Molecular Genetics of Follicular-Derived Thyroid Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Macerola E
PROVIDER: S-EPMC7961716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The pathogenesis of the development and progression of thyroid cancer (TC) is far from being clear at present. Accumulated evidence suggests that it is a complex polygenic disorder for which genetic factors play an important role in disease aetiology. Here we review the literature to report the genetic variations and alterations that have been described in the aetiology of TC. The functional effects of some mutations and single nucleotide polymorphisms on TC are validated, establishing the role of sequence variations in this cancer. However, large prospective studies are still required to evaluate the diagnostic and prognostic value of these genetic determinants in clinical practice.
| S-EPMC6865173 | biostudies-literature
Project description:Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be "sporadic" is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.
| S-EPMC7960606 | biostudies-literature
Project description:BackgroundExploring the immune interface of follicular cell-derived thyroid cancer has prognostic and therapeutic potential. The available literature is lacking for comprehensive immunophenotyping in relation to clinical outcomes. In this study, we identify circulating immunophenotypes associated with thyroid cancer prognosis.MethodsWe conducted a pilot observational study of adults with follicular cell-derived thyroid cancer who underwent surgery at our tertiary care referral center and had consented for flow cytometry on peripheral blood collected at the time of thyroidectomy.ResultsOf the 32 included subjects, 20 (62%) had well differentiated, 5 (16%) had poorly differentiated, and 7 (22%) had anaplastic thyroid cancer. The most frequent AJCC stage was 4 (59%) and the ATA risk of recurrence category was high (56%). Patients with AJCC stage 3/4 demonstrated fewer circulating mononuclear cells (CD45+), more monocytes (CD14+), fewer total lymphocytes (CD14-), fewer T cells (CD3+), fewer CD4+ T cells, fewer gamma-delta T cells, fewer natural killer (NK) T-like cells, more myeloid-derived suppressor cells (MDSCs; Lin-CD33+HLADR-), and more effector memory T cells but similar CD8+ T cells compared to stage1/2. Immunophenotype comparisons by ATA risk stratification and course of thyroid cancer were comparable to those observed for stage, except for significant differences in memory T cell subtypes. The median follow-up was 58 months.ConclusionsAggressive follicular cell-derived thyroid cancer either at presentation or during follow-up is associated with down-regulation of the T cell populations specifically CD4+ T cells, gamma-delta T cells, and NK T-like cells but up-regulation of MDSCs and altered memory T cells. These immunophenotypes are potential prognostic biomarkers supporting future investigation for developing targeted immunotherapies against advanced thyroid cancer.
| S-EPMC10792034 | biostudies-literature
Project description:To evaluate the potential of targeted photoacoustic imaging as a noninvasive method for detection of follicular thyroid carcinoma.We determined the presence and activity of two members of matrix metalloproteinase family (MMP), MMP-2 and MMP-9, suggested as biomarkers for malignant thyroid lesions, in FTC133 thyroid tumors subcutaneously implanted in nude mice. The imaging agent used to visualize tumors was MMP-activatable photoacoustic probe, Alexa750-CXeeeeXPLGLAGrrrrrXK-BHQ3. Cleavage of the MMP-activatable agent was imaged after intratumoral and intravenous injections in living mice optically, observing the increase in Alexa750 fluorescence, and photoacoustically, using a dual-wavelength imaging method.Active forms of both MMP-2 and MMP-9 enzymes were found in FTC133 tumor homogenates, with MMP-9 detected in greater amounts. The molecular imaging agent was determined to be activated by both enzymes in vitro, with MMP-9 being more efficient in this regard. Both optical and photoacoustic imaging showed significantly higher signal in tumors of mice injected with the active agent than in tumors injected with the control, nonactivatable, agent.With the combination of high spatial resolution and signal specificity, targeted photoacoustic imaging holds great promise as a noninvasive method for early diagnosis of follicular thyroid carcinomas.
| S-EPMC3602312 | biostudies-literature
Project description:Follicular cell-derived thyroid cancers are heterogenous and morphological classification is a complex and highly specialized task. Hence, identification of somatic alterations could provide insights to tumor biology and serve as an add-on diagnostic tool. Furthermore, results from these add-on tools could point in the direction of a more personalized treatment strategy. In the present study we set out to identify and validate the somatic mutation profile in a sample-set of follicular cell-derived thyroid neoplasia. One-hundred-and-one archived formalin fixed paraffin embedded (FFPE) tissue samples from patients diagnosed with follicular cell-derived thyroid neoplasia were included, and upon DNA-extraction and qualitative measurements 99 samples were eligible for amplicon-based next-generation-sequencing. Libraries were generated using the TruSeq Amplicon Cancer Panel, followed by sequencing using a MiSeq. Upon data processing and variant filtering all variants were manually assessed to exclude false positive mutations in the final curated list. Moreover, hot-spot mutations were validated using an independent platform from Agilent. Each diagnostic group were correlated to mutation burden and individual mutations were classified according to recent guidelines for somatic mutation classification. Close to 100% of the archived FFPE samples were eligible for DNA-library preparation and amplicon sequencing based on DNA quality criterion. The distribution of mutations in the specific diagnostic groups resulted in a higher mutation frequency among the most dedifferentiated than in the groups with a more differentiated cell profile. Based on the distribution mutations across the samples and using hierarchical clustering, we generated four tentative mutational signatures; highly mutated tumors; tumors with mainly NRAS and TP53 mutations; BRAF mutated tumors and tumors with none or single sporadic mutations. Future studies including more samples and follow-up data may amend these signatures, however our results imply that morphological classification of follicular cell derived thyroid neoplasia could be supplemented with a somatic mutational signature. Taken together, broad screening of the somatic alterations in FFPE tissue of thyroid neoplasia is comprehensible and essential for future identification of possible treatment targets and personalized medicine.
| S-EPMC7105679 | biostudies-literature
Project description:Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-?, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies.
| S-EPMC3749486 | biostudies-literature
Project description:Certain ultrasound features are associated with an increased risk of thyroid malignancy. However, they were studied mainly in papillary thyroid cancers (PTCs); these results cannot be simply extrapolated for the differentiation of follicular thyroid adenomas and cancers (FTAs and FTCs). The aim of our study was to perform a meta-analysis to identify sonographic features suggesting malignancy in the case of follicular lesions, potentially differentiating FTA and FTC. We searched thirteen databases from January 2006 to December 2020 to find all relevant, full-text journal articles written in English. Analyses assessed the accuracy of malignancy detection in case of follicular lesions, potentially differentiating FTA and FTC included the odds ratio (OR), sensitivity, specificity, positive and negative predictive values. A random-effects model was used to summarize collected data. Twenty studies describing sonographic features of 10,215 nodules met the inclusion criteria. The highest overall ORs to increase the risk of malignancy were calculated for tumor protrusion (OR = 10.19; 95% confidence interval: 2.62-39.71), microcalcifications or mixed type of calcifications (coexisting micro and macrocalcifications): 6.09 (3.22-11.50), irregular margins: 5.11 (2.90-8.99), marked hypoechogenicity: 4.59 (3.23-6.54), and irregular shape: 3.6 (1.19-10.92). The most crucial feature associated with an increased risk of FTC is capsule protrusion, followed by the presence of calcifications, irrespectively of their type.
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Project description:BackgroundOver the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world. However, the genomic mechanisms impacting thyroid carcinogenesis remain elusive.MethodsWe employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (Thrb(PV/PV)) in the thyroid receptor ?1 (TR?1) and applied quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in Thrb(PV)(/PV), Thrb(PV/)(+), and Thrb(+/+) mouse thyrocytes before and after histological presentation of FTC.ResultsUsing quantitative fluorescent in situ hybridization (Q-FISH) and TeloView™ image analysis, we found altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1 month of age, Thrb(PV/PV) mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of 1 month, 3D telomeric profiles of Thrb(PV/PV) thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers, suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in Thrb(PV/PV) mice well before the presentation of histological signs of thyroid carcinoma.ConclusionsWe identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma.
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Project description:Exosomes are nano‑sized extracellular vesicles that can be released from cancer cells. It has been shown that cancer cell‑derived exosomes may be associated with carcinogenesis by transferring signaling proteins from malignant to neighboring non‑malignant cells. In addition, annexin A1 (ANXA1) is a well‑known oncogene, that can be released from extracellular vesicles by cancer cells. However, the role of exosomal ANXA1 in the cell‑to‑cell communication of thyroid cancer and thyroid follicular epithelial cells remains unclear. In the present study, the protein expression levels of ANXA1 in thyroid cancer cells and thyroid cancer cell‑derived exosomes were analyzed using western blot analysis. In addition, Cell Counting Kit‑8 and Transwell assays were used to determine cell viability and invasion, respectively. The protein expression levels of ANXA1 were increased in thyroid cancer tissues and thyroid cancer cell lines. In addition, overexpression of ANXA1 significantly increased the proliferation and invasion of the SW579 cells, while knockdown of ANXA1 expression exerted the opposite results. Furthermore, ANXA1 was transferred from the SW579 cells to the Nthy‑ori3‑1 cells via exosomes. Exosomal ANXA1 markedly promoted the proliferation, invasion and epithelial‑to‑mesenchymal transition of the Nthy‑ori3‑1 cells. In addition, SW579 cell‑derived exosomal ANXA1 promoted tumor growth in a xenograft mouse model. Collectively, these findings indicated that SW579 cell‑derived exosomal ANXA1 promoted thyroid cancer development and Nthy‑ori3‑1 cell malignant transformation. Therefore, these findings may aid in the development of effective treatment methods for thyroid cancer.
| S-EPMC8651231 | biostudies-literature
Project description:Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P < 0.001] but not in minimally invasive (MI)-FTC and widely invasive (WI)-FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI-FTC with WT-TERT and M-TERT; EA-FTC with WT-TERT), Group 2 (WI-FTC with WT-TERT), and Group 3 (EA-FTC with M-TERT; WI-FTC with M-TERT). Both PVE (22.44 vs. 9.63, respectively) and C-index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C-index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups. Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability.
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