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Gene network and biological pathways associated with susceptibility to differentiated thyroid carcinoma.

ABSTRACT: Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.

SUBMITTER: Kulkarni O

PROVIDER: S-EPMC8076215 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Functional variations in the ATM gene and susceptibility to differentiated thyroid carcinoma.

Project description:ContextATM is critical in response to ionizing radiation-induced DNA damage.ObjectiveVariations in ATM are hypothesized to affect individual susceptibility to thyroid cancer. Our objective was to evaluate the association between ATM polymorphisms and thyroid cancer risk.Design, participants, and methodsSix ATM single nucleotide polymorphisms (SNP) were genotyped in two independent case-control series including 592 patients with differentiated thyroid carcinoma (DTC) and 885 healthy individuals. An unconditional logistic regression model was applied to calculate odds ratios (OR) and 95% confidence intervals (CI) for each SNP with respect to risk of DTC and the combination effect of SNP on cancer risk.ResultsThe risk-allele frequencies of all the SNP were similar in the two case-control populations. Under a dominant model of inheritance, the G allele of ATM rs189037 exhibited a protective effect against DTC (adjusted OR = 0.8; 95% CI, 0.6-1.0; P = 0.04), and the G allele of rs1800057 was associated with increased risk of DTC (adjusted OR = 1.9; 95% CI, 1.1-3.1; P = 0.02). A protective haplotype (A-G-C-T-C-A) was associated with decreased risk of DTC in non-Hispanic whites (adjusted OR = 0.2; 95% CI, 0.0-0.8; P = 0.03). A significant dose-response relationship was observed between the total number of risk alleles of ATM and DTC risk (P = 0.01). Carriers of a combination of six to seven and eight to 10 risk alleles were at 30% (adjusted OR = 1.3; 95% CI, 1.0-1.7) and 50% (adjusted OR = 1.5; 95% CI, 1.1-2.1) increased risk of DTC, respectively.ConclusionIndividual susceptibility to DTC may be attributable to polymorphisms of ATM, and the associations warrant confirmation in independent studies.

| S-EPMC3387410 | biostudies-literature

Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach.

Project description:To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.

| S-EPMC9513665 | biostudies-literature

Significance of MDM2 and P14 ARF polymorphisms in susceptibility to differentiated thyroid carcinoma.

Project description:Murine double minute 2 (MDM2) oncoprotein and p14(ARF) tumor suppressor play pivotal roles in regulating p53 and function in the MAPK pathway, which is mutated frequently in differentiated thyroid carcinoma (DTC). We hypothesized that functional polymorphisms in the promoters of MDM2 and p14(ARF) contribute to the interindividual difference in predisposition to DTC.MDM2-rs2279744, MDM2-rs937283, p14(ARF)-rs3731217, and p14(ARF)-rs3088440 were genotyped in 303 patients with DTC and 511 cancer-free healthy controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).MDM2-rs2279744 and p14(ARF)-rs3731217 were associated with a significantly increased risk of DTC (MDM2-rs2279744: TT versus TG/GG; OR, 1.5; 95% CI, 1.1-2.0; p14(ARF)-rs3731217: TG/GG versus TT; OR, 1.7; 95% CI, 1.2-2.3). No association was found for MDM2-rs937283 or p14(ARF)-rs3088440. Individuals carrying 3-4 risk genotypes of MDM2 and p14(ARF) had 2.2 times (95% CI, 1.4-3.5) the risk for DTC of individuals carrying 0-1 risk genotypes (P trend = .021). The combined effect of MDM2 and p14(ARF) on risk of DTC was confined to young subjects (? 45 years), nonsmokers, nondrinkers, and subjects with a first-degree family history of cancer. These associations were quite similar in strength when cases were restricted to those with papillary thyroid cancer.Our results suggest that polymorphisms of MDM2 and p14(ARF) contribute to the interindividual difference in susceptibility to DTC, either alone or more likely jointly. The observed associations warrant further confirmation in independent studies.

| S-EPMC3610784 | biostudies-literature

Functional polymorphisms in the insulin-like binding protein-3 gene may modulate susceptibility to differentiated thyroid carcinoma in Caucasian Americans.

Project description:The insulin-like growth factor (IGF) pathway is believed to play a pivotal role in thyroid carcinogenesis. Polymorphisms of IGF-1 and IGF binding protein-3 (IGFBP-3) have been associated with modulation of risk for the emergence of assorted common malignancies, but studies of the influence of such polymorphisms on risk of differentiated thyroid carcinoma (DTC) are lacking. In a case-control study of 173 DTC patients, 101 patients with benign thyroid disease, and 401 controls, an unconditional logistical regression model adjusted for age and sex was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polymorphisms of IGF-1 and IGFBP-3 and DTC risk. IGFBP-3 rs2132572 GA/AA genotypes were associated with a decreased risk of DTC (adjusted OR = 0.6, 95% CI: 0.4-0.9), particularly multifocal DTC (adjusted OR = 0.3, 95% CI: 0.1-0.7). The association with DTC was more evident in subjects with a first-degree family history of cancer (adjusted OR = 0.4, 95% CI: 0.2-0.7, P(interaction) ?= 0.013) and non-drinkers (adjusted OR = 0.4, 95% CI: 0.2-0.7, P(interaction) ?= 0.028). A four single nucleotide polymorphism haplotype of IGFBP-3 was associated with a decreased risk of DTC (adjusted OR = 0.7, 95% CI: 0.5-1.0, P = 0.030). Our study suggests that polymorphic IGFBP-3 may be involved in susceptibility to DTC.

| S-EPMC3473095 | biostudies-literature

<i>CCND1</i> gene polymorphic variants in patients with differentiated thyroid carcinoma.

Project description:Alterations in the CCND1 gene affect the cell cycle and are frequently observed in a variety of cancers. While the most frequent mutations that occur in thyroid tumor tissue have been characterized, the genetic factors that predispose individuals to differentiated thyroid cancer (DTC) remain to be elucidated. The present study examined whether the CCND1 c.723G>A (rs9344; p.Pro241=) and c.669C>T (rs3862792; p.Phe223=) variants have an impact on DTC susceptibility. A cohort consisting of 652 patients diagnosed with DTC were analyzed and comapred with a reference group of 799 subjects from the general population. Pyrosequencing was used as the genotyping technique. In order to determine the statistical significance of differences observed in the genotypic and allelic frequencies between the compared groups, GraphPad Prism 4 was used. At the rs9344 locus in the DTC patients, a higher frequency of allele A [P=0.032; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.014-1.361] and the AA homozygous genotype (P=0.028; OR, 1.41; 95% CI, 1.059-1.989) was observed compared with the control population group. The differences were stronger for papillary carcinomas (OR 1.45; 95% CI, 1.059-1.989), but were not significant in follicular tumors. No statistically significant differences were noted in the frequency of genotypes or alleles at the rs3862792 locus in the examined groups. The present findings indicate that the c.723A variant of the CCDN1 gene may be a susceptibility low penetrance allele in the development of papillary thyroid cancer in the population studied, however it does not impact on multifocality, metastatic ability or age at diagnosis. A cumulative effect of the analyzed CCND1 gene variants was also excluded.

| S-EPMC4247015 | biostudies-literature

Multikinase inhibitors use in differentiated thyroid carcinoma.

Project description:Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC) includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs) that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required.

| S-EPMC4260520 | biostudies-literature

Anaplastic and poorly differentiated thyroid carcinomas: genetic evidence of high‐grade transformation from differentiated thyroid carcinoma

Project description: Not available

| S-EPMC10796291 | biostudies-literature

Hobnail variant of papillary thyroid carcinoma: molecular profiling and comparison to classical papillary thyroid carcinoma, poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma.

Project description:BackgroundAs a rare but aggressive papillary thyroid carcinoma (PTC) variant, the genetic changes of hobnail variant of PTC (HVPTC) are still unclear.ResultsThe prevalence of HVPTC was 1.69% (18/1062) of all PTC diagnosed in our cohort. 73 samples from 55 patients (17 HVPTC, 26 CPTC, 7 PDTC and 5 ATC) were successfully analyzed using targeted NGS with an 18-gene panel. Thirty-seven mutation variant types were identified among 11 genes. BRAF V600E mutation was the most common mutation, which is present in almost all HVPTC samples (16/17, 94%), most CPTC samples (20/26, 77%), and none of the ATC and PDTC samples. TERT promoter mutation (C228T) was identified in 2 ATC and one HVPTC patient. RAS and TP53 mutation are almost exclusively present among ATC and PDTC samples although TP53 mutation was also observed in 3 HVPTC patients. Six different GNAS mutations were identified among 8 CPTC patients (31%) and none of the HVPTC patients. The only patient who died of disease progression harbored concomitant TERT C228T mutation, BRAF V600E mutation and TP53 mutation.MethodsHVPTC cases were identified from a group of 1062 consecutive surgical specimens diagnosed as PTC between 2000 and 2010. Targeted next-generation sequencing (NGS) was applied to investigate the mutation spectrum of HVPTC, compared to classical PTC (CPTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC).ConclusionAs an aggressive variant of PTC, HVPTC has relatively specific molecular features, which is somewhat different from both CPTC and ATC/PDTC and may underlie its relatively aggressive behavior.

| S-EPMC5400643 | biostudies-literature

SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility.

Project description:BackgroundPapillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative.ObjectivesThe objective of this study was to identify susceptibility genes for PTC.MethodsA genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies.ResultsLinkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants.ConclusionsOur findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.

| S-EPMC3644596 | biostudies-literature

Nonoperative management of low-risk differentiated thyroid carcinoma.

Project description:Purpose of reviewThe global incidence of small papillary thyroid carcinoma (PTC) is increasing remarkably, mostly due to the increased use of imaging studies worldwide. The issue of how to manage low-risk small PTC has become urgent. In this review, we focus on how to treat low-risk papillary thyroid microcarcinomas (PMCs; i.e., PTCs measuring ≤10 mm).Recent findingsStudies of large numbers of patients with low-risk PMC clarified that most of the PMCs did not grow or grew very slowly and were harmless. Active observations of these patients discriminated rare progressive cases from the majority. Surgery performed after the detection of progression signs was not too late, and surgery immediately after the detection and diagnosis of low-risk PMC may be overtreatment for most patients. Interestingly, low-risk PMCs in elderly patients were most unlikely to progress, in sharp contrast to clinical PTC. The reason for this phenomenon remains unknown.SummaryActive observation without immediate surgery can be a leading alternative to the classical surgical treatment in the majority of the patients with low-risk PMC. It is not too late to perform surgery after the detection of progression signs for these patients.Video abstracthttp://links.lww.com/COON/A10

| S-EPMC4255758 | biostudies-literature

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