Thyroid Cancer Susceptibility Research Articles

Investigating the Association of Polygenic Risk Scores With Thyroid Cancer Susceptibility in a Han Chinese Population.

Thyroid cancer, the leading endocrine tumor with a rising global incidence, especially in women, is influenced by both genetic and environmental factors. This study examines the relationship between polygenic risk scores (PRS) and thyroid cancer susceptibility in the Han Chinese population, as well as the impact of genetic variants on clinical outcomes. Analyzing data from 57 257 participants in the Taiwan Precision Medicine Initiative, the study employed the Affymetrix Genome-Wide TWB 2.0 SNP Array for genotyping. PRS were calculated using single nucleotide polymorphisms (SNPs) from prior genome-wide association studies, specifically PGS000087 and PGS000797, and correlated with clinical parameters like age, sex, comorbidities, and treatment methods. Among 4063 participants with thyroid tumors (839 malignant, 3224 benign), higher PRS quartiles correlated significantly with increased thyroid cancer incidence. The highest quartile showed a 1.15-fold (PGS000797) and 1.14-fold (PGS000087) greater risk than the lowest quartile. Key findings included an association between higher PRS quartiles and younger onset age, along with a notable link to chronic kidney disease and thyroid hormone levels in specific SNPs. The study demonstrates PRS's utility in predicting thyroid cancer risk in the Han Chinese population, with higher PRS associated with increased risk and distinct clinical features. While this study focuses on the Han Chinese population, we recognize the importance of comparing PRS performance across different ancestries to fully understand ethnic genetic diversity in cancer risk assessment. Future studies should aim to include such comparative analysis.

Association of HOTAIR, MIR155HG, TERC, miR-155, -196a2, and -146a Genes Polymorphisms with Papillary Thyroid Cancer Susceptibility and Prognosis

Polymorphisms in long non-coding RNA and microRNA genes may play a significant role in the susceptibility and progression of papillary thyroid carcinoma (PTC). The current study investigates the polymorphisms HOTAIR rs920778, MIR155HG rs1893650, TERC rs10936599, miR-155 rs767649, miR-196a2 rs11614913 and miR-146a rs2910164 in 102 PTC patients and 106 age- and sex-matched controls of the Caucasian Serbian population, using real-time PCR. We observed differences in genotype distributions of the HOTAIR rs920778 (p = 0.016) and MIR155HG rs1893650 (p = 0.0002) polymorphisms between PTC patients and controls. HOTAIR rs920778 was associated with increased PTC susceptibility (adjusted OR = 1.497, p = 0.021), with the TT variant genotype increasing the risk compared to the CC genotype (OR = 2.466, p = 0.012) and C allele carriers (CC + CT) (OR = 1.585, p = 0.006). The HOTAIR rs920778 TT genotype was associated with lymph node metastasis (p = 0.022), tumor recurrence (p = 0.016), and progression-free survival (p = 0.010) compared to C allele carriers. Multivariate Cox regression revealed that ATA risk (HR = 14.210, p = 0.000004) and HOTAIR rs920778 (HR = 2.811, p = 0.010) emerged as independent prognostic factors in PTC. A novel polymorphism, MIR155HG rs1893650, was negatively correlated with susceptibility to PTC, with TC heterozygotes exerting a protective effect (OR = 0.268, p = 0.0001). These results suggest that the polymorphisms HOTAIR rs920778 and MIR155HG rs1893650 could be potential prognostic and risk biomarkers in papillary thyroid carcinomas.

SOWAHB polymorphisms affect thyroid cancer risk in the Chinese Han population

ABSTRACT Objectives This study aimed to detect the correlation between SOWAHB polymorphisms and Thyroid cancer (TC) risk in the Chinese Han population. Methods We genotyped SOWAHB variants in 510 TC patients and 509 controls using Agena MassARRAY. We assessed the association between SOWAHB polymorphisms and TC susceptibility, with the significant results evaluated through FPRP analysis. We predicted TC risk by the SNP-SNP interaction, analyzed by MDR. Results Carriers with rs2703129 CC had a lower probability of TC (codominant, recessive: p = 0.002), while subjects with rs1874564 AG had an increased risk of developing TC (codominant, recessive: p = 0.000, log-additive: p = 0.028). In subjects aged > 45 years, rs2703129 may reduce TC predisposition (codominant: p = 0.011, recessive: p = 0.007), but there was an increased association between rs1874564 and TC risk (codominant: p = 0.030, dominant: p = 0.047). Also, rs2703129 was associated with a lower risk of TC among males (codominant: p = 0.018, recessive: p = 0.013). Conversely, rs1874564 was associated with an increased risk of TC in females (codominant: p = 0.001, dominant: p = 0.003). Conclusion SOWAHB SNPs were related to the occurrence of TC, and rs2703129 may be a protective site for TC.

Exploring the Potential Association between COVID-19 and Thyroid Cancer: A Mendelian Randomization Study.

In order to address the ongoing debate surrounding the potential link between COVID-19 and thyroid cancer, our study was specifically designed to investigate the association between these two factors. We acquired summary data from a genome-wide association study (GWAS) concerning COVID-19 susceptibility and severity of COVID-19 in the European population, with a focus on their relationship with thyroid cancer. We applied three distinct methodologies to evaluate the causality between COVID-19 and thyroid cancer, employing Mendelian randomization (MR)-Egger, weighted median (WM), and inverse variance-weighted (IVW) approaches. Furthermore, we utilized a variety of techniques to assess pleiotropy and heterogeneity, including the MR-Egger intercept, MR-pleiotropy residual sum and outlier method (PRESSO), and Cochran's Q test. The MR analysis revealed associations between the susceptibility of COVID-19 and thyroid cancer (IVW odds ratio [OR]: 2.826, 95% confidence interval [CI]: [0.842, 9.483], P = 0.093) as well as between the risk of COVID-19 hospitalization and thyroid cancer (IVW OR: 1.630, 95% CI: [1.050, 2.529], P = 0.029). However, the relationship between COVID-19 and the occurrence of severe thyroid cancer cases was less evident (IVW OR: 1.061, 95% CI: [0.575, 1.956], P = 0.850). Our sensitivity analyses did not reveal any signs of horizontal pleiotropy or heterogeneity. Our MR study provided compelling evidence supporting a causal connection between the risk of COVID-19 hospitalization and thyroid cancer. Nevertheless, the MR results derived from genetic data do not support a causal link between susceptibility to COVID-19 and the risk of thyroid cancer or between very severe cases of COVID-19 and the risk of thyroid cancer. These findings have significant implications for further investigations into the impact of COVID-19 on health and the etiology of thyroid cancer.

Evaluating the association of rs6983267 polymorphism of the CCAT2 gene with thyroid cancer susceptibility in the Iranian Azeri population.

Thyroid cancer is the most common malignancy of the endocrine system. LncRNAs play critical role in various cellular processes and are associated with several diseases. CCAT2 is a lncRNA molecule overexpressed in thyroid cancer. Single nucleotide polymorphisms in CCAT2 gene can cause changes in the structure and function of CCAT2 transcripts and susceptibility to several diseases. This study aimed to evaluate the association of rs6983267 in CCAT2 gene with thyroid cancer susceptibility in the Azeri population of Iran. In this "case-control" study, genomic DNA was extracted from peripheral blood of 102 individuals affected by thyroid cancer and 103 healthy individuals as controls. Genotyping was performed using TETRA-ARMS polymerase chain reaction. Statistical analysis showed no significant association between genotypes and/or alleles with the occurrence of thyroid cancer in the studied population, patients' gender, and tumor type. Nevertheless, we found that the allelic and genotypic distribution of this SNP was associated with the size of thyroid tumors in patients. It is assumed that investigating more individuals from both case and control group may further determine the genotypic and allelic frequencies of this SNP locus in Iranian-Azeri population.

Association of HOTAIR (rs920778 C>T) Polymorphism with Thyroid Cancer Susceptibility in the Northwest of Iran

Association of HOTAIR (rs920778 C>T) Polymorphism with Thyroid Cancer Susceptibility in the Northwest of Iran

Women and thyroid cancer incidence: overdiagnosis versus biological risk.

Our aim is to discuss the concepts of sex and gender in the context of thyroid cancer epidemiology. It has been long-established in global epidemiologic data that thyroid cancer incidence rates are higher in women than men. However, what has been less well understood is whether this reflects sex disparities in cancer susceptibility, gender disparities in detection, or a combination. A recent meta-analysis of autopsy data from individuals who were not known to have thyroid cancer in their lifetime demonstrated no difference in the prevalence of thyroid cancer in women and men, suggesting that gender differences may be the reason for gender-based differences in thyroid cancer detection. This finding, and sex differences in auto immunity and other factors that may affect cancer susceptibility are explored. Additional research to explore gender- and sex-specific data on thyroid cancer would inform our understanding of the differences and similarities between men and women in susceptibility and detection of thyroid cancer and help to optimize disease management for all genders and both sexes.

Epidemiology of Thyroid Cancer.

Epidemiology of Thyroid Cancer.

Cathepsin F genetic mutation is associated with familial papillary thyroid cancer

BackgroundThyroid cancer is one of the most common cancers in the world. Genetic factors are important in the occurrence and development of thyroid cancer, and genetic diagnosis has become an important basis for the prognosis of benign and malignant nodules. We identify a family of six siblings with inherited thyroid cancer susceptibility. All six members of this generation have been definitely diagnosed with papillary thyroid carcinoma. This work aims at confirming the relevant causative genes for thyroid cancer in this pedigree. MethodsWe extract DNA from the peripheral blood of six individuals and perform whole genome sequencing. Sanger sequencing and immunohistochemistry further testify the cathepsin F (CTSF) mutation and expression. ResultsWe identify 57 single nucleotide variations (SNVs) out of at least 4 affected family members via certain filter criteria. The CTSF gene found in five of the six family members is here considered the most promising candidate gene mutation for familial thyroid cancer. Besides, our research also proves several known genes including CTSB, TEKT4, ESR1, MSH6, DIRC3, GNAS, and BANCR that act as probable oncogenic drivers in this family. The Sanger sequencing identifies the existence and veracity of CTSF somatic mutations. The CTSF immunohistochemistry of thyroid cancer tissue specimens displays that higher CTSF expression in mutated patients than that in wild-type patient as well as pericarcinomatous tissue. ConclusionsWe conclude that the evaluation of CTSF gene mutations of patients in thyroid cancer families may be predictive and valuable for the familial heredity of thyroid cancer.

Role of STAT3 Expression in Thyroid Cancer: A Meta-Analysis and Systematic Review Based on the Chinese Population.

Background Signal transduction and activator of transcription 3 (STAT3) is an oncogene with transcriptional activity. In recent years, there have been several studies concerning the clinicopathological significance of the expression of the STAT3 protein in thyroid cancer. However, the results are still inconsistent. In this study, we conducted a meta-analysis to evaluate the relationship between the expression of STAT3 protein and thyroid cancer susceptibility and its clinicopathological characteristics. Methods We searched the China National Knowledge Infrastructure (CNKI) database, Chinese Biomedical Literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wanfang, PubMed, and EMBASE. The time frame of the publication search was from the establishment of each of the databases until December 2021. We performed a meta-analysis to quantitatively evaluate the relationship between the expression of the STAT3 protein in thyroid cancer and its clinicopathological characteristics. Results A total of eight articles were included in the meta-analysis, covering 448 thyroid cancer patients and 227 controls. Results indicated that the expression of STAT3 protein in thyroid cancer tissue is highly expressed (OR = 14.41, 95% CI (6.94, 29.91), p < 0.001). Besides, we also discovered that STAT3 protein is negatively correlated with thyroid cancer tumor diameter and TNM stage (OR = 0.13, 95% CI (0.05, 0.33), p < 0.001; OR = 0.40, 95% CI (0.24, 0.67), p < 0.001) and positively correlated with lymph node metastasis (OR = 2.83, 95% CI (1.08, 7.46), p = 0.035). However, STAT3 expression is not related to gender (OR = 0.88, 95% CI (0.54, 1.44), p = 0.609), age (OR = 0.54, 95% CI (0.21, 1.36), p = 0.191), capsular invasion (OR = 2.98, 95% CI (0.23, 38.29), p = 0.403), or tumor multiplicity (OR = 0.25, 95% CI (0.003, 19.28), p = 0.533). Conclusions This study reveals that STAT3 protein expression is significantly related to the susceptibility and clinicopathological characteristics of thyroid cancer. It also suggests that STAT3 may be a potential predictor of the clinical progression of thyroid cancer.

Ferroptosis-Related APOE, BCL3 and ALOX5AP Gene Polymorphisms are Associated with the Risk of Thyroid Cancer.

PurposeThis study aimed to evaluate the association between polymorphisms in the ferroptosis-related genes apolipoprotein E (APOE), BCL3 transcription coactivator (BCL3) and arachidonate 5-lipoxygenase activating protein (ALOX5AP) and the risk of thyroid cancer.MethodsSix single nucleotide polymorphisms (SNPs) of APOE (rs429358 and rs7412), BCL3 (rs34698726 and rs8100239) and ALOX5AP (rs4076128 and rs4073259) were genotyped in 520 papillary thyroid carcinoma cases and 520 healthy controls using the MassARRAY platform.ResultsThe rs429358-TC, rs34698726-TA/TT, and rs8100239-AT/AA genotypes exhibited an elevated risk of thyroid cancer (prs429358 = 0.002, prs34698726 = 0.007, prs8100239 = 0.002), while rs7412-CT/TT and rs4076128-GA/GG were found to be protective genotypes against the risk of disease (prs7412 = 0.0003, prs4076128 = 0.0001). Genetic model analysis showed that APOE-rs429358 was correlated with an increased risk of disease under dominant and log-additive models (pdominant = 0.0004, plog-additive = 0.0006). BCL3-s34698726 and rs8100239 were associated with an elevated risk of disease under all three genetic models (p < 0.05). In contrast, APOE-rs7412 was related to a decreased risk of thyroid cancer under dominant and log-additive models (pdominant = 0.0001, plog-additive = 0.0001). Moreover, ALOX5AP-rs4076128 was also correlated with a reduced risk of disease under all three genetic models (p < 0.05).ConclusionThe results help us better understand how genetic polymorphisms in ferroptosis-related genes are relevant to thyroid cancer susceptibility.

Genetic Variants Associated with Thyroid Cancer Risk: Comprehensive Research Synopsis, Meta-Analysis, and Cumulative Epidemiological Evidence.

Purpose With the increasing incidence of thyroid cancer (TC), associations between genetic polymorphisms and TC risk have attracted a lot of attention. Considering that the results of associations of genetic variants with TC were usually inconsistent based on publications until now, we attempted to comprehensively evaluate the real evidence of associations between single nucleotide polymorphisms (SNPs) and TC risk. Method We performed meta-analyses on 36 SNPs in 23 genes associated with TC susceptibility based on the data from 99 articles and comprehensively valued the epidemiological evidence of significant associations through the Venice criteria and false-positive report probability (FPRP) test. OR and P value were also calculated for 19 SNPs in 13 genes based on the insufficient data from 22 articles. Results 19 SNPs were found significantly associated with TC susceptibility. Of these, strong epidemiological evidence of associations was identified for the following seven SNPs: POU5F1B rs6983267, FOXE1 rs966423, TERT rs2736100, NKX2-1 rs944289, FOXE1 rs1867277, FOXE1 rs2439302, and RET rs1799939, in which moderate associations were found in four SNPs and weak associations were found in eight SNPs. In addition, probable significant associations with TC were found in nine SNPs. Conclusion Our study systematically evaluated associations between SNPs and TC risk and offered reference information for further understanding of polymorphisms and TC susceptibility.

Genetic polymorphisms in the PCNXL2 gene are risk factors for thyroid cancer in the Chinese population.

Background: Thyroid cancer is the most common endocrine malignancy and the fastest growing cancer worldwide. Thyroid cancer has the largest genetic component of all cancers. Previous genome-wide association studies indicated that genetic polymorphism in PCNXL2 is related to thyroid cancer susceptibility in European populations. This study aims to determine the influence of PCNXL2 polymorphisms on thyroid cancer risk in Chinese individuals. Methods: This case-control study identified four polymorphisms in PCNXL2 among 510 thyroid cancer cases and 509 healthy controls. The associations of PCNXL2 polymorphisms with thyroid cancer susceptibility were detected by calculating odds ratios. Multifactor dimensionality reduction was performed to detect the impact of SNP (single nucleotide polymorphism)-SNP interactions on the risk of thyroid cancer. Results: The study showed that rs10910660 in PCNXL2 was related to thyroid cancer susceptibility. Rs12129938 played a protective role in thyroid cancer susceptibility. Stratification analysis indicated that rs10910660 increased thyroid cancer risk at age >45years. Rs12129938 enhanced susceptibility to thyroid cancer at age >45years, while this SNP decreased thyroid cancer risk at age ≤45years. Rs4649295 was associated with lower susceptibility to thyroid cancer at age ≤45years. An association was observedbetween rs6424270and rs12129938 with decreased susceptibility to thyroid cancer in women. Rs10910660 was related to thyroid cancer risk in men. The combination of rs6424270, rs10910660, rs12129938and rs4649295 was the best model to predict thyroid cancer. Conclusion: Thisstudy suggests that PCNXL2 polymorphisms are risk factors for thyroid cancer in the Chinese population.

PTCSC3-mediated glycolysis suppresses thyroid cancer progression via interfering with PGK1 degradation.

The Warburg effect (aerobic glycolysis), a hallmark of cancer, serves as a promising target for diagnosis and therapy. Growing evidence indicates that long non‐coding RNAs (lncRNAs) play an important role in aerobic glycolysis of various tumours. However, the correlation between lncRNAs and glycolysis in thyroid cancer cells is still poorly understood. In this study, we showed that lncRNA papillary thyroid cancer susceptibility candidate 3 (PTCSC3) was significantly downregulated in papillary thyroid carcinoma (PTC). Overexpression of PTCSC3 significantly inhibited the aerobic glycolysis and tumour growth of PTC cells. Consistently, PTCSC3 overexpression suppressed tumour progress in vivo. Mechanistically, PTCSC3 inhibits aerobic glycolysis and proliferation of PTC by directly interacting with PGK1, a key enzyme in glycolytic pathway. As a result, PTCSC3 performs its role in PTC development via PGK1 and may be a potential therapeutic target for PTC treatment.

The effect of VAV3 polymorphisms on thyroid cancer.

The incidence of thyroid cancer is rising rapidly in China, but there are few studies on the risk factors of thyroid cancer in the Chinese Han population. We performed this case-control study of 510 patients and 509 controls to for determine the linkage of VAV3 variants (rs17019602, rs7521681, rs4915076, and rs1777451) with thyroid cancer susceptibility by computing the odds ratio (OR) and 95% confidence intervals (CI). Multi-factor dimension reduction (MDR) analysis was conducted to assess interaction of VAV3 genetic variants. We found that rs7521681 was remarkably related to a higher risk of thyroid cancer (OR = 1.74, p = 0.012), whereas rs4915076 (OR = 0.66, p = 0.001) significantly decreased thyroid cancer susceptibility. Stratified analyses showed that rs4915076 had a protective role in thyroid cancer in both ages >45 years (OR = 0.70, p = 0.017) and age ≤45 years (OR = 0.63, p = 0.007). Rs17019602 could increase the susceptibility of thyroid cancer in men (OR = 4.76, p = 0.049). Rs7521681 was related to an increased risk of thyroid cancer in women (OR = 1.97, p = 0.012). Rs4915076 could protect individuals from thyroid cancer both in men (OR = 0.60, p = 0.031) and women (OR = 0.68, p = 0.010). Moreover, rs4915076 was the best single-locus model to predict thyroid cancer. Interestingly, the interaction model of rs17019602, rs7521681, rs4915076, rs1777451, and age was a candidate gene-environment model. Our results indicated VAV3 variants were associated with thyroid cancer, which provides a new sight into etiology of thyroid cancer.

FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo.

Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.

Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility

BackgroundUnderstanding the molecular mechanisms underlying papillary thyroid cancer (PTC) proved to be vital not only for diagnostic purposes but also for tailored treatments. Despite the strong evidence of heritability, only a small subset of alterations has been implicated in PTC pathogenesis. To this reason, we used targeted next-generation sequencing (NGS) to identify candidate variants implicated in PTC pathogenesis, progression, and invasiveness.MethodsA total of 42 primary PTC tissues were investigated using a targeted next-generation sequencing (NGS) panel enlisting 47 genes involved in DNA repair and tumor progression.ResultsWe identified 57 point mutations in 78.5% of samples (n = 32). Thirty-two somatic mutations were identified exclusively in known thyroid cancer genes (BRAF, KRAS, NRAS, and TERT). Unpredictably, 45% of the all identified mutations (n = 25) resulted to be germline, most affecting DNA repair genes. Interestingly, none of the latter variants was in the main population databases. Following ACMG classification, 20% of pathogenic/likely pathogenic and 68% of variant of unknown significance were identified.ConclusionsOverall, our results support the hypothesis that rare germline variants in DNA repair genes are accountable for PTC susceptibility. More data, including the segregation analysis in affected families, should be collected before definitely annotate these alterations and to establish their potential prognostic and treatment implications.

ASO Author Reflections: Developing a Clinician-Friendly Resource to Promote Awareness of Non-Medullary Thyroid Cancer Susceptibility Genes and Their Associated Diseases.

ASO Author Reflections: Developing a Clinician-Friendly Resource to Promote Awareness of Non-Medullary Thyroid Cancer Susceptibility Genes and Their Associated Diseases.

Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues.

Species differences in hepatic metabolism of thyroxine (T4) by uridine diphosphate glucuronosyl transferase (UGT) and susceptibility to thyroid hormone imbalance could underlie differences in thyroid carcinogenesis caused by hepatic enzyme inducers in rats and humans. To investigate this hypothesis we examined profiles of hepatic UGT induction by the prototypical CAR activator phenobarbital (PB) in rat and human liver 3D microtissues. The rationale for this approach was that 3D microtissues would generate data more relevant to humans. Rat and human liver 3D microtissues were exposed to PB over a range of concentrations (500 u M - 2000 u M) and times (24-96 hr). Microarray and proteomics analyses were performed on parallel samples to generate integrated differentially expressed gene (DEG) datasets. Bioinformatics analysis of DEG data, including CAR response element (CRE) sequence analysis of UGT promoters, was used to assess species differences in UGT induction relative to CAR-mediated transactivation potential. A higher proportion of human UGT promoters were found to contain consensus CREs compared to the rat homologs. UGTs 1a6, 2b17 and 2b37 were upregulated by PB in rat liver 3D microtissues, but unaltered in human liver 3D microtissues. By contrast, human UGTs 1A8, 1A10 and 2B10 showed higher levels of induction (RNA and /or protein) compared to the rat homologs. There was general concordance between the presence of CREs and the induction of UGT RNA. As UGT1A and 2B isoforms metabolise T4, these results suggest that differences in UGT induction could contribute to differential susceptibility to CAR-mediated thyroid carcinogenesis in rats and humans.

Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer

Thyroid cancer is the most frequent endocrine malignancy with the majority of cases derived from thyroid follicular cells and caused by sporadic mutations. However, when at least two or more first degree relatives present thyroid cancer, it is classified as familial non-medullary thyroid cancer (FNMTC) that may comprise 3–9% of all thyroid cancer. In this context, 5% of FNMTC are related to hereditary syndromes such as Cowden and Werner Syndromes, displaying specific genetic predisposition factors. On the other hand, the other 95% of cases are classified as non-syndromic FNMTC. Over the last 20 years, several candidate genes emerged in different studies of families worldwide. Nevertheless, the identification of a prevalent polymorphism or germinative mutation has not progressed in FNMTC. In this work, an overview of genetic alteration related to syndromic and non-syndromic FNMTC is presented.