Somatic genetic alterations in a large cohort of pediatric thyroid nodules.
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ABSTRACT:
SUBMITTER: Pekova B
PROVIDER: S-EPMC6590202 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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Project description:Thyroid nodules are found in nearly half of the adult population. Accumulating evidence suggests that the gut microbiota plays an important role in thyroid metabolism, yet the association between gut microbiota capacity, thyroid nodules, and thyroid function has not been studied comprehensively. We performed a gut microbiome genome-wide association study in 196 patients with thyroid nodules and 283 controls by using whole-genome shotgun sequencing. We found that participants with high-grade thyroid nodules have decreased number of gut microbial species and gene families compared with those with lower grade nodules and controls. There are also significant alterations in the overall microbial composition in participants with high-grade thyroid nodules. The gut microbiome in participants with high-grade thyroid nodules is characterized by greater amino acid degradation and lower butyrate production. The relative abundances of multiple butyrate producing microbes are reduced in patients with high-grade thyroid nodules and the relative abundances of L-histidine metabolism pathways are associated with thyrotropin-releasing hormone. Our study describes the gut microbiome characteristics in thyroid nodules and a gut-thyroid link and highlight specific gut microbiota as a potential therapeutic target to regulate thyroid metabolism.
| S-EPMC8005713 | biostudies-literature
Project description:Thyroid nodules are less frequent in children than adults. Childhood thyroid nodules carry specific features, including a higher risk of malignancy than nodules in adults, rendering them unique in terms of management. Subsequently, they should be considered a distinct clinical entity with specific imaging recommendations. Initial evaluation requires a thorough workup, including clinical examination, and a detailed personal and familial history to determine the presence of possible risk factors. Laboratory and radiologic evaluation play an integral part in the diagnostic algorithm, with ultrasonography (US) being the first diagnostic test in all patients. US elastography has been recently introduced as an incremental method, reducing the subjectivity of the clinical diagnosis of nodule firmness associated with increased malignancy risk. However, fine-needle aspiration biopsy (FNAB) remains the mainstay in the diagnostic work-up of thyroid nodules and is documented to be best method for differentiating benign from malignant thyroid nodules. In addition, thyroid scintigraphy provides functional imaging information, which has a role both in the diagnostic management of thyroid nodules and during follow up in malignancies. Finally, despite providing additional information in certain clinical scenarios, 18F-fludeoxyglucose Positron Emission Tomography (18F-FDG-PET), computed tomography (CT), and magnetic resonance imaging (MRI) imaging are not routinely recommended for the evaluation of patients with newly detected thyroid nodules or in all cases of thyroid cancer. The objective of this review is to summarize the concepts in imaging and imaging-based management of nodular thyroid disease in the pediatric population, acknowledging the unique features that this patient group carries and the specific approach it requires.
| S-EPMC7074552 | biostudies-literature
Project description:Sporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%-80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC.
| S-EPMC6817656 | biostudies-literature
Project description:BackgroundCirculating cell-free DNA (cfDNA) serves as a biomarker in multiple malignant diseases. However, controversy still surrounds the role of cfDNA detection in the diagnosis and monitoring of papillary thyroid carcinoma (PTC). This study set out to identify the role of cfDNA detection in distinguishing between benign and malignant thyroid nodules.MethodsTissue, blood cell, and plasma samples were collected from 10 patients with benign nodules and 10 patients with malignant nodules. The DNA isolated from these samples was subject to PCR-based amplification using primers designed for 50 proto-oncogenes and tumor suppressor genes. PCR products were sequenced using Illumina technology, and the mutations were detected with varScan among sequencing data for each sample and comparative analysis was carried out.ResultsThrough amplicon sequencing, we found one non-synonymous somatic mutation in the benign nodules and three in the malignant nodules. Among these four mutations, BRAFV600E mutation was detected in the tissue samples of 8 out of the 10 PTC patients, but it was not detected in the benign nodules. However, no BRAFV600E mutation was detected in cfDNA. Further differential analysis of cfDNA indicated that some genes had more mutations in benign patients than in malignant patients, such as MET and IDH, and some genes had more mutations in malignant patients, such as PIK3CA and EZH2.ConclusionsWe found that BRAFV600E mutation was a credible disease-related mutation in PTC; however, it could not be detected in cfDNA. Moreover, there was a large difference in mutation gene distribution between benign and malignant thyroid nodules.
| S-EPMC7607131 | biostudies-literature
Project description:ImportanceThyroid cancer is the most common pediatric endocrine malignant neoplasm. Disparities in the workup of thyroid nodules may be significantly associated with thyroid cancer outcomes.ObjectiveTo determine the association of sociodemographic factors with the odds of receiving a biopsy, timeliness of the procedure, and risk of nodule malignancy.Design, setting, and participantsThis was a retrospective cross-sectional study using insurance claims data from the Optum Clinformatics Data Mart database. The study cohort comprised pediatric patients diagnosed with single thyroid nodules between 2003 and 2020. Data analysis was performed from January 1, 2003, to June 30, 2020.Main outcomes and measuresMultivariable logistic regression models were used to identify demographic variables associated with biopsy and nodule malignant neoplasm. A multivariable linear regression model was used to assess the time between thyroid nodule diagnosis and biopsy.ResultsOf 11 643 children (median [IQR] age at diagnosis or procedure, 15 [12-17] years; 8549 [73.2%] were female and 3126 [26.8%] were male) diagnosed with single thyroid nodules, 2117 (18.2%) received a biopsy. Among the patients who received a biopsy, 304 (14.4%) were found to have a malignant nodule. Greater parental education was associated with a shorter diagnosis-to-biopsy interval (mean difference, -7.24 days; 95% CI, -13.75 to -0.73). Older age at nodule diagnosis (odds ratio [OR], 1.11; 95% CI, 1.09-1.13) and female gender (OR, 1.25; 95% CI, 1.11-1.40) were associated with increased odds of receiving a biopsy, while Black/African American (OR, 0.80; 95% CI, 0.65-0.99) and Hispanic (OR, 0.84; 95% CI, 0.72-0.99) patients had lower odds of receiving a biopsy compared with White patients. Finally, female gender (OR, 1.08; 95% CI, 0.80-1.47) was not associated with lower odds of nodule malignant neoplasm.Conclusions and relevanceFindings of this cross-sectional study highlight disparities in the diagnostic management of pediatric thyroid nodules. These results call for future work to ensure equitable access to thyroid care for all children.
| S-EPMC9562096 | biostudies-literature
Project description:Fine needle aspiration biopsy provides one of the most important data that determines the treatment algorithm of thyroid nodules. Nevertheless, the reliability of fine needle aspiration biopsy is controversial in large nodules. The aim of this study was to evaluate the adequacy of fine needle aspiration biopsy in thyroid nodules that are four cm or greater.We retrospectively examined 219 patients files who underwent thyroidectomy for thyroid nodules that were greater than four centimeter between May 2007 and December 2012. Seventy-four patients with hyperthyroidism, and 18 patients without preoperative fine needle aspiration cytology were excluded from the study. Histopathologic results after thyroidectomy were compared with preoperative cytology results, and sensitivity and specificity rates were calculated.False-negativity, sensitivity and specificity rates of fine needle aspiration biopsy of thyroid nodules were found to be 9.7%, 55.5%, and 85%, respectively. Within any nodule of the 127 patients, 28 (22.0%) had thyroid cancer. However, when only nodules of at least 4 cm were evaluated, thyroid cancer was detected in 22 (17.3%) patients.In this study, fine needle aspiration biopsy of large thyroid nodules was found to have a high false-negativity rate. The limitations of fine-needle aspiration biopsy should be taken into consideration in treatment planning of thyroid nodules larger than four centimeters.
| S-EPMC5448564 | biostudies-other
Project description:Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.
| S-EPMC4335266 | biostudies-literature
Project description:Importance:Thyroid nodules are common incidental findings. Ultrasonography and molecular testing can be used to assess risk of malignant neoplasm. Objective:To examine whether a model developed through automated machine learning can stratify thyroid nodules as high or low genetic risk by ultrasonography imaging alone compared with stratification by molecular testing for high- and low-risk mutations. Design, Setting, and Participants:This diagnostic study was conducted at a single tertiary care urban academic institution and included patients (n?=?121) who underwent ultrasonography and molecular testing for thyroid nodules from January 1, 2017, through August 1, 2018. Nodules were classified as high risk or low risk on the basis of results of an institutional molecular testing panel for thyroid risk genes. All thyroid nodules that underwent genetic sequencing for cytological results with Bethesda System categories III and IV were reviewed. Patients without diagnostic ultrasonographic images within 6 months of fine-needle aspiration or who received definitive treatment at an outside medical center were excluded. Main Outcomes and Measures:Thyroid nodules were categorized by the model as high risk or low risk using ultrasonographic images. Results were compared using genetic testing. Results:Among the 134 lesions identified in 121 patients (mean [SD] age, 55.7 [14.2] years; 102 women [84.3%]), 683 diagnostic ultrasonographic images were selected. Of the 683 images, 556 (81.4%) were used for training the model, 74 (10.8%) for validation, and 53 (7.8%) for testing. Most nodules had no mutation (75 [56.0%]), whereas 43 nodules (32.1%) had a high-risk mutation and 16 (11.9%) had an unknown or a low-risk mutation (?2?=?39.060; P?<?.001). In total, 228 images (33.4%) were of nodules classified as genetically high risk (n?=?43), and 455 (66.6%) were of low-risk nodules (n?=?91). The model performed with a sensitivity of 45% (95% CI,?23.1%-68.5%), a specificity of 97% (95% CI,?84.2%-99.9%), a positive predictive value of 90% (95% CI,?55.2%-98.5%), a negative predictive value of 74.4% (95% CI,?66.1%-81.3%), and an overall accuracy of 77.4% (95% CI,?63.8%-97.7%). Conclusions and Relevance:The study found that the model developed through automated machine learning could produce high specificity for identifying nodules with high-risk mutations on molecular testing. This finding shows promise for the diagnostic applications of machine learning interpretation of sonographic imaging of indeterminate thyroid nodules.
| S-EPMC6813575 | biostudies-literature
Project description:BACKGROUND:Thyroid nodules are less common in pediatric patients (i.e., those ?18 years) than they are in adults. The Bethesda System for Reporting Thyroid Cytopathology allows for individual risk stratification, but a significant number of nodules are indeterminate. Incorporating gene mutation panels and gene expression classifiers may aid in preoperative diagnosis. The overall aim of this study was to assess the prevalence of oncogene alterations in a representative pediatric population and across a broad-spectrum of thyroid tumor diagnoses. METHODS:This was a retrospective cross-sectional evaluation of 115 archived samples, including: 47 benign (29 follicular adenoma, 11 diffuse hyperplasia, four thyroiditis, and three multinodular goiter), six follicular thyroid carcinomas (FTC), 24 follicular variant of papillary thyroid carcinomas (fvPTC), 27 classic variant of PTC (cPTC), eight diffuse sclerosing variant of PTC (dsvPTC), and three other PTC. Molecular testing was performed by multiplex qualitative polymerase chain reaction followed by bead array cytometry. Oncogene results were analyzed for association with age, sex, histology, lymph node metastasis, and intrathyroidal spread. RESULTS:A mutation in one of the 17 molecular markers evaluated was found in: 2/6 (33%) FTC, 8/24 (33%) fvPTC, 17/27 (63%) cPTC, and 4/8 (50%) dsvPTC. Mutations in RAS or PAX8/PPARG were exclusive to FTC and fvPTC. BRAF was the most common mutation in cPTC (12/17; 71%), and RET/PTC was the only mutation associated with dsvPTC. Overall, a mutation was found in 32/68 (47%) malignant specimens, with a single follicular adenoma positive for PAX8/PPARG. The relative distribution of gene alterations in pediatric lesions was similar to adults. The presence of a BRAF mutation in pediatric cPTC did not predict a more invasive phenotype. CONCLUSIONS:Of 33 nodules with genetic alterations, 32 were malignant. Mutations in RAS were most frequently associated with FTC, RET/PTC rearrangements with dsvPTC, and invasive fvPTC, and BRAF with cPTC. These results suggest a clinical role for mutational analysis of pediatric nodules to guide the surgical approach.
| S-EPMC5770125 | biostudies-literature
Project description:ObjectivesUltrasound diagnosis of thyroid nodules has greatly increased their detection rate. Their risk for malignancy is estimated between 7 and 15% in data from specialized centers which are used for guidelines recommendations. This high rate causes considerable anxiety to patients upon first diagnosis. Here, we retrospectively analyzed the malignancy rate of sonographically diagnosed nodules larger than 1 cm from a primary/secondary care center when long-term longitudinal follow-up was included.Patients/methodsIn the study, 17,592 patients were diagnosed with a thyroid nodule larger than 1 cm, of whom 7776 were assessed by fine-needle aspiration cytology (FNAC) and 9816 by sonography alone. 9568 patients were initially discharged due to innocent results of FNAC and/or ultrasound. In 1904 patients, definitive histology was obtained, and 6731 cases were included in the long-term follow-up (up to 23 years, median 5 years).ResultsMalignancy was histologically confirmed in 189 patients (1.1% of all) when excluding accidentally diagnosed papillary microcarcinomas. 155 were diagnosed during the first year of management, 25 in years 2-5 of follow-up, 9 in years 6-10 and nil in 1165 patients followed beyond 10 years.ConclusionsThe malignancy rate of thyroid nodules from primary/secondary care was much lower than that previously reported. During follow-up for more than 5 years, their rate rapidly dropped to less than 1/1000 cases. This low malignancy rate may help to reassure patients first confronted with the diagnosis of a thyroid nodule, substantially reduce their anxiety and avoid unwarranted diagnostic and therapeutic procedures.
| S-EPMC9254276 | biostudies-literature