Characterization Of Papillary Thyroid Carcinoma Research Articles

Genomic characterization of papillary thyroid carcinoma in Chinese Shandong population.

e18085 Background: With the emergence of mutation-based diagnosis and therapies for patients with papillary thyroid carcinoma (PTC), molecular profiling has become an important component of care. Although next-generation sequencing (NGS) gene panels are accessible to clinicians, the key genetic alterations of PTC in Chinese Shandong population were rarely descripted. Methods: A total of 127 papillary thyroid carcinoma patients were enrolled in this cohort, including 49 (38.6%) males and 78 (61.4%) females from January 2020 to May 2022. The median age were all 48 years. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were all collected and analyzed from these patients. Somatic and germline mutations were identified including 38 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA), gene fusions and rearrangements. Results: A total of 117 out of 127 papillary thyroid carcinoma were NGS-positive (92.1%), with a high prevalence of BRAF V600E mutations (52.0%, 66/127) and MLH1 mutations (23.6%, 30/127), and a low prevalence of RAS mutations (10.2%, 13/127)， ROS1 (9.4%, 12/127). Overall, 257 somatic mutations including 249 SNVs (6 splicing, 4 stopgain, 4 frameshift，and 235 nonsynonymous), 3 fusions, 3 deletions, and 1 insertions in 38 genes were identified in the PTC samples. Gene fusions, involving the RET and NTRK1 genes, were identified in three PTCs (2.4%), including NTRK1-TPM3, NTRK1-SQSTM1 and CCDC6-RET. And the three fusions patients were all BRAF V600E-negative cases. Furthermore, in our cohort, BRAF V600E mutation carriers also owned other actionable, the most frequent one was MLH1 (34.8%), followed by RET (15.2%), ROS1 (10.6%), and ATM (10.6%). We also found that three PTC patients carried germline variants of uncertain significance, including ATM (p.L857P), MET (p.L211W) and RET (p.C515R), which are heterozygous mutations. Conclusions: We described the distinct molecular profile in the Chinese Shandong population with PTC. Most patients had at least one potentially actionable mutation, predominantly driven by BRAF V600E and MLH1 alterations. These findings may help in moving toward the more comprehensive and effective personalized treatment of papillary thyroid carcinoma in Chinese.

SAT-LB25 A Multi-Omics Analysis of Advanced Papillary Thyroid Cancer

Molecular profiling of papillary thyroid carcinoma has largely been confined to exome sequencing of non-aggressive cancer.1,2 Canonical mutations in BRAF and RAS are significantly represented in thyroid tumors, but these mutations have not resulted in diagnostics and therapeutics for advanced disease. To broadly examine the molecular landscape of advanced disease, we conducted a multi-omic analysis of 34 cases of advanced papillary thyroid carcinoma, including patient-matched lymph node metastases, primary tumor, adjacent-normal thyroid and germline. Our genome-wide multi-omic analysis links the regions of activated chromatin with expressed transcripts and proteins, identifying regulatory elements at primary tumor and nodal metastases stages of thyroid cancer progression. Distal regulatory elements putatively upregulate expression of MAPK-pathway genes in both tumors and metastases (36 genes (p =0.0057) in tumors and 76 genes (p =0.0011) in metastases). Furthermore, tumors and metastases harbor accessible chromatin regions that appear to be bound by MAPK transcription factors, FOS and JUN (p-value <10-150 for tumors and metastases). This study identifies regulatory elements that mediate MAPK activity in tumors and metastases of advanced papillary thyroid carcinoma and may ultimately lead to diagnostics and therapeutics that utilize advanced-thyroid-cancer-specific epigenetic targets. References• Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014• Masoodi T, et al. Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer. Thyroid. 2020

In vivo Raman spectroscopic characterization of papillary thyroid carcinoma

The increasing incidence of lesions in the thyroid gland requires great attention due to the difficulty of diagnosis in some cases, which often leads to inadequate treatments. The diagnosis is commonly based on clinical perceptions and ultrasonography-guided fine needle aspiration (FNAB), often presenting inconclusive results which may indicate surgery as the main treatment for these cases. Therefore, the need to biochemically characterize the thyroid gland during surgery is extremely important. In this context, Raman spectroscopy is considered as a potential technique for the characterization of structures and identification of neoplasms. This study aimed at structuring and implementing a Raman system for the differentiation between normal and altered tissues in the thyroid gland in vivo. We used a HOLOSPEC f/1.8i system coupled to a laser of 785 nm wavelength and 70 mW power as an excitation source, and a 100 μm optical fiber. The spectra were collected during the surgical procedure under the supervision of the responsible physician, from 8 patients who were diagnosed with papillary thyroid cancer (PTC). Spectral analysis revealed several peaks characteristic of cancer, such as 834, 947, 1255, 1451 and 1601 cm−1. A high similarity was observed between ex vivo and in vivo spectra of papillary carcinomas, confirming the efficacy of the technique in the biochemical identification of the analyzed tissue. In this first phase of study, besides observing that in vivo PTC spectra are compatible with ex vivo PTC obtained in previous studies, it was possible to establish a calibration protocol for the in vivo analysis process. In this way, we conclude that the use of Raman spectroscopy in vivo can aid in the diagnosis of thyroid pathologies, as well as assist the physician during surgical procedures.

Molecular characterization of papillary thyroid carcinoma: a potential three-lncRNA prognostic signature.

PurposePapillary thyroid carcinoma (PTC), the most frequent type of malignant thyroid tumor, lacks novel and reliable biomarkers of patients’ prognosis. In the current study, we mined The Cancer Genome Atlas (TCGA) to develop lncRNA signature of PTC.Patients and methodsThe intersection of PTC lncRNAs was obtained from the TCGA database using integrative computational method. By the univariate and multivariate Cox analysis, key lncRNAs were identified to construct the prognostic model. Then, all patients were divided into the high-risk group and low-risk group to perform the Kaplan–Meier (K–M) survival curves and time-dependent receiver operating characteristic (ROC) curve, estimating the prognostic power of the prognostic model. Functional enrichment analysis was also performed. Finally, we verified the results of the TCGA analysis by the Gene Expression Omnibus (GEO) databases and quantitative real-time PCR (qRT-PCR).ResultsAfter the comprehensive analysis, a three-lncRNA signature (PRSS3P2, KRTAP5-AS1 and PWAR5) was obtained. Interestingly, patients with low-risk scores tended to gain obviously longer survival time, and the area under the time-dependent ROC curve was 0.739. Furthermore, gene ontology (GO) and pathway analysis revealed the tumorigenic and prognostic function of the three lncRNAs. We also found three potential transcription factors to help understand the mechanisms of the PTC-specific lncRNAs. Finally, the GEO databases and qRT-PCR validation were consistent with our TCGA bioinformatics results.ConclusionWe built a three-lncRNA signature by mining the TCGA database, which could effectively predict the prognosis of PTC.

Abstract LB-182: Notch signaling pathway is transcriptionally elevated in anaplastic thyroid cancer

Abstract Anaplastic thyroid cancer (ATC), contrary to well-differentiated papillary thyroid cancer (PTC), is one of the most aggressive human malignancies. Anaplastic thyroid cancer is responsible for more than half of all thyroid cancer deaths, with an overall mortality rate about 70% at 6 months and 81% at 12 months, despite only accounting for &amp;lt;2% of thyroid cancer incidence [1]. Both PTC and ATC are MAPK-driven cancers that have two mutually exclusive drivers with distinct signaling consequences: BRAF V600E mutation and RAS mutation [2-3]. In PTC, BRAF (V600E)-like tumors showed higher MAPK transcriptional output and lower expression of genes related with iodine metabolism, and RAS-like tumors showed lower MAPK signaling and comparatively higher expression of iodine metabolism genes. However, in ATC both BRAF mutant and RAS mutant tumors showed BRAF-like tumor transcriptional output. Down-regulation of Notch signaling by gamma-secretase inhibitor (GSI) or Notch1 RNAi reduced PTC cell proliferation [3]. Here by combining multiple gene expression microarray studies (TCGA, GSE27155, GSE29265 and GSE33630), we showed that compared with normal thyroid tissue the Notch signaling pathway was up-regulated in both PTC and ATC. However, ATC and PTC showed different activation patterns in terms of expression of Notch receptors, ligands and downstream targets. Compared with normal thyroid tissue, Notch1, Notch3 and JAG1 were up-regulated in both ATC and PTC, but were much higher in ATC. Compared with normal thyroid tissue, HEY1, HES4 and NRARP were up-regulated in both ATC and PTC. Comparing with PTC, HEY1 was also higher in ATC. However, HES1 was down-regulated in ATC but up-regulated in PTC. It was also reported that both Notch1 and Hes1 were up-regulated by activation of MAPK signaling in thyroid follicular cells with RET/PTC3 or BRAF (T1799A) [4]. Notch1 protein level was also higher in PTC [3]. All of the evidence above supports the hypothesis that Notch pathway may be a key signaling component along with aberrant activation of MAPK pathway in ATC. These data suggest inhibition of Notch signaling alone and/or combination with MAPK signaling inhibitors, such as BRAF inhibitor or ERK inhibitor, may be of benefit in ATC, and support investigation in a clinical trial. 1. Anaplastic Thyroid Carcinoma: Treatment Outcome and Prognostic Factors. Cancer 103 1330-1335,2015. 2. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell 159, 676-690, 2014. 3. Notch Pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Translational oncology, 6,197-205, 2013. 4. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. JCI, 126, 1052-1066, 2016. Citation Format: Yan Ding, Hui-Rong Qian, Bharvin K R Patel, Gerald Joseph Oakley, Karim A. Benhadji, Emma Bowden, Amit Aggarwal. Notch signaling pathway is transcriptionally elevated in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-182.

Intrinsic LINE-1 Hypomethylation and Decreased Brca1 Expression are Associated with DNA Repair Delay in Irradiated Thyroid Cells.

Exposure to ionizing radiation greatly increases the risk of developing papillary thyroid carcinoma (PTC), especially during childhood, mainly due to gradual inactivation of DNA repair genes and DNA damages. Recent molecular characterization of PTC revealed DNA methylation deregulation of several promoters of DNA repair genes. Thus, epigenetic silencing might be a plausible mechanism for the activity loss of tumor suppressor genes in radiation-induced thyroid tumors. Herein, we investigated the impact of ionizing radiation on global methylation and CpG islands within promoter regions of homologous recombination (HR) and non-homologous end joining (NHEJ) genes, as well as its effects on gene expression, using two well-established normal differentiated thyroid cell lines (FRTL5 and PCCL3). Our data reveal that X-ray exposure promoted G2/M arrest in normal thyroid cell lines. The FRTL5 cells displayed a slower kinetics of double-strand breaks (DSB) repair and a lower long interspersed nuclear element-1 (LINE-1) methylation than the PCCL3 cells. Nevertheless, acute X-ray exposure does not alter the expression of genes involved in HR and NHEJ pathways, apart from the downregulation of Brca1 in thyroid cells. On the other hand, HR and NHEJ gene expressions were upregulated in radiation-induced senescent thyroid cells. Taken together, these data suggest that FRTL5 cells intrinsically have less efficient DNA DSB repair machinery than PCCL3 cells, as well as genomic instability, which could predispose the FRTL5 cells to unrepaired DSB lesions and, therefore, gene mutations.

Follicular cell thyroid neoplasia: insights from genomics and The Cancer Genome Atlas research network.

The present review is focused on the recently published study on the genomics of papillary thyroid carcinoma performed by The Cancer Genome Atlas Research Network and its implications for the follicular variant of papillary carcinoma. The Cancer Genome Atlas study of papillary thyroid carcinoma comprehensively examined the cancer genome of nearly 500 primary tumors. Using a highly integrated bioinformatic analysis, papillary carcinoma was shown at the genomic level to consist of two highly distinct classes that reflected both tumor histology and underlying genotype. Tumors with true papillary architecture were dominated by BRAF(V600E) mutations and RET kinase fusions and were designated as BRAF(V600E)-like. Tumors with follicular architecture were conversely dominated by RAS mutations and were designated as RAS-like. Given the strong genotype:phenotype correlation known to be present in thyroid cancer, the separation of BRAF(V600E)-like and RAS-like tumors has profound implications for its classification, especially the follicular variant of papillary carcinoma. The recent genomic characterization of papillary thyroid carcinoma is challenging the established pathological classification of thyroid cancer with significance for the care of patients.

TCGA genomic characterization of papillary thyroid carcinoma

TCGA genomic characterization of papillary thyroid carcinoma

Integrated Genomic Characterization of Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups ofBRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

Integrated Genomic Characterization of Papillary Thyroid Carcinoma

Integrated Genomic Characterization of Papillary Thyroid Carcinoma

Histological characterization of papillary thyroid carcinoma in children, adolescents and young adults in Russia after the Chernobyl accident

The purpose of the study was to analyze the histological features of post-Chernobyl papillary thyroid carcinoma (PTC) that occurred in children, adolescents and young adults living in radionuclide-contaminated territories of the Russian Federation. We reviewed the histological sections of thyroid carcinoma in 123 patients (39 males and 84 females) aged 0–16 years at the time of accident from Bryansk, Kaluga, Oriol and Tula regions of Russia. All patients were surgically treated in the Clinic of Medical Radiological Research Center, Russian Academy of Medical Sciences during 1990–2000. The age range of patients at the time of surgery was 8–29 years. Papillary thyroid carcinoma was diagnosed in 109 cases (89%), follicular carcinoma in 10 (8%), medullary carcinoma in 4 (3%). In 54% of papillary thyroid carcinomas, the age of patients during the accident was 0–4 years. The classic papillary architecture of papillary thyroid carcinomas (or dominant papillary component) occurred in 25%; dominant follicular architecture in 46%; dominant solid in 11%. Twelve percent of tumors had mixed architecture without dominant architectural component. Diffuse sclerosing and other variants occurred in 6%. We analyzed the histological features of papillary thyroid carcinomas depending on the age of patients at accident (analyzed groups of 0–4 and 5–16 years), age at operation (groups of 8–14, 15–19 and 20–29 years) and the duration of a latent period (analyzed groups of 4–10 and 11–14 years). No significant differences of papillary thyroid carcinoma architecture depending on the patient's age at accident and on a duration of latent period have been revealed. We found that the occurrence of classic papillary architecture (or dominant papillary component) of papillary thyroid carcinoma often occurred in the 20–29 years age group at operation (33%) than in the 8–14 years age group (16%).