):3981. Epub 2020 Aug 7.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
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http://dx.doi.org/10.1038/s41467-020-17718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414135PMC
August 2020

p21-Activated Kinases in Thyroid Cancer.

Endocrinology 2020 08;161(8)

Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and Cancer Biology Program, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio.

The family of p21-activated kinases (PAKs) are oncogenic proteins that regulate critical cellular functions. PAKs play central signaling roles in the integrin/CDC42/Rho, ERK/MAPK, PI3K/AKT, NF-κB, and Wnt/β-catenin pathways, functioning both as kinases and scaffolds to regulate cell motility, mitosis and proliferation, cytoskeletal rearrangement, and other cellular activities. PAKs have been implicated in both the development and progression of a wide range of cancers, including breast cancer, pancreatic melanoma, thyroid cancer, and others. Here we will discuss the current knowledge on the structure and biological functions of both group I and group II PAKs, as well as the roles that PAKs play in oncogenesis and progression, with a focus on thyroid cancer and emerging data regarding BRAF/PAK signaling.
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http://dx.doi.org/10.1210/endocr/bqaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417880PMC
August 2020

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The state of science in medullary thyroid carcinoma: current challenges and unmet needs.

Endocr Relat Cancer 2020 08;27(8):T27-T39

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston, TX, USA.

The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.
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http://dx.doi.org/10.1530/ERC-20-0110DOI Listing
August 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Cancer Res 2021 Feb 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Assessing thyroid cancer risk using polygenic risk scores.

Proc Natl Acad Sci U S A 2020 03 4;117(11):5997-6002. Epub 2020 Mar 4.

Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points ( ≤ 1.0 × 10). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.
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http://dx.doi.org/10.1073/pnas.1919976117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084156PMC
March 2020

Compensation, Productivity, and Other Demographics of Academic Divisions of Endocrinology, Diabetes, and Metabolism.

J Endocr Soc 2019 Aug 7;3(8):1485-1502. Epub 2019 Jun 7.

Division of Endocrinology, Diabetes, and Metabolism, University of Rochester Medical School, Rochester, New York.

The landscape for academic endocrinology divisions has continued to evolve rapidly;thus, finding reliable data that can be used as benchmarks has become more difficult. Resources are available for salary and relative value units, with the Association of American Medical Colleges, Medical Group Management Association, and Faculty Practice Solutions Center the most commonly used databases. However, details regarding how these data are collected and what they include are unclear. For example, does the income include bonus and/or incentive payments? How are work relative value units defined (individual rendering vs supervising advanced practitioners or fellows or residents)? How is a clinical full-time equivalent defined? In addition, other important data that would be relevant to running an academic division of endocrinology are not available from these, or any other resources, including support staff numbers and compensation or fellowship funding and training information. Therefore, an unmet need exists for reliable data that divisions can use to help shape their visions and goals. To address this demand, the Association of Endocrine Chiefs and Directors, in collaboration with the Endocrine Society, developed a detailed survey for members to address the financial, productivity, composition, and educational issues that they regularly face. Twenty academic institutions throughout the United States completed in the survey in 2018. In the present report, we have provided the results of the survey and some initial interpretations of the findings. Our hope is that the information presented will prove useful as academic endocrinology divisions continue to evolve.
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http://dx.doi.org/10.1210/js.2019-00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676069PMC
August 2019

Afirma Gene Sequencing Classifier Compared with Gene Expression Classifier in Indeterminate Thyroid Nodules.

Thyroid 2019 08 17;29(8):1115-1124. Epub 2019 Jul 17.

1Division of Endocrinology, Diabetes, and Metabolism; The Ohio State University and Arthur G. James Cancer Center, Columbus, Ohio.

The Afirma Gene Expression Classifier (GEC) has been used to further characterize cytologically indeterminate (cyto-I) thyroid nodules into either benign or suspicious categories. However, its relatively low positive predictive value (PPV) limited its use as a classifier for patients with suspicious results. The Afirma Gene Sequencing Classifier (GSC) was developed to improve PPV while maintaining a high negative predictive value (NPV), yet real-world assessment of its performance is lacking. We analyzed all patients who had cyto-I nodules and molecular testing with either GEC or GSC between 2011 and 2018 at a single academic medical center. Clinical information was obtained for 343 GEC-tested nodules and 164 GSC-tested nodules. The GSC had a statistically significant higher benign call rate (76.2% vs. 48.1%,  < 0.001), PPV (60.0% vs. 33.3%,  = 0.01), and specificity (94.3% vs. 61.4%,  < 0.001) than the GEC. Improvement was statistically significant in both Bethesda III and Bethesda IV nodules. In particular, the benign call rate of GSC was significantly higher in nodules with Hürthle cell changes (88.8% vs. 25.7%,  < 0.01). The rate of surgical intervention in the indeterminate nodule cohort has decreased by 66.4% since switching to the GSC; 52.5% of indeterminate nodules went to surgery while using the GEC compared with 17.6% with the GSC ( < 0.001). This reduction was statistically significant in nodules with Bethesda III diagnoses, demonstrating a 70.9% decrease (GEC 51.3% vs. GSC 14.9%,  < 0.001), and in nodules with Bethesda IV cytology, a 39.2% decrease was noted (GEC 54.8% vs. GSC 33.3%,  = 0.003). Data from a single academic tertiary center show an improved specificity and PPV while maintaining high sensitivity and NPV for GSC compared with GEC. A statistically significant increase in benign call rates was observed in GSC compared with GEC, likely indicating fewer false positive results. After implementation of GSC, surgical interventions have been reduced by 68%.
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http://dx.doi.org/10.1089/thy.2018.0733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141558PMC
August 2019

MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition.

Endocr Relat Cancer 2019 08;26(8):699-712

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA.

The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P < 0.0001) and reduced carcinoma formation (P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.
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http://dx.doi.org/10.1530/ERC-19-0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062234PMC
August 2019

Inhibiting BRAF Oncogene-Mediated Radioresistance Effectively Radiosensitizes BRAF-Mutant Thyroid Cancer Cells by Constraining DNA Double-Strand Break Repair.

Clin Cancer Res 2019 08 16;25(15):4749-4760. Epub 2019 May 16.

Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio.

Purpose: Activating BRAF mutations, most commonly BRAF, are a major oncogenic driver of many cancers. We explored whether BRAF promotes radiation resistance and whether selectively targeting BRAF with a BRAF inhibitor (vemurafenib, BRAFi) sensitizes BRAF thyroid cancer cells to radiotherapy.

Experimental Design: Immunoblotting, neutral comet, immunocytochemistry, functional reporter, and clonogenic assays were used to analyze the outcome and molecular characteristics following radiotherapy with or without BRAF or vemurafenib in thyroid cancer cells.

Results: BRAF thyroid cancer cell lines were associated with resistance to ionizing radiation (IR), and expression of BRAF into wild-type BRAF thyroid cancer cells led to IR resistance. BRAFi inhibited ERK signaling in BRAF mutants, but not BRAF wild-type thyroid cancer cell lines. BRAFi selectively radiosensitized and delayed resolution of IR-induced γH2AX nuclear foci in BRAF cells. Moreover, BRAFi impaired global DNA repair and altered the resolution of 53BP1 and RAD51 nuclear foci in BRAF cells following IR. BRAF mutants displayed enhanced nonhomologous end-joining (NHEJ) repair activity, which was abolished by BRAFi. Intriguingly, BRAF mutation led to upregulation of XLF, a component of NHEJ, which was prevented by BRAFi. Importantly, BRAFi in combination with radiotherapy resulted in marked and sustained tumor regression of BRAF thyroid tumor xenografts.

Conclusions: BRAF mutation promotes NHEJ activity leading to radioresistance and BRAFi selectively radiosensitizes BRAF thyroid cancer cells through inhibiting NHEJ. Our findings suggest that combining BRAFi and radiation may improve the therapeutic outcome of patients with BRAF-mutant thyroid cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677585PMC
August 2019

KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer.

J Natl Compr Canc Netw 2019 05;17(5):409-413

Division of Medical Oncology.

BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine-refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V-activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.
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http://dx.doi.org/10.6004/jnccn.2019.7292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673655PMC
May 2019

Long-Term Efficacy of Lymph Node Reoperation for Persistent Papillary Thyroid Cancer: 13-Year Follow-Up.

Ann Surg Oncol 2019 Jun 28;26(6):1737-1743. Epub 2019 Feb 28.

Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus, OH, USA.

Background: Current recommendations for persistent or recurrent locoregional papillary thyroid cancer (PTC) include consideration of surgical resection versus active surveillance. The purpose of this study is to determine long-term outcomes after surgical resection of recurrent or persistent metastatic PTC in cervical lymph nodes after failure of initial surgery and radioactive iodine therapy using newer validated clinical outcomes measures.

Methods: Outcomes of 70 patients who underwent cervical lymphadenectomy (n = 110) from 1999 to 2013 for recurrent or persistent locoregional PTC metastases were reviewed. Measures included biochemical remission (BCR) based on Tg levels, American Thyroid Association classifications for response to treatment [biochemical incomplete response (BIR), structural incomplete response (SIR), indeterminate response (IR), and excellent response (ER)], need for reoperation, surgical complications, disease progression, and death.

Results: The median follow-up was 13.1 years, with only two additional reoperations since 2010, one of which had no metastasis on pathology with the other developing anaplastic thyroid cancer in background PTC. ER was achieved in 31 (44%) patients, all of whom remained in ER at time of last follow-up (median 14.1 years). There were no structural recurrences in patients with persistent BIR or IR after reoperation. Patients with SIR had stable disease, except for one who died due to anaplastic thyroid cancer.

Conclusions: Patients who achieved ER after reoperation had no need for further treatment. Patients with persistent detectable Tg levels after reoperation rarely developed structural recurrence. ATA outcomes can be safely used to guide treatment decisions over a decade after reoperation for PTC.
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http://dx.doi.org/10.1245/s10434-019-07263-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511284PMC
June 2019

NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018.

J Natl Compr Canc Netw 2018 12;16(12):1429-1440

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for V600E-mutated anaplastic thyroid carcinoma.
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http://dx.doi.org/10.6004/jnccn.2018.0089DOI Listing
December 2018

Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study.

JAMA Oncol 2019 02;5(2):204-212

Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery.

Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules.

Design, Setting, And Participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules.

Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3).

Main Outcomes And Measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules.

Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%.

Conclusions And Relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.
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http://dx.doi.org/10.1001/jamaoncol.2018.4616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439562PMC
February 2019

Transcriptional targeting of oncogene addiction in medullary thyroid cancer.

JCI Insight 2018 08 23;3(16). Epub 2018 Aug 23.

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA.

Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.
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http://dx.doi.org/10.1172/jci.insight.122225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141185PMC
August 2018

Neck Ultrasound in Patients with Follicular Thyroid Carcinoma.

Horm Cancer 2018 12 7;9(6):433-439. Epub 2018 Aug 7.

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Cancer Center, 5th Floor McCampbell Hall, 1581 Dodd Drive, Columbus, OH, 43210, USA.

There are limited data on the role of neck ultrasound (US) in the surveillance of patients with follicular thyroid cancer (FTC). Here, we analyze the likelihood of US to find structural disease in patients with FTC and evaluate if initial American Thyroid Association (ATA) risk stratification and the response to therapy categories [the latter based on thyroglobulin (Tg) levels] modify that likelihood. We conducted a retrospective cohort study of 32 patients with FTC in our institution. We included all patients with well-differentiated FTC who underwent total thyroidectomy and radioactive iodine (RAI) treatment without neck structural disease at the time of RAI and with Tg and US at least 6 months after RAI. After a median follow-up of 4.3 years, two patients (6.3%) had structural disease by US. None of the 18 patients with initial ATA low-risk disease had structural disease by US in contrast to higher, but not significant, frequency of 18.2% (2/11) in patients with initial ATA high-risk disease (p = 0.14). Based on Tg levels, 24/32 patients had excellent response to therapy and 8/32 had biochemical incomplete/indeterminate response. None of the patients with excellent response had structural disease by US versus 2/8 (25%) patients with biochemical incomplete/indeterminate response all of whom had other sites of structural disease (p = 0.054). Our findings suggest that neck US in FTC is unlikely to find structural disease with initial low-risk ATA or excellent response to therapy but can detect structural disease in some patients with initial ATA high-risk or incomplete/indeterminate responses to therapy.
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http://dx.doi.org/10.1007/s12672-018-0345-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336495PMC
December 2018

Selected Radiation Safety Aspects Including Transportation and Lodging After Outpatient I Therapy for Differentiated Thyroid Cancer.

Thyroid 2017 12;27(12):1558-1565

1 MedStar Health Research Institute , Washington, DC.

Background: Whether radioactive iodine (I) treatments for differentiated thyroid cancer should be performed as an outpatient or inpatient remains controversial. The objective of this study was to survey selected aspects of radiation safety of patients treated with I for differentiated thyroid cancer as an outpatient.

Methods: An e-mail invitation was sent to over 15,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc. to complete a web-based survey on selected aspects of radiation safety regarding their last outpatient I treatment.

Results: A total of 1549 patients completed the survey. Forty-five percent (699/1541) of the respondents reported no discussion on the choice of an inpatient or outpatient treatment. Moreover, 5% (79/1541) of the respondents reported that their insurance company made the decision. Survey respondents recalled receiving oral and written radiation safety instructions 97% (1459/1504) and 93% (1351/1447) of the time, respectively. Nuclear medicine physicians delivered oral and written instructions to 54% (807/1504) and 41% (602/1462) of the respondents, respectively. Eighty-eight percent (1208/1370) of the respondents were discharged within 1 hour after receiving their I treatment, and 97% (1334/1373) traveled in their own car after being released from the treating facility. Immediately post-therapy, 94% (1398/1488) of the respondents stayed at their own home or a relative's home, while 5% (76/1488) resided in a public lodging. The specific recommendations received by patients about radiation precautions varied widely among the respondents. Ninety-nine percent (1451/1467) of the respondents believed they were compliant with the instructions.

Conclusion: This is the largest, patient-based survey published regarding selected radiation safety aspects of outpatient I treatment. This survey suggests several concerns about radiation safety, such as the decision process regarding inpatient versus outpatient treatment, instructions about radiation safety, transportation, and lodging after radioiodine therapy. These concerns warrant further discussion, guidelines, and/or policies.
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http://dx.doi.org/10.1089/thy.2017.0124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003059PMC
December 2017

Reduced Retinoblastoma Protein Expression Is Associated with Decreased Patient Survival in Medullary Thyroid Cancer.

Thyroid 2017 12;27(12):1523-1533

1 Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center , Columbus, Ohio.

Background: The retinoblastoma (RB) transcriptional corepressor 1 protein functions to slow cell-cycle progression. Inactivation of RB by reduced expression and/or hyperphosphorylation allow for enhanced progression through the cell cycle. Murine models develop medullary thyroid carcinoma (MTC) after generalized loss of RB. However, RB expression in MTC has only been evaluated in a small number of tumors, with differing results. The objective of this study was to determine whether reduced expression of RB and/or overexpression of hyperphosphorylated RB predict MTC aggressive behavior.

Methods: Formalin-fixed, paraffin-embedded primary thyroid tumors and lymph node metastases from MTC patients were evaluated for calcitonin, RB, and phosphorylated RB (pRB) expression by immunohistochemistry. Two expert pathologists evaluated the slides in a blinded manner, and the immunohistochemistry results were compared to disease-specific survival as a primary endpoint.

Results: Seventy-four MTC samples from 56 patients were analyzed in this study, including 51 primary tumors and 23 lymph node metastases. The median follow-up time was 6.75 years after surgery (range 0.64-24.30 years), and the median primary tumor size was 30 mm (range 6-96 mm). Sixty-six percent of cases were classified as stage IV. RB nuclear expression was diffusely present in 88% of primary tumors and 78% of lymph node metastases. Nuclear pRB expression was present in 22% of primary tumors and 22% of lymph node metastases. On univariate analysis, reduced RB (<75% tumor cell staining) trended with lower MTC-specific survival for primary tumor and metastatic nodes (primary tumor hazard ratio = 3.54 [confidence interval 0.81-15.47], p = 0.08; and lymph node hazard ratio = 4.35 [confidence interval 0.87-21.83], p = 0.05). For primary tumors, multivariable analysis showed that low nuclear RB expression was independently associated with worse disease-specific (p = 0.01) and overall (p = 0.02) survival. pRB levels were not associated with survival for either primary tumor or lymph node metastases.

Conclusions: Reduced RB expression is associated with decreased patient survival in univariate and multivariable analyses, independent from patient age at surgery or advanced TNM stage. Future studies involving larger MTC patient populations are warranted to determine if lower RB expression levels may serve as a biomarker for aggressive disease in patients with MTC.
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http://dx.doi.org/10.1089/thy.2017.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734142PMC
December 2017

United States and European Multicenter Prospective Study for the Analytical Performance and Clinical Validation of a Novel Sensitive Fully Automated Immunoassay for Calcitonin.

Clin Chem 2017 Sep 7;63(9):1489-1496. Epub 2017 Jul 7.

Institute for Clinical Chemistry, Leipzig University, Germany.

Background: The objective of this study is the validation and proof of clinical relevance of a novel electrochemiluminescence immunoassay (ECLIA) for the determination of serum calcitonin (CT) in patients with medullary thyroid carcinoma (MTC) and in different diseases of the thyroid and of calcium homeostasis.

Methods: This was a multicenter prospective study on basal serum CT concentrations performed in 9 US and European referral institutions. In addition, stimulated CT concentrations were measured in 50 healthy volunteers after intravenous calcium administration (2.5 mg/kg bodyweight).

Results: In total, 1929 patients and healthy controls were included. Limits of blank, detection, and quantification for the ECLIA were 0.3, 0.5, and 1 ng/L, respectively. Highest intra- and interassay coefficients of variation were 7.4% (CT concentration, 0.8 ng/L) and 7.0% (1.1 ng/L), respectively. Medians (interval) of serum CT concentrations in 783 healthy controls were 0.8 ng/L (<0.5-12.7) and 3 ng/L (<0.5-18) for females and males, respectively (97.5th percentile, 6.8 and 11.6 ng/L, respectively). Diagnostic sensitivity and specificity were 100%/97.1% and 96.2%/96.4%, for female/males, respectively. Patients (male/female) with primary hyperparathyroidism, renal failure, and neuroendocrine tumors showed CT concentrations >97.5th percentile in 33%/4.7%, 18.5%/10%, and 8.3%/12%, females/males, respectively. Peak serum CT concentrations were reached 2 min after calcium administration (161.7 and 111.8 ng/L in males and females, respectively; < 0.001).

Conclusions: Excellent analytical performance, low interindividual variability, and low impact of confounders for increased CT concentrations in non-MTC patients indicate that the investigated assay has appropriate clinical utility. Calcium-stimulated CT results suggest good test applicability owing to low interindividual variability.
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http://dx.doi.org/10.1373/clinchem.2016.270009DOI Listing
September 2017

Biological Evaluation of a Fluorescent-Imaging Agent for Medullary Thyroid Cancer in an Orthotopic Model.

J Clin Endocrinol Metab 2017 09;102(9):3268-3277

Department of Surgery, Ohio State University-Wexner Medical Center, Arthur G. James Comprehensive Cancer Center and Ohio State University, Columbus, Ohio 43210.

Context: The primary and definitive treatment of medullary thyroid cancer (MTC) is surgical resection. Recurrent or residual disease is typically a result of incomplete surgical removal.

Objective: Our objective is to develop a compound that assists in intraoperative visualization of cancer, which would have the potential to improve surgical cure rates and outcomes.

Results: We report the biological characterization of Compound-17, which is labeled with IRdye800, allowing fluorescent visualization of MTC mouse models. We found that the agent has high affinity for two human MTC cell lines (TT and MZ-CRC1) in vitro and in vivo. We further tested the affinity of the compound in a newly developed MTC orthotopic xenograft model and found that Compound-17 produces fluorescent signals within MTC-derived orthotopic xenografts in comparison with a sequence-jumbled control compound and surrounding normal tissues.

Conclusions: Compound-17 is a unique and effective molecule for MTC identification that may have therapeutic potential.
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http://dx.doi.org/10.1210/jc.2017-00573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587064PMC
September 2017

RCAN1-4 is a thyroid cancer growth and metastasis suppressor.

JCI Insight 2017 03 9;2(5):e90651. Epub 2017 Mar 9.

Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine.

Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells. Subcutaneous xenograft models demonstrated that RCAN1-4 knockdown promotes tumor growth. Intravenous metastasis models demonstrated that RCAN1-4 loss promotes tumor metastases to the lungs and their subsequent growth. Finally, stable induction of RCAN1-4 expression reduced thyroid cancer cell growth and invasion. Microarray analysis predicted that nuclear factor, erythroid 2-like 3 (NFE2L3) was a pivotal downstream effector of RCAN1-4. NFE2L3 overexpression was shown to be necessary for RCAN1-4-mediated enhanced growth and invasiveness and NEF2L3 overexpression independently increased cell invasion. In human samples, NFE2L3 was overexpressed in TCGA thyroid cancer samples versus normal tissues and NFE2L3 overexpression was demonstrated in distant metastasis samples from thyroid cancer patients. In conclusion, we provide the first evidence to our knowledge that RCAN1-4 is a growth and metastasis suppressor in vivo and that it functions in part through NFE2L3.
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http://dx.doi.org/10.1172/jci.insight.90651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333959PMC
March 2017

A genome-wide association study yields five novel thyroid cancer risk loci.

Nat Commun 2017 02 14;8:14517. Epub 2017 Feb 14.

deCODE genetics/AMGEN, 101 Reykjavik, Iceland.

The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P<3 × 10): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.
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http://dx.doi.org/10.1038/ncomms14517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316879PMC
February 2017

Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells.

Hum Mol Genet 2017 04;26(7):1365-1375

Genomic Medicine Institute.

Thyroid cancer is a major component cancer of Cowden syndrome (CS), a disorder typically associated with germline mutations in PTEN. Germline variants in succinate dehydrogenase genes (SDHx) co-occurring with PTEN germline mutations confer a 2-fold increased prevalence (OR 2.7) of thyroid cancer compared to PTEN-associated CS but 50% decreased prevalence (OR 0.54) of thyroid cancer compared to SDHx-associated CS. We have previously shown that CS-associated SDHD variants G12S and H50R induce PTEN oxidation and nuclear accumulation in thyroid cancer. Our current study shows that SDHD-G12S and -H50R variants cause down-regulation of autophagy, demonstrating a role for SDHD in autophagy-associated pathogenesis of differentiated thyroid cancer. These findings could explain the increased prevalence of thyroid cancer in CS patients with SDHx germline mutations compared to those with PTEN mutations alone. Importantly, we demonstrate the dependence of this process on functional wild-type PTEN with reversal of decreased autophagy after PTEN knockdown. The latter could explain the clinically observed decrease in thyroid cancer prevalence in patients with co-existent PTEN mutations and SDHx variants. We also show that SDHD-G12S/H50R promotes mono-ubiquitination of PTEN, causing its translocation into the nucleus, upregulation of AKT and consequent phosphorylation of FOXO3a. Furthermore, SDHD-G12S/H50R-mediated increase in acetylation of FOXO3a further enhances AKT-associated phosphorylation of FOXO3a. This combination of phosphorylation and acetylation of FOXO3a results in its nuclear export for degradation and consequent down-regulation of FOXO3a-target autophagy-related gene (ATG) expression. Overall, our study reveals a novel mechanism of crosstalk amongst SDHD, PTEN and autophagy pathways and their potential roles in thyroid carcinogenesis.
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http://dx.doi.org/10.1093/hmg/ddx037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390680PMC
April 2017

Germline compound heterozygous poly-glutamine deletion in USF3 may be involved in predisposition to heritable and sporadic epithelial thyroid carcinoma.

Hum Mol Genet 2017 01;26(2):243-257

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.

Cowden syndrome (CS) is an autosomal dominant disorder that predisposes to breast, thyroid, and other epithelial cancers. Differentiated thyroid carcinoma (DTC), as one of the major component cancers of CS, is the fastest rising incident cancer in the USA, and the most familial of all solid tumours. To identify additional candidate genes of CS and potentially DTC, we analysed a multi-generation CS-like family with papillary thyroid cancer (PTC), applying a combined linkage-based and whole-genome sequencing strategy and identified an in-frame germline compound heterozygous deletion, p.[Gln1478del];[Gln1476-Gln1478del] in USF3 (previously known as KIAA2018). Among 90 unrelated CS/CS-like individuals, 29% were found to have p.[Gln1478del];[Gln1476-Gln1478del]. Of 497 TCGA PTC individuals, 138 (27%) were found to carry this germline compound deletion, with somatically decreased tumour USF3 expression. We demonstrate an increased migration phenotype along with enhanced epithelial-to-mesenchymal transition (EMT) signature after USF3 knockdown or USF3 p.[Gln1478del];[Gln1476-Gln1478del] overexpression, which sensitizes cells to the endoplasmic reticulum (ER) stress. Loss of USF3 function induced cell necrosis-like features and impaired respiratory capacity while providing a glutamine-dependent cell survival advantage, strongly suggests a metabolic survival and migration-favouring microenvironment for carcinogenesis. Therefore, USF3 may be involved in the predisposition of thyroid cancer. Importantly, the results that glutamine-dependent survival and sensitivity to ER stress in USF3-deficient cells provide avenues for therapeutic and adjunct preventive interventions for both sporadic cancer as well as cancer predisposition syndromes with similar mechanisms.
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http://dx.doi.org/10.1093/hmg/ddw382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351935PMC
January 2017