Genetic susceptibility to hereditary non-medullary thyroid cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Kamani T
PROVIDER: S-EPMC8900298 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
Publications
Genetic susceptibility to hereditary non-medullary thyroid cancer.
Kamani Tina T Charkhchi Parsa P Zahedi Afshan A Akbari Mohammad R MR
Hereditary cancer in clinical practice 20220307 1
Non-medullary thyroid cancer (NMTC) is the most common type of thyroid cancer. With the increasing incidence of NMTC in recent years, the familial form of the disease has also become more common than previously reported, accounting for 5-15% of NMTC cases. Familial NMTC is further classified as non-syndromic and the less common syndromic FNMTC. Although syndromic NMTC has well-known genetic risk factors, the gene(s) responsible for the vast majority of non-syndromic FNMTC cases are yet to be ide ...[more]
Similar Datasets
Project description: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.
| S-EPMC7698903 | biostudies-literature
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.
| S-EPMC3989221 | biostudies-literature
Project description:Familial non-medullary thyroid cancer (FNMTC) is a well-differentiated thyroid cancer (DTC) of follicular cell origin in two or more first-degree relatives. Patients typically demonstrate an autosomal dominant inheritance pattern with incomplete penetrance. While known genes and chromosomal loci account for some FNMTC, the molecular basis for most FNMTC remains elusive. To identify the variation(s) causing FNMTC in an extended consanguineous family consisting of 16 papillary thyroid carcinoma (PTC) cases, we performed whole exome sequence (WES) analysis of six family patients. We demonstrated an association of ARHGEF28, FBXW10, and SLC47A1 genes with FNMTC. The variations in these genes may affect the structures of their encoded proteins and, thus, their function. The most promising causative gene is ARHGEF28, which has high expression in the thyroid, and its protein-protein interactions (PPIs) suggest predisposition of PTC through ARHGEF28-SQSTM1-TP53 or ARHGEF28-PTCSC2-FOXE1-TP53 associations. Using DNA from a patient's thyroid malignant tissue, we analyzed the possible cooperation of somatic variations with these genes. We revealed two somatic heterozygote variations in XRCC1 and HRAS genes known to implicate thyroid cancer. Thus, the predisposition by the germline variations and a second hit by somatic variations could lead to the progression to PTC.
| S-EPMC10179265 | biostudies-literature
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.
| S-EPMC4632085 | biostudies-literature
Project description:Medullary thyroid carcinoma (MTC) is an infrequent, calcitonin producing neuroendocrine tumor and initiates from the parafollicular C cells of the thyroid gland. Several genetic and epigenetic alterations are collaterally responsible for medullary thyroid carcinogenesis. In this review article, we shed light on all the genetic and epigenetic hallmarks of MTC. From the genetic perspective, RET, HRAS, and KRAS are the most important genes that are characterized in MTC. From the epigenetic perspective, Ras-association domain family member 1A, telomerase reverse transcriptase promoter methylations, overexpression of histone methyltransferases, EZH2 and SMYD3, and wide ranging increase and decrease in non-coding RNAs can be responsible for medullary thyroid carcinogenesis.
| S-EPMC5889499 | biostudies-literature
Project description:Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)-MLHL, MSH2, MSH6, PMS2, and EPCAM-is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.
| S-EPMC8315151 | biostudies-literature
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
Project description:The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%-15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors. Moreover, we discuss whether the genetic polymorphism rs966423 in DIRC3 has any potential as a prognostic factor of papillary thyroid cancer.
| S-EPMC6678600 | biostudies-literature
Project description:BackgroundAlthough a family history of thyroid cancer is one of the main risk factors for thyroid cancer, the benefit of screening individuals with a family history of thyroid cancer is not known.MethodsA prospective cohort study was performed with yearly screening using neck ultrasound and fine-needle aspiration biopsy of thyroid nodule(s) >0.5 cm in at-risk individuals whose relatives were diagnosed with familial non-medullary thyroid cancer (FNMTC). The eligibility criteria were the presence of thyroid cancer in two or more first-degree relatives and being older than seven years of age. Twenty-five kindred were enrolled in the study (12 families with two members affected, and 13 with three or more members affected at enrollment).ResultsThyroid cancer was detected by screening in 4.6% (2/43) of at-risk individuals from families with two members affected, and in 22.7% (15/66) of at-risk members from families with three or more patients affected (p = 0.01). FNMTC detected by screening was characterized by a smaller tumor size (0.7 ± 0.5 cm vs. 1.5 ± 1.1 cm; p = 0.006), a lower rate of central neck lymph node metastases (17.6% vs. 51.1%; p = 0.02), less extensive surgery (hemithyroidectomy 23.5% vs. 0%; p = 0.002), and a lower rate of radioactive iodine therapy (23.5% vs. 79%; p < 0.001) compared to those affected at enrollment.ConclusionsScreening of at-risk family members resulted in earlier detection of low-risk FNMTC and was associated with a less aggressive initial treatment. Screening with thyroid ultrasound should be considered in kindred with three or more family members affected by FNMTC. Since active screening might be associated with the risk of overtreatment, it should be implemented with caution, specifically in elderly individuals.
| S-EPMC5564020 | biostudies-literature
Project description:PurposeVandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits rearranged during transfection kinase activity. Vandetanib (300 mg/d) has previously demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer (MTC). This study investigated the efficacy and safety of 100 mg/d vandetanib in patients with advanced hereditary MTC.Patients and methodsEligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d vandetanib. Upon disease progression, eligible patients could enter postprogression treatment with 300 mg/d vandetanib until a withdrawal criterion was met. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors.ResultsThe study comprised 19 patients (13 males, six females; mean age 45 yr). Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% (95% confidence interval 3.4-39.6). Stable disease lasting 24 wk or longer was reported in a further 10 patients (53%); the disease control rate was therefore 68% (95% confidence interval 43.4-87.4). Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 16% (three of 19) and 5% (one of 19) of patients, respectively. Adverse events were predominantly grade 1 or 2 and consistent with previous vandetanib monotherapy studies.ConclusionsVandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile.
| S-EPMC2902067 | biostudies-literature