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Childhood progression of hereditary medullary thyroid cancer - Reply
... Its GC rich promoter locates in the nucleotide sequence of exon1. The main RET transcript length is 5659 base pairs and is translated to 1114 amino acid-residue protein (Machens et al., 2003). The RET protein is 170 KDa, present on the cell surface, and highly phosphorylated on tyrosine residues (Asai et al., 1995). ...
... Mutation of the extracellular cysteine in codon 634 in exon 11 of RET causes ligand-independent dimerization of receptor molecules, enhanced phosphorylation of intracellular substrates and cell transformation. Mutation of the intracellular TK (for example codon 918) has no effect on receptor dimerization but does cause constitutive activation of intracellular signaling pathways and also results in cellular transformation (Machens et al., 2003). Further, rearrangements of RET (RET/PTC) are associated with papillary thyroid carcinoma (PTC) commonly seen in tumors of children and tumors associated with radiation exposure (Tallini and Asa, 2001). ...
... There is a significant age-related progression from CCH to MTC that correlates with the transformative capacity for the particular RET mutation. C-cells are more susceptible to oncogenic RET activation than adrenal medullary or parathyroid cells (Machens et al., 2003). The mutations characteristic of FMTC also occur in exons 10 and 11. ...
Thyroid cancer is the most common endocrine neoplasia. The medullary thyroid carcinoma (MTC) is one of the most aggressive forms of thyroid malignancy,accounting for up to 10% of all types of this disease. The mode of inheritance of MTC is autosomal dominantly and gain of function mutations in the RET proto-oncogene are well known to contribute to its development. MTC occurs as hereditary (25%) and sporadic (75%) forms. Hereditary MTC has syndromic (multiple endocrine neoplasia type 2A, B; MEN2A, MEN2B) and non-syndromic (Familial MTC, FMTC) types. Over the last two decades, elucidation of the genetic basis of tumorigenesis has provided useful screening tools for affected families. Advances in genetic screening of the RET have enabled early detection of hereditary MTCs and prophylactic thyroidectomy for relatives who may not show any symptom sof the disease. In this review we emphasize the main RET mutations in syndromic and non syndromic forms of MTC, and focus on the importance of RET genetic screening for early diagnosis and management of MTC patients, based on American Thyroid Association guidelines and genotype-phenotype correlation
... About 25% of MEN 2A patients can also develop PHPT [63]. MTC is generally the first manifestation of MEN2A and develops between the ages of 5 to 25 years [16]. PHEO usually presents after MTC or concomitantly; however, it has been reported as the first sign of the syndrome in 13–27% of MEN 2A cases [64, 65]. ...
... It is the only malignant tumor and the most severe disease of the syndrome so that in the majority of cases the prognosis of the disease is mainly related with the prognosis of the MTC. An age-related progression to MTC has been described with younger age of onset for MEN 2B (youngest reported 0.6 year), older age for FMTC (usually adult age > 20 years), and intermediate age (starting from 1.5 years, but childhood age is the most prevalent) [16] (Table 3). Up to 70% of MTC patients have already cervical lymph node metastases at the diagnosis [77] and this is a unfavorable prognostic factor for the cure of the disease. ...
... These mutations are mainly affecting the non cysteine codons located at exons 5, 8, 13, 14 and 15 with 20% to 30% of mutations located at one of the five cysteine residues (codons 609, 611, 618, 620, and 634). A different geographic distribution has been reported especially for cysteine and non cysteine mutations [15, 16, 76] (Table 4); ...
Multiple endocrine neoplasia (MEN) are clinical inherited syndromes affecting different endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. Heterozygous MEN 1 germline mutations have been detected in about 70-80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the endocrine neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of the RET protooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specific RET mutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target the RET pathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment.
... Amplification was carried out in a volume of 50 μL containing 1.5 μL of 10×buffer, 50 ng DNA, 0.3 μL of each dNTPs (10 mM) (Boehringer Mannheim Co.), 1 μL of each exons 10 and 11 primers (10 μM) (TIB MOLBIOL Synthesalabor Co.), 0.25 μL MgCl 2 (50 mM), and one U Taq polymerase (Boehringer Mannheim Co.). PCR reaction for both exons 10 and 11 was 30 cycles and performed in an automatic thermocycler (Omnigene & Hybaid Co.) under the following conditions: denaturation at 93 @BULLET C for 45 seconds, annealing at 67 @BULLET C for 30 seconds and extension at 72 @BULLET C for another 45 seconds, and final extension at 72 @BULLET C for 10 minutes [18, 27]. For amplification of the DNA segment containing RET exon 16, the following primers were used: (16F 5 GTGCCC- AGGAGTGTCTACCA3 ) and (16R 5 CAGGACCACAGG- AGGGTAAC3 ). ...
... A PCR reaction of exon 16 was performed in a 15 μL mixture containing 50 ng DNA, 0.35 μL of MgCl 2 (50 mM), 0.5 μL of each dNTPs (10 mM) (Boehringer Mannheim Co.), 0.6 μL of each exon 16 primers (10 μM) (TIB MOLBIOL Synthesalabor Co.), 1.5 μL of 10 × buffer, and one U Taq polymerase (Boehringer Mannheim Co.). PCR reaction for exon 16 was 30 cycles and performed in an automatic thermocycler (Omnigene & Hybaid Co.) under the following conditions: denaturation at 92 @BULLET C for 10 minutes and 93 @BULLET C for 45 seconds, annealing at 59.5 @BULLET C for 30 seconds, extension at 72 @BULLET C for 55 seconds, and final extension at 72 @BULLET C for 10 minutes272829. The amplified PCR products were digested by each of Taq I, BstU I, Mbo II, Rsa I, Nla IV (England Biolabs), and Cfo I (Roehe Molecular Biochemicals) restriction enzymes for exon 10. ...
... The amplified PCR products were digested by each of Taq I, BstU I, Mbo II, Rsa I, Nla IV (England Biolabs), and Cfo I (Roehe Molecular Biochemicals) restriction enzymes for exon 10. The products were digested with the following restriction enzymes Cfo I, Rsa I, Hae III, and Dde I for exon 11, and FokI for exon 16 (England Biolabs) in the restriction buffer according to the manufacturer's instructions [10, 27, 28]. The RFLP-produced patterns by these restriction enzymes in the presence and absence of each RET exon 10, 11, and 16 mutations have been shown inTable 1. ...
Medullary thyroid carcinoma occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%), 11 (13%), and 16 (0.9%). Moreover, a novel germline mutation was detected in exon 11 (S686N). Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%). The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC.
... Since then, DNA analysis has become available to identify patients with hereditary MTC and to perform predictive testing in asymptomatic family members of mutation carriers. A genotype-phenotype relationship exists for different RET proto-oncogene mutations [9, 10]. The expression of MTC in terms of aggressiveness varies between the different codon mutations . ...
... By then, many had already progressed into late-stage MTC with lymph node or distant metastases. The availability of presymptomatic DNA analysis by direct detection of germline RET protooncogene mutations provided a rationale to perform prophylactic surgery because in 95% of patients with MEN 2 and FMTC, C-cell hyperplasia develops into MTC [4, 9, 10, 12, 13]. In recent years, timing of prophylactic thyroidectomy in asymptomatic carriers of germline RET gene mutations has been customized based on the age and type of mutation [9, 10]. ...
... The availability of presymptomatic DNA analysis by direct detection of germline RET protooncogene mutations provided a rationale to perform prophylactic surgery because in 95% of patients with MEN 2 and FMTC, C-cell hyperplasia develops into MTC [4, 9, 10, 12, 13]. In recent years, timing of prophylactic thyroidectomy in asymptomatic carriers of germline RET gene mutations has been customized based on the age and type of mutation [9, 10]. In an effort to further optimize the management of these children, we conducted a nationwide study, including all Dutch patients who underwent total thyroidectomy in childhood in the past 25 years. ...
Background
Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients.
Methods
In a nationwide case–control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease.
Results
A total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease.
Conclusions
Prophylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients.
... This is the first study of molecular genetic screening of MTC patients (familial and sporadic) in the Azari population of north-west Iran. Identification of the mutations in the RET proto-oncogene confirms the clinical diagnosis and identifies asymptomatic family members with FMTC or MEN2 syndrome [23] . Since sporadic MTC (isolated, non-familial MTC) seems to be the presenting clinical feature for some MEN2 patients, RET genotyping is often performed for patients with sporadic MTC [24]. ...
... Mutations of the extracellular RET cysteine-rich domain at codon 634, 609, 611, and 620 resulted in ligand-independent dimerization of receptor molecules, enhanced phosphorylation of intracellular substrates, and cell transformation. Germline mutations in codons 609, 611, 618, 620, 634, and 768 have been discovered predominantly in MEN2 and FMTC [23]. The mutations at codon 634, accounted for 84.4% of all mutations found in the Azari patients with MTC from our study in north-west Iran. ...
Background:
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor from the para follicular C cells of the thyroid gland. It occurs either sporadically or as part of an inherited syndrome. It is caused by an autosomal dominant mutation in the RET (Rearranged during Transfection) proto-oncogene.
Methods:
The studied population consisted of 47 patients diagnosed with MTC in a specific population of northwest Iran along with their three children. Blood samples were collected from all subjects, genomic DNA was extracted and RET exons 10, 11, 13, 14, 15, and 16 were analyzed using PCR and direct sequencing.
Results:
32 missense mutations were identified in exons 10 (6.25%) and 11 (84.4%). Moreover, two novel mutations in codon 595 in exon 10 (E595D and E595A) and a new mutation in codon 689 exon 11 (S689T) were detected, and a new nucleotide change was found in exon 11 (T675T). Four different polymorphisms were also identified in exons 11, 13, 14, and 15. Based on our data, the frequency profile of RET mutations in the Azari population of Iran with MTC is 61.7%. The most frequent mutation in our population was C364G, whereas in most populations it is C634R.
Conclusions:
These results underline the importance of the genetic background of family members of any patient with MTC.
... The youngest age at diagnosis of phaeochromocytoma reported in literature was 12 years, also in a codon 918 mutation carrier [9]. But others observed early manifestation at the age of 12 years in the case of a patient with mutation in codon 634 [12]. The youngest patient age ever reported with disclosed phaeochromocytoma determines the moment of implementation of screening protocol. ...
Introduction: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant genetic syndrome caused by germline mutation in RET proto-oncogene. The most common mutations are in a cysteine rich domain. Phaeochromocytoma will develop in approximately 50% of RET proto-oncogene carriers.
Material and methods: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy).
Results: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma.
Conclusions: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma. (Endokrynol Pol 2016; 67 (1): 54–58)
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... The youngest age at diagnosis of phaeochromocytoma reported in literature was 12 years, also in a codon 918 mutation carrier [9]. But others observed early manifestation at the age of 12 years in the case of a patient with mutation in codon 634 [12]. The youngest patient age ever reported with disclosed phaeochromocytoma determines the moment of implementation of screening protocol. ...
Proto-oncogene RET encodes a receptor tyrosine kinase. Germline point mutations of RET result in development of multiple endocrine neoplasia, type 2 (MEN 2). MEN 2 phenotype is correlated with intragene localization of germline mutation. The disease has three main subtypes, MEN 2A, MEN 2B and FMTC. Each of subtypes is associated with high risk of medullary thyroid cancer, MEN 2A and MEN 2B with 50% risk of pheochromocytoma, MEN 2A with 1530% risk of primary hyperparathyroidism. Pheochromocytomas in MEN 2 patients are usually localized in adrenal glands, being benign, and often bilateral.
The aim of this study was to evaluate the development of pheochromocytomas in patients with germline proto-oncogene RET mutations. Among 228 gene carriers, most often MEN 2 was caused by mutation in codon 634 (36.85%). Pheochromocytoma was diagnosed in 36 patients, in 24 with mutation in codon 634, in six in codon 918 and in three in codon 620, in two in codon 618 and in one in codon 611. The youngest age at pheochromocytoma onset was 15 years, this was in patient with mutation in codon 918. In 6 (16.7%) gene carriers the pheochreomocytoma was the first manifestation of MEN 2. Most of patients in time of pheochromocytoma diagnosis didnt present classical symptoms. Pheochromocytomas were detected with use of adrenal imaging (TK, MR, MIBG scintigraphy) and determination of urinary metoxycatecholamines. In 11 (30.5%) tumor was bilateral, initially with mean size of 3.6 cm.
This study demonstrates necessity of regular follow-up in germline proto-oncogene RET mutation carriers using additional exams, not only clinical evaluation. Taking in to account different interferences influencing biochemical assessment, we suggest that adrenal imaging (TK/MR) should be used as complementary follow-up method. The start of regular monitoring depends on the age of the known youngest patient with diagnosed pheochromocytoma.
... It is reported that biochemical cure predicted a survival rate of 97.7% at 10 years [10]. Within the past decade the prognosis has improved mainly because of earlier diagnosis and improvement in surgical procedures [10, 11]. Nevertheless, more than 50% of thyroidectomized patients are not cured after surgery, as persistent elevation of basal serum calcitonin levels, which implies residual tumor, is frequently observed after primary surgery [5, 10] . ...
Purpose. Measurement of serum calcitonin is important in the followup of patients with medullary thyroid carcinoma (MTC) and reliably reflects the presence of the disease. This is the largest study so far in bibliography investigating the diagnostic accuracy of combined [(18)F]FDG-PET/CT in patients with MTC and elevated calcitonin levels. Methods. Between February 2007 and February 2011, 59 [(18)F]FDG-PET/CT were performed on 51 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Conventional morphologic imaging methods were negative or showed equivocal findings. Results. Among the 59 [(18)F]FDG-PET/CT, 29 were positive (26 had true-positive and 3 false-positive findings) and 30 negative. The overall per-patient sensitivity of [(18)F]FDG-PET/CT was 44.1%. Using as cut-off point the calcitonin value of 1000 pg/ml, in patients with calcitonin exceeding this value, sensitivity raised to 86.7%. The overall sensitivity of [(18)F]FDG-PET/CT was lower (23%) in patients with MEN IIA syndrome. Conclusion. The findings of this paper show that [(18)F]FDG-PET/CT is valuable for the detection of recurrence in patients with highly elevated calcitonin levels, >1000 pg/mL, but in patients with lower calcitonin levels, its contribution is questionable. Also, there is evidence that the sensitivity of [(18)F]FDG-PET/CT is lower in patients with MTC as part of MEN IIA syndrome.
... Since then, several vaccination trials have been performed in murine models and as well in man. Vaccination studies with CT-loaded DCs were performed in a transgenic mouse model for MTC mice displaying the identical mutation (substitution of Cys for Arg) within the RET protooncogene at codon 634 as most patients with multiple endocrine neoplasia type 2A [77, 78]. As in patients with hereditary MTC, Ret/Cal mice develop diffuse C cell hyperplasia and MTC with increased serum CT levels [77]. ...
Up to now, there are no curative therapies available for the subset of metastasized undifferentiated/anaplastic thyroid carcinomas. This review describes the possible use of immunocompetent cells which may help to restore the antitumor immune recognition for treating an existing tumor or preventing its recurrence. The most prominent experimental strategy is the use of dendritic cells (DCs) which are highly potent in presenting tumor antigens. Activated DCs subsequently migrate to draining lymph nodes where they present antigens to naïve lymphocytes and induce cytotoxic T cells (CTL). Alternatively to DC therapy, adoptive cell transfer may be performed by either using natural killer cells or ex vivo maturated CTLs. Within this review article we will focus on recent advances in the understanding of anti-tumor immune responses, for example, in thyroid carcinomas including the advances which have been made for the identification of potential tumor antigens in thyroid malignancies.
... Similar findings have been obtained in patients with 649L (transmembrane domain) RET mutation. It has been reported that either patients carrying this mutation developed a mild MTC phenotype, thus delaying its diagnosis at an older age and confirming data already reported in literature [98, 99], or double RET mutants, 649L and 634, exhibited a more aggressive course, with the clinical phenotype dominated by the " more severe " mutation, C634 [96, 100, 101]. Prophylactic thyroidectomy in 649L mutant carriers should be correlated to the levels of stimulated calcitonin [101]. ...
The thyroid cancer is a rare oncological entity, representing no more than 1% of all human malignant neoplasms. Recently, it has been demonstrated a sharp increase in incidence of differentiated thyroid carcinoma, equally occurring in both sexes. So far, multiple genetic alterations have been identified in differentiated thyroid carcinoma, leading to investigate the clinical utility of genetic studies. In particular, molecular genetic approaches searching for gene mutations in the material collected by fine needle ago-biopsy may have a particular utility in small nodules and in those specimens with an indeterminate cytology. The expansion of knowledge about genetic mutations occurring in different thyroid tumors has characterized recent years, allowing the identification of a correlation between specific mutations and phenotypic characteristics of thyroid cancers, essential for their prognosis. This review will briefly report on the histological features and the new entity represented by thyroid microcarcinoma and will focus on both environmental and genetic aspects associated with the occurrence of thyroid cancer.
... Mutations in the RET proto-oncogenes have been implicated in nearly 95% of cases of hereditary MTC associated with MEN types 2A and 2B and FMTC. Interestingly, in hereditary MTC, recent data suggest that specific germline RET mutations are associated with agespecific penetrance of cancer development and lymph node metastases [2, 15]. The most common mutation in MEN 2A (codon 634) occurs in up to 80% of MEN 2 families and nearly half of affected children develop MTC by ages 5–10. ...
Medullary thyroid cancer (MTC) is a rare neuroendocrine neoplasm that accounts for approximately 5% of all thyroid malignancies. The natural history of MTC is characterized by early lymph node and distant metastases, making complete surgical cure often impossible. Conventional chemotherapy and external beam radiation have been largely ineffective in altering the natural history of MTC. Therefore, there is a great need to develop novel therapeutic strategies to affect symptom control and reduce tumor burden in patients with widely disseminated disease. Here, we review several pathways which have been shown to be vital in MTC tumorigenesis and focus on the pathways of interest for which targeted drug therapies are currently being developed.
... The typical age at onset of biochemical evidence of MTC in untreated patients with MEN2A is 15 to 20 years. However, MTC is frequent in children ages 10 years and younger515253. Most patients with MEN2A have an affected parent. ...
The multiple endocrine neoplasia (MEN) syndromes are rare autosomal-dominant conditions that predispose affected individuals to benign and malignant tumors of the pituitary, thyroid, parathyroids, adrenals, endocrine pancreas, paraganglia, or nonendocrine organs. The classic MEN syndromes include MEN type 1 and MEN type 2. However, several other hereditary conditions should also be considered in the category of MEN: von Hippel-Lindau syndrome, the familial paraganglioma syndromes, Cowden syndrome, Carney complex, and hyperparathyroidism jaw-tumor syndrome. In addition, researchers are becoming aware of other familial endocrine neoplasia syndromes with an unknown genetic basis that might also fall into the category of MEN. This article reviews the clinical features, diagnosis, and surgical management of the various MEN syndromes and genetic risk assessment for patients presenting with one or more endocrine neoplasms.
Importance:
Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants.
Objective:
To evaluate the clinical treatment and patient outcomes after identification of P/LP RET proto-oncogene variants associated with the risk of MTC via a population genomic screening program.
Design, setting, participants:
This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure.
Main outcomes and measures:
The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging.
Results:
Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients (27%; 11 women [55%] and 9 men [45%]; median age, 48 years [range, 22-73 years]) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease.
Conclusions and relevance:
In this cross-sectional study, all malignant neoplasms identified on surgical pathology were clinically occult, with surgical intervention based solely on the identification of the P/LP RET variant via population genomic screening. This finding suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes.
Background:
The American Thyroid Association (ATA) has established guidelines for prophylactic thyroidectomy in multiple endocrine neoplasia type 2A (MEN2A) based on rearranged during transfection (RET) mutations. In silico analysis, which uses computer modeling to predict alterations in protein structure, is a new method for studying these mutations.
Methods:
We describe a kindred with MEN2A, all sharing a well-documented RET mutation, p.C634Y, as well as a mutation of undetermined significance, p.I852M, which we analyzed via in silico analysis.
Results:
The p.C634Y mutation resulted in severe predicted RET alterations, whereas the p.I852M resulted in only modest changes. Both mutations together resulted in only a small additional disruptive effect in protein structure beyond that which occurred with p.C634Y alone.
Conclusion:
Although in silico analysis may be helpful in quantitating changes in protein structure that occur in patients who have novel RET mutations (single or multiple), additional factors must account for the highly variable aggressiveness of the disease (C-cell hyperplasia/medullary thyroid carcinoma [MTC]) noted in our kindred. © 2016 Wiley Periodicals, Inc. Head Neck, 2016.
Purpose:
Although targeted sequencing improves outcomes for many cancer patients, it remains uncertain how somatic and germ-line whole-exome sequencing (WES) will integrate into care.
Methods:
We conducted surveys and interviews within a study of WES integration at an academic center to determine oncologists' attitudes about WES and to identify lung and colorectal cancer patients' preferences for learning WES findings.
Results:
One-hundred sixty-seven patients (85% white, 58% female, mean age 60) and 27 oncologists (22% female) participated. Although oncologists had extensive experience ordering somatic tests (median 100/year), they had little experience ordering germ-line tests. Oncologists intended to disclose most WES results to patients but anticipated numerous challenges in using WES. Patients had moderately low levels of genetic knowledge (mean 4 correct out of 7). Most patients chose to learn results that could help select a clinical trial, pharmacogenetic and positive prognostic results, and results suggesting inherited predisposition to cancer and treatable noncancer conditions (all ≥95%). Fewer chose to receive negative prognostic results (84%) and results suggesting predisposition to untreatable noncancer conditions (85%).
Conclusion:
The majority of patients want most cancer-related and incidental WES results. Patients' low levels of genetic knowledge and oncologists' inexperience with large-scale sequencing present challenges to implementing paired WES in practice.Genet Med advance online publication 11 February 2016Genetics in Medicine (2016); doi:10.1038/gim.2015.207.
Objective: Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma (MTC) are autosomal dominant inherited diseases caused by genetic mutations of the RET proto-oncogene. Prophylactic total thyroidectomy in carriers of activating RET proto-oncogenes, depending on mutation-based risk level, is recommended in the United States and many other countries. Measurement of calcitonin following stimulation with intravenous calcium gluconate has been widely adopted as a screening test for MTC.
Methods: Here, we describe a carrier of the RET V804M mutation in whom total thyroidectomy was performed at age 54 years after a calcium infusion test with the only available insurance-reimbursable calcitonin assay (an earlier generation calcitonin assay than currently reported) was employed. The case's older brother, who was also a RET V804M mutation carrier, was diagnosed with MTC at the age of 60 years, and his mother died of thyroid cancer with systemic metastases at the age of 76 years.
Results: During the calcium infusion test, the patient's serum calcitonin level increased from 40 to 161 pg/mL, a test result considered positive by the calcitonin assay specifications. C-cell hyperplasia, but not MTC, was noted in 2 of 11 thyroid tissue sections.
Conclusion: Although data from a more recent calcitonin assay and further information regarding the patient's mother's thyroid cancer would have been ideal, the present report adds to the literature regarding the clinical impact of the RET V804M mutation and the lack of specificity of older calcitonin assays for the diagnosis of MTC.
Objective:
Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision-making.
Design and patients:
We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers.
Measurement and results:
The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0·7-2·8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma.
Conclusions:
A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description.
Background:
Twenty-five percent of medullary thyroid cancer (MTC) cases are hereditary. The ideal age for prophylactic thyroidectomy is based on the specific RET mutation involved. The purpose of this study was to determine whether such age-appropriate prophylactic thyroidectomy results in improved disease-free survival.
Methods:
Twenty-eight patients underwent thyroidectomy for hereditary MTC at our institution. Age-appropriate thyroidectomy was defined according to the North American Neuroendocrine Tumor Society (NANETS) guidelines. Patients who had age-appropriate surgery (group 1, n = 9) were compared to those who had thyroidectomy past the recommended age (group 2, n = 19).
Results:
The mean age was 13 ± 2 years, and 61 % were female. Patients in group 1 were younger than in group 2 (4 ± 1 vs. 17 ± 2 years, p < 0.01). There were no significant differences in gender or RET mutation types between these two groups. Group 1 patients were cured with no disease recurrence compared with group 2 patients who had a 42 % recurrence rate (p = 0.05). Subanalysis of group 2 identified that patients who underwent surgery without evidence of disease did so at a shorter period following the guidelines compared with those who underwent therapeutic surgery (2 ± 2 vs. 16 ± 2 years, p = 0.01) and had longer disease-free survival (100 vs. 27 %, p = 0.005).
Conclusions:
Patients with hereditary MTC should undergo age-appropriate thyroidectomy based on RET mutational status to avoid recurrence. Patients who are past the recommended age should have surgery as early as possible to improve disease-free survival.
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Multiple endocrine neoplasia type 2 is historically composed of three clinical subtypes, all of which are associated with germline mutations in the RET proto-oncogene. Multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and multiple endocrine neoplasia type 2B are collectively associated with a 70-100% risk of medullary thyroid carcinoma by age 70 years. Pheochromocytomas are identified in 50% of individuals with multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B. Furthermore, those with multiple endocrine neoplasia type 2A have a 20-30% risk for primary hyperparathyroidism. Individuals with multiple endocrine neoplasia type 2B often have distinct physical features including mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, ganglioneuromatosis of the gastrointestinal tract, distinctive facies with enlarged lips, and a "Marfanoid" body habitus. Clinical recognition and accurate diagnosis of individuals and families who are at risk of harboring a germline RET mutation is critical for the prevention and management of potentially life-threatening neoplasms. This overview summarizes the clinical description of multiple endocrine neoplasia type 2, diagnosis and testing strategies, management and surveillance, and differential diagnosis for other related syndromes.
The RET proto-oncogene (REarranged during Transfection; RET) plays an important role in the causation of many thyroid tumours. Germline RET proto-oncogene missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, MEN2B).
We investigated a cohort of MEN2-related patients referred to Tygerberg Hospital, W Cape (2003-2009). The study cohort was divided into three groups based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group of MEN pathologies). Families with identified high-risk factors were recalled. Serum calcitonin levels were monitored where indicated. DNA was extracted from whole blood by standard techniques and polymerase chain reaction (PCR) products screened for RET gene variations by heteroduplex single-strand duplication techniques (heteroduplex single-strand conformation polymorphism analysis) being validated with automated sequencing techniques showing conformational variants in acrylamide gel.
We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups were represented (white (12), black (11) and mixed race (17)). Nine were index MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell into the MEN2B category. The remaining 19 were unaffected relatives screened for carrier status, among whom afamilial recurrence was observed in 7. On genetic testing, an RET point mutation at the high-risk 634 cysteine allele was identified in 11 cases. A further cysteine radical mutation at the 620 position was related to MEN2 in 3 families plus 1 other family referred from elsewhere. Other less-recognised gene variations were detected throughout the RET gene in 70% of cases and included the 691 position on codon 11 (11 cases); the 432 position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC patients have had thyroidectomies, of which 2 were prophylactic (C-cell hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery.
RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa. Prophylactic surgery may prevent MTC, so genetic screening is important to identify and treat high-risk patients.
Genetic testing of RET proto-oncogen allows an early diagnosis of Multiple Endocrine Neoplasia syndrome type 2 and establish a correlation between genotype and clinical manifestations. The purpose of this study was to demonstrate the benefits of an early diagnosis with genetic testing followed by prompt surgery on the cure of MTC versus a later diagnosis with serum calcitonin.
Retrospective descriptive study of 8 members of a MEN 2A family by C634Y mutation. We performed serum calcitonin screening until 1999 and subsequently RET genetic testing was obtained. Carriers underwent total thyroidectomy and periodic determination of calcitonin, urinary metanephrines, calcium, phosphorus and neck and abdominal imaging techniques.
Five patients were diagnosed by calcitonin familial screening and all of them have high calcitonin by now. Three patients were diagnosed by genetic testing (an adult and two children) and they are free of disease. Calcitonin was closely monitored in children and they underwent surgery when it started to raise, at 6 and 10 years old respectively, finding nodular C-cell hyperplasia in both. Of 8 carriers 3 developed pheochromocytomas, bilateral and asynchronous, one-half had normal urinary metanephrines and two of them were simultaneous with MTC. No patient had biochemical data suggesting hyperparathyroidism although in one patient multiple parathyroid adenomas were found at thyroidectomy.
RET genetic analysis has achieved an early diagnosis and treatment with no development of MTC in our patients, adjusting the time and type of surgery and allowing a genotype-phenotype correlation. It demonstrates how a genetic alteration is associated with a pathology that we can prevent and manage improving the prognosis of our patients.
Spindle cell proliferations of the thyroid gland are uncommon lesions that encompass a wide spectrum of reactive, hyperplastic, and neoplastic processes. Spindle cells may occur in subsets of papillary carcinomas and follicular adenomas where they are thought to represent metaplastic foci. The goals of the present study are to further characterize the metaplastic nature of spindle cell foci of the thyroid (SCFT), to define their immunohistochemical profiles and to review their differential diagnoses. The study group included: multinodular goiter (2), follicular adenoma (2), and minimally invasive follicular carcinoma (2). SCFTs were composed of elongate cells with thin or slightly plump nuclei with finely granular chromatin and inconspicuous nucleoli. Rare mitotic figures were present but there was no necrosis or inflammation. All cases were positive for thyroglobulin, thyroid transcription factor (TTF)-1, and TTF-2. TTF-1 and TTF-2 had a characteristic nuclear localization although the intensity of staining for TTF-1 was consistently greater than that of TTF-2. Each of the 6 cases was positive for vimentin whereas 5 of the 6 cases were positive for broad-spectrum cytokeratins. None of the cases was positive for high molecular weight cytokeratin, cytokeratin-19, smooth muscle actin, desmin, calcitonin, chromogranin, or synaptophysin. The proliferative rate was less than 1% in all cases. Staining for TTF-1 and TTF-2 provided high specificity for identification of SCFT since these markers were not subject to the same diffusion artifact inherent in thyroglobulin-stained sections. The results of this study further support the hypothesis that SCFT result from metaplastic transformation of follicular cells.
Procalcitonin has been well established as an important marker of sepsis and systemic infection. The authors evaluated the diagnostic and predictive value of calcitonin and its prohormone procalcitonin in medullary thyroid cancer.
The authors systematically explored the ability of calcitonin and procalcitonin to identify medullary thyroid cancer and predict the endpoints local recurrence and distant metastases, as well as the progression-free survival. Patients with C-cell hyperplasia; patients after thyroidectomy for differentiated thyroid cancer, goiter, or Graves disease; and healthy subjects served as controls. The study was performed in accordance with the Reporting Recommendations for Tumor Marker Prognostic Studies of the National Cancer Institute.
Sixty-nine medullary thyroid cancer patients and 96 controls were included (median observed interval: 10.9 years [range, 1.4-47.5 years]; 981.8 patient-years). The 1-year, 5-year, 10-year, and 20-year recurrence rates were 9%, 34%, 45%, and 56%, respectively. Calcitonin had a higher diagnostic accuracy for detecting medullary thyroid cancer than procalcitonin (area under the curve [AUC], 0.94; 95% confidence interval [95% CI], 0.90-0.99 vs AUC, 0.89; 95% CI, 0.83-0.95 [P = .038]). The procalcitonin:calcitonin ratio predicted disease progression (AUC, 0.63; 95% CI, 0.51-0.75 [P = .036]) and progression-free survival (hazards ratio, 1.49; 95% CI, 1.09-2.04 [P = .013]).
The results of the current study indicate a superior diagnostic accuracy of calcitonin and an independent predictive value of the procalcitonin:calcitonin ratio. These findings may lead to improved diagnostic and therapeutic strategies for medullary thyroid cancer patients.
The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.
Objective:
Sporadic late-onset medullary carcinoma of the thyroid is quite rare. Usually, the patient presents with a thyroid mass or neck node metastasis along with high levels of calcitonin and preoperative fine needle aspiration biopsy suggestive of medullary carcinoma of the thyroid. The role of genetic testing in such individuals, along with testing of other family members, remains somewhat unclear at this stage, especially in patients presenting with familial medullary thyroid carcinoma. Genetic testing with RET proto-oncogene mutational studies is very popular in familial medullary thyroid carcinoma, especially in children, with routine prophylactic thyroidectomy. However, its indications in adults remain unclear at this time.
Case study:
Recently, a 69-year-old woman presented with a thyroid mass and underwent total thyroidectomy and central compartment dissection. She was found to have medullary carcinoma of the thyroid. The patient had four children, three of whom were found to have a RET mutation similar to their mother's, V804M. In view of the RET mutation, the three children were offered prophylactic thyroidectomy at ages 42, 45, and 47. The patient's son was noted to have extensive C-cell hyperplasia in both lobes of the thyroid. The other two individuals had benign pathology with no evidence of C-cell hyperplasia.
Conclusions:
There is no definite consensus of opinion about the need for prophylactic total thyroidectomy in adults with RET mutation. The rarely reported 804 mutation is, however, a predictor of medullary carcinoma of the thyroid. One individual in this group had extensive C-cell hyperplasia, suggesting that he would have developed medullary carcinoma of the thyroid in the future. Prophylactic thyroidectomy should be recommended in patients with RET mutation and a family history of medullary carcinoma of the thyroid; however, its role in adult family members needs to be evaluated with larger registry of prophylactic thyroidectomy. Whether these adults with rare 804-mutation could be observed and followed with serial calcitonin, ultrasound, or calcitonin stimulation tests remains to be studied.
This article summarizes the clinical features and molecular pathogenesis of medullary thyroid cancer (MTC) and focuses on the current use of molecular, biochemical, and imaging disease markers as a basis for selection of appropriate therapy. Clinicians treating patients who have MTC face the following challenges: (1) distinguishing MTC as early as possible from benign nodular disease and differentiated thyroid cancer to choose the appropriate initial surgery, (2) managing low-level residual cancer in otherwise asymptomatic individuals, and (3) treating progressive metastatic disease. Early clinical trials using small molecules targeting Ret or vascular endothelial growth factor receptors suggest that such approaches could be effective and well tolerated. This article highlights early progress in targeted therapy of MTC and significant challenges in disease monitoring to appropriately select and evaluate patients being treated with these therapies.
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