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

ABSTRACT: 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.

SUBMITTER: Miasaki FY

PROVIDER: S-EPMC7698903 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Miasaki Fabíola Yukiko FY Fuziwara Cesar Seigi CS Carvalho Gisah Amaral de GA Kimura Edna Teruko ET

Genes 20201118 11

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 facto ...[more]

PMID: 33218058

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Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.

Project description:Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500× coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients.

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Familial non-medullary thyroid cancer: a critical review.

Project description:BackgroundFamilial non-medullary thyroid carcinoma (FNMTC), mainly of papillary histotype (FPTC), is defined by the presence of the disease in two or more first-degree relatives in the absence of other known familial syndromes. With the increasing incidence of PTC in the recent years, the familial form of the disease has also become more common than previously reported and constitutes nearly 10% of all thyroid cancers. Many aspects of FNMTC are debated, concerning both clinical and genetic aspects. Several studies reported that, in comparison with sporadic PTCs, FPTCs are more aggressive at disease presentation, while other authors reported no differences in the clinical behavior of sporadic and familial PTCs. For this reason, recent guidelines do not recommend screening of family members of patients with diagnosis of differentiated thyroid cancer (DTC). FNMTC is described as a polygenic disorder associated with multiple low- to moderate-penetrance susceptibility genes and incomplete penetrance. At the moment, the genetic factors contributing to the development of FNMTC remain poorly understood, though many putative genes have been proposed in the recent years.PurposeBased on current literature and our experience with FNMTC, in this review, we critically discussed the most relevant controversies, including its definition, the genetic background and some clinical aspects as screening and treatment.

| S-EPMC8049908 | biostudies-literature

Role of genetic variants of autophagy genes in susceptibility for non-medullary thyroid cancer and patients outcome.

Project description:Autophagy is a central process in regulation of cell survival, cell death and proliferation and plays an important role in carcinogenesis, including thyroid carcinoma. Genetic variation in autophagy components has been demonstrated to influence the capacity to execute autophagy and is associated with disease susceptibility, progression and outcome. In the present study, we assessed whether genetic variation in autophagy genes contributes to susceptibility to develop thyroid carcinoma, disease progression and/or patient outcome. The results indicate that patients carrying the ATG5 single nucleotide polymorphisms rs2245214 have a higher probability to develop thyroid carcinoma (OR 1.85 (95% CI 1.04-3.23), P?=?0.042). In contrast, no significant differences could be observed for the other genetic variants studied in terms of thyroid carcinoma susceptibility. Furthermore, none of the selected genetic variants were associated with clinical parameters of disease progression and outcome. In conclusion, genetic variation in ATG5, a central player in the autophagy process, is found to be associated with increased susceptibility for thyroid carcinoma, indicating a role for autophagy in thyroid carcinogenesis.

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Results of Screening in Familial Non-Medullary Thyroid Cancer.

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Genetics of Familial Non-Medullary Thyroid Carcinoma (FNMTC).

Project description:Non-medullary thyroid carcinoma (NMTC) is the most frequent endocrine tumor and originates from the follicular epithelial cells of the thyroid. Familial NMTC (FNMTC) has been defined in pedigrees where two or more first-degree relatives of the patient present the disease in absence of other predisposing environmental factors. Compared to sporadic cases, FNMTCs are often multifocal, recurring more frequently and showing an early age at onset with a worse outcome. FNMTC cases show a high degree of genetic heterogeneity, thus impairing the identification of the underlying molecular causes. Over the last two decades, many efforts in identifying the susceptibility genes in large pedigrees were carried out using linkage-based approaches and genome-wide association studies, leading to the identification of susceptibility loci and variants associated with NMTC risk. The introduction of next-generation sequencing technologies has greatly contributed to the elucidation of FNMTC predisposition, leading to the identification of novel candidate variants, shortening the time and cost of gene tests. In this review we report the most significant genes identified for the FNMTC predisposition. Integrating these new molecular findings in the clinical data of patients is fundamental for an early detection and the development of tailored therapies, in order to optimize patient management.

| S-EPMC8125431 | biostudies-literature

NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer.

Project description:Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3-9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.

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Clinical and Genetic Features of a Large Monocentric Series of Familial Non-Medullary Thyroid Cancers.

Project description:Several low penetration susceptibility risk loci or genes have been proposed in recent years with a possible causative role for familial non-medullary thyroid cancer (FNMTC), though the results are still not conclusive or reliable. Among all the candidates, here fully reviewed, a new extremely rare germline variant c.3607A>G (p.Y1203H) of the DUOX2 gene, has been recently reported to co-segregate with the affected members of one non-syndromic FNMTC family. We aimed to validate this finding in our series of 33 unrelated FNMTC Italian families, previously found to be negative for two susceptibility germline variants in the HABP2 and MAP2K5 genes. Unfortunately, the DUOX2 p.Y1203H variant was not found in either the 74 affected or the 12 not affected family members of our series. We obtained interesting data by comparing the clinico-pathological data of the affected members of our kindreds with a large consecutive series of sporadic cases, followed at our site. We found that familial tumors had a statistically significant more aggressive presentation at diagnosis, though not resulting in a worst outcome. In conclusion, we report genetic and clinical data in a large series of FNMTC kindreds. Our families are negative for variants reported as likely causative, namely those lying in the HABP2, MAP2K5 and DUOX2 genes. The extensive review of the current knowledge on the genetic risk factors for non-syndromic FNMTCs underlies how the management of these tumors remains mainly clinical. Despite the more aggressive presentation of familial cases, an appropriate treatment leads to an outcome similar to that observed for sporadic cases.

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The HABP2 G534E variant is an unlikely cause of familial non-medullary thyroid cancer.

Project description:CONTEXT:A recent study reported the non-synonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial non-medullary thyroid cancer (NMTC). OBJECTIVE:The objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multi-center population based study of NMTC cases from the British Isles. DESIGN AND SETTING:A case-control analysis of rs7080536 genotypes was performed using 2,105 TCUKIN cases and 5,172 UK controls. PARTICIPANTS:Cases comprised 2,105 NMTC cases. Patients sub-groups with papillary (N=1,056), follicular (N=691) and Hurthle cell (N=86) TC cases were studied separately. Controls comprised 5,172 individuals from the 1958 Birth Cohort (58C) and the National Blood Donor Service (NBS) study. The controls had previously been genotyped using genome-wide SNP arrays by the Wellcome Trust Case Control Consortium study. OUTCOME:Measures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression. RESULTS:The frequency of HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (OR=0.896, 95% CI: 0.746-1.071, P=0.233). We also failed to detect an association between HABP2 G534E and cases with papillary (1056 cases, G534E frequency= 3.5%, OR=0.74, P=0.017), follicular (691 cases, G534E frequency= 4.7%, OR=1.00, P=1.000) or Hurthle cell (86 cases, G534E frequency= 6.3%, OR=1.40, P=0.279) histology. CONCLUSIONS:We found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC and additional data are required before using this variant in NMTC risk assessment.

| S-EPMC4803181 | biostudies-literature

Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary thyroid cancer.

Project description:BACKGROUND: Familial non-medullary thyroid cancer (fNMTC) is a complex genetic disorder that is more aggressive than its sporadic counterpart. Thus far, three genetic loci have been implicated in susceptibility to fNMTC by linkage analysis. METHODS: We used linkage analysis to test the significance of two of the known susceptibility loci for fNMTC, TCO on 19p13 and NMTC1 on 2q21 in 10 fNMTC families, nine of which present with cell oxyphilia, a rare histological phenotype associated with TCO. Furthermore, we used two-locus linkage analysis to examine the possibility that the TCO and NMTC1 loci interact to increase the risk of NMTC. RESULTS: The 10 families provided evidence for linkage at both TCO and NMTC, with LOD scores of 1.56 and 2.85, respectively. Two-locus linkage analysis, using a multiplicative risk model for the development of NMTC, achieved a maximum LOD of 3.92, with an LOD of 4.51 when assuming 70% of families were linked, indicating that the segregation in these families is consistent with an interaction model. Most of this evidence came from a large Tyrolean family that singularly achieved a two-locus LOD of 3.21. CONCLUSIONS: These results provide further evidence that susceptibility genes for fNMTC exist at 19p13 and 2q21, and furthermore, raise the possibility that in a subset of fNMTC pedigrees, these loci interact resulting in significantly increased risk of NMTC for patients that carry both susceptibility loci.

| S-EPMC1735809 | biostudies-other

Akt1 genetic variants confer increased susceptibility to thyroid cancer.

Project description:The PI3K-Akt-mTOR pathway plays a central role in the development of non-medullary thyroid carcinoma (NMTC). Although somatic mutations have been identified in these genes in NMTC patients, the role of germline variants has not been investigated. Here, we selected frequently occurring genetic variants in AKT1, AKT2, AKT3, PIK3CA and MTOR and have assessed their effect on NMTC susceptibility, progression and clinical outcome in a Dutch discovery cohort (154 patients, 188 controls) and a Romanian validation cohort (159 patients, 260 controls). Significant associations with NMTC susceptibility were observed for AKT1 polymorphisms rs3803304, rs2494732 and rs2498804 in the Dutch discovery cohort, of which the AKT1 rs3803304 association was confirmed in the Romanian validation cohort. No associations were observed between PI3K-Akt-mTOR polymorphisms and clinical parameters including histology, TNM staging, treatment response and clinical outcome. Functionally, cells bearing the associated AKT1 rs3803304 risk allele exhibit increased levels of phosphorylated Akt protein, potentially leading to elevated signaling activity of the oncogenic Akt pathway. All together, germline encoded polymorphisms in the PI3K-Akt-mTOR pathway could represent important risk factors in development of NMTC.

| S-EPMC7774771 | biostudies-literature

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