GLOBAL ENDOCRINOLOGY: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review

in European Journal of Endocrinology
View More View Less
  • 1 Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
  • | 2 Thyroid Unit, Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Correspondence should be addressed to A L Maia; Email: almaia@ufrgs.br
Free access

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

Abstract

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

Invited Author’s profile

Dr Ana Luiza Maia is Full Professor of Medicine at the Endocrine Division, Medical School, Universidade Federal do Rio Grande do Sul, and Head of the Thyroid Unit, Hospital de Clínicas de Porto Alegre, Brazil. Dr Maia leads studies of molecular diagnosis and genotype–phenotype correlations in Multiple Endocrine Neoplasia Type 2 patients in Brazil. Her research interests also includes thyroid hormone metabolism and clinical and pathological features of patients with thyroid carcinomas.

Introduction

RET pathogenic variants (1) cause multiple endocrine neoplasia type 2 (MEN2), an autosomal-dominant hereditary syndrome characterized by an association with endocrine tumors (2, 3, 4, 5, 6, 7, 8). MEN2 is classified into subtypes, MEN type 2A and MEN type 2B according to its clinical manifestations, which are distinguished by a high penetrance of medullary thyroid carcinoma (MTC) and, to a lesser extent, pheochromocytoma (PHEO) and primary hyperparathyroidism (PHPT) (8, 9, 10).

The RET gene encodes a transmembrane receptor, and gain-of-function missense variants in the extracellular or cytoplasmic regions of the RET protein promote continuous phosphorylation of a distinct set of tyrosine residues, triggering intracellular signaling pathways for cell survival, differentiation, and proliferation (8, 9, 10). The several reported RET pathogenic variants and their corresponding locations are illustrated in Fig. 1. The oncogenic codon-specific RET pathogenic variants present strong correlations with the MEN2 phenotype (7, 8, 9, 10, 11). A large proportion of MEN2A patients presenting with PHEO or PHPT, or both, have RET pathogenic variants in the cysteine-rich extracellular domain, particularly in exons 10 and 11 (8, 9). Interestingly, it seems that the disease phenotype and aggressiveness might vary accordingly with specific codon 634 amino acid exchanges (12, 13). RET variants in codons 609, 611, 618, and 620 are also frequently occurring genetic alterations. Amino acid changes in the intracellular domain of RET in exon 13 (codons 768, 790, and 791), exon 14 (codons 804 and 844), and exon 15 (codon 891) are usually associated with an isolated MTC phenotype. The rare association with cutaneous amyloidosis occurs almost exclusively in carriers of codon 634 variants (14), while Hirschsprung’s disease has been observed only in kindreds with variants in codons 609, 611, 618, and 620 (15). No RET variants are found in 2–5% of apparently hereditary MTC cases (16, 17). Of note, whole-exome sequencing has recently identified a germline RET variant in two siblings with hereditary RET-negative MTC (18). The vast majority of patients with MEN2B harbor the RET variant p.Met918Thr, and a recent international multicentric study in which 345 individuals were evaluated showed the importance of increasing awareness of the extraendocrine symptoms characteristic of this syndrome (19).

Figure 1
Figure 1

(A) Left: RET protein and domains; middle: RET variants and their corresponding locations (in bold, variants unambiguously pathogenic); (B) RET pathogenic variants and their corresponding codons and relative incidence of MEN2-associated neoplasias. Pheo, pheochromocytoma; HPH, hyperparathyroidism.

Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0753

MTC occurs in more than 95% of MEN2 patients, and several studies have shown that early thyroidectomy is an effective treatment as it prevents or cures MTC before it spreads (7, 8, 9, 10, 11). In addition, a correlation between the affected RET codon and disease aggressiveness and progression has been demonstrated (7, 8, 9, 10, 11, 20, 21). Therefore, guidelines issued by several societies, as the American Thyroid Association (ATA), European Thyroid Association, and Brazilian Society of Endocrinology and Metabolism stratify RET pathogenic variants into three levels, highest, high, and moderate risk, based on the risk and timing of the development of MTC (21, 22, 23, 24, 25).

Although customarily deemed a rare disease, the earlier diagnosis with the consequent finding of asymptomatic carriers of MEN2 has increased its prevalence, from 1 patient per 200 000 or 500 000 inhabitants to nearly 1:80 000 inhabitants (26). As an example, in Norway, a country where epidemiological data from the entire population have recently been published, the incidence of patients with RET variants associated with MEN2 was 1:66 438 live births, while the prevalence of MEN2 was 1:79 462 (27).

Geographic spectrum of RET variants

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift (which includes founder and bottleneck effects), and migrations. Frequent germline genetic variants tend to be older, while rarer genetic variants have probably appeared in more recent times (28). In large populations, selection tends to have a greater impact on allele frequency than on genetic drift. In contrast, genetic drift plays a more important role in small populations. Thus, many pathogenic variants must have appeared centuries ago and continue to be passed on to new generations (29).

Several studies have shown that the RET variant profile may vary according to geographical area (26, 27, 30, 31, 32, 33, 34, 35, 36, 37). In fact, recent ethnographic fieldwork and haplotype analysis traced founder variants from Brazil back to the Iberian Peninsula and Greece (33, 35), while Machens et al. attempted to unearth European ancestral heritage using German RET data (36). Moreover, an international consortium found that the penetrance of PHEO in MEN2 patients carrying RET variants in exons 10 and 11 is lower in countries from South America than in Europe, indicating that other genetic or environmental modifiers could explain this difference (37).

Here, we aimed to collect worldwide RET gene genotyping data to analyze the distribution and frequency of RET pathogenic variants from a global perspective. Thus, we conducted a review of the literature, employing a PubMed/Medline search using the following key words: RET Mutation in all affected codons, RET Epidemiology, RET and multiple countries, MEN2 Epidemiology, MEN2 guidelines, and Medullary Thyroid Cancer. We also searched for RET in various databases (the Cancer Genetics Web, OMIM from Johns Hopkins University, International Cancer Genome Consortium, Cancer Genome Anatomy Project, COSMIC Sanger Institute, and Leiden Open Variation Database and Arup). Additionally, the references of included studies were screened for additional publications. No language or time restriction was adopted. The last search was performed on January 7, 2021.

Largest series on MEN2-related RET pathogenic variants from Germany, France, Italy, United Kingdom, Brazil, Japan, and United States of America

Table 1 compares the results of RET pathogenic variants causing MEN2 in the largest published series, originating from Germany (n = 533) (9, 26, 29, 36, 38, 39), France (n = 437) (39, 40, 41), Italy (n = 237) (17, 31, 32, 42), United Kingdom (UK) (n = 110) (43), Brazil (n = 554) (44), United States of America (USA) (n = 403) (45, 46, 47, 48, 49, 50, 51, 52), and Japan (n = 390) (53, 54, 55, 56, 57).

Table 1

Relative frequency of MEN2-related RET pathogenic variants in major consolidated series.

ATA risk categoryAmino acid changeRelative frequency, n (%)
Germany (n = 567)France (n = 437)Italy (n = 237)UK (n = 110)Brazil (n = 554)Japan (n = 390)USA (n = 403)
Highestp.Met918Thr39 (7.4)30 (6.9)17 (7.2)15 (13.5)32 (5.8)18 (4.6)46 (11.4)
Highp.Cys634(F/G/R/S/W/Y)184 (34.8)144 (32.9)86 (36.2)32 (29)262 (47.0)144 (37.0)0
p.T338I01 (<1)1 (<1)001 (<1)163 (40.4)
p.Ala883Phe*1 (<1)2 (0.5)02 (1.8)02 (0.5)0
Moderatep.Cys515(F/S)04 (0.9)1 (<1)004 (1)0
p.Cys531R02 (0.5)0002 (0.5)0
p.Gly533Cys1 (<1)3 (0.6))03 (0.7)59 (10.6)3 (0.7)7 (1.8)
p.Cys541Arg01 (<1)0001 (<1)0
p.Cys609(F/G/R/S/W)7 (1.3)5 (1.1)6 (2.5)5 (4.5)12 (2.2)6 (1.5)44 (10.9)
p.Cys611(F/Y)42 (7.9)12 (2.7)1 (<1)012 (2.2)24 (6.2)8 (2)
p.Cys618(F/G/R/G/S/Y)53 (10.0)29 (6.6)15 (6.3)12 (11)11 (2.0)68 (17.4)43 (10.7)
p.Cys620(F/R/S/Y)38 (7.2)31 (7.1)9 (3.8)11 (10)56 (10.1)39 (10)38 (9.4)
p.Cys630Arg4 (0.7)1 (<1)4 (1.7)02 (<1)11 (2.8)2 (<1)
p.K666(E/N/T)06 (1.4)1 (<1)1 (<1)01 (<1)11 (3.2)
p.Glu768Asp10 (1,9)10 (2.3)9 (3.8)3 (2.7)14 (2.5)19 (4.9)0
p.Leu790Phe61 (11.6)43 (9.9)8 (3.4)4 (3.6)4 (<1)1 (<1)2 (<1)
p.Val804 (L/M)67 (12.7)92 (21.0)52 (21.9)14 (13.0)46 (8.3)12 (3.0)29 (7.2)
p.Ala883Thr01 (<1)1 (<1)001 (<1)0
p.Ser891Ala25 (4.7)20 (4.6)23 (9.7)8 (7.3)23 (4.1)10 (2.6)10 (2.5)
p.Ser904Phe1 (<1)01 (<1)4 (3.6)000
p.Met918Val01 (<1)2 (<1)021 (3.8)00

*The 2015 ATA categorization of p.Ala883Phe as carrying “very high risk” is no longer current, as per Mathiesen et al. 2017 (80).

The pathogenic variants at codon 634 (p.Cys634Phe, p.Cys634Gly, p.Cys634Arg, p.Cys634Ser, p.Cys634Trp, and p.Cys634Tyr) are the most prevalent, found in between 30 and 50% of affected patients; the p.Val804Met variant is the second in frequency in France, Germany, and Italy, followed by p.Leu790Phe in Germany and France, p.Ser891Ala in Italy, and p.Gly533Cys and p.Cys620 in Brazil. The frequency of variants occurring at codon 618 is between 6 and 10% in European countries. The other pathogenic variants are found in less than 10% of MEN2 patients, mainly at codons Cys609, Cys611, and Cys630. The MEN2B phenotype, caused by the variant p.Met918Thr, was similarly distributed in all seven countries, corresponding to 4.6–13.5% of affected patients.

French data represent the results of a multicenter observational study led by the French Group of Endocrine Tumors including data from 18 different centers (40, 41). In addition to the 437 patients depicted in Table 1, the French Group has included new patients (n = 36) who present variants not classified by the ATA, thus far considered probably pathogenic, benign, or a variant of unknown significance; the clinical follow-up of these patients and further phenotype–genotype information will be necessary to classify the MTC risk profile (41). In addition, the data included three different double variants (p.Val804Met; p.Arg844Leu), (p.Lys603Gln; p.Leu790Phe), and (p.Asp631Tyr; p.Tyr791Phe).

The data from Germany on RET genotyping are comprehensive and up-to-date (9, 26, 29, 36, 38, 39). It is interesting to note that one of the German centers, when describing their 40 years of experience with 263 MTC patients (9), presented some differences in RET genotypes in comparison with the total number of cases in Germany (39); thus, in this series, there were more patients with p.Cys634Tyr (n = 49) than patients with p.Cys634Arg (n = 30) and an equal number of patients with p.Leu790Phe and p.Ser891Ala variants (9, 39), further demonstrating heterogeneity in RET genotypes throughout Germany (36).

The Italian records on RET genotyping are also comprehensive and current (17, 31, 32, 42). It is interesting to note the high prevalence of the pathogenic variant p.Val804Met in the Italian data and the founder effects of variants p.Ser891Ala in northern Italy (58) and p.Val804Met in Sardinia (59).

Since France, Italy, and Germany are neighboring countries in Western Europe and all have comprehensive DNA-based screening programs for MEN2, it is somewhat anticipated that their data would be relatively similar; however, there are few appealing differences. The p.Val804Met variant is more frequent in Italy (20.2–25.6%) and France (17.2–21.4%) than in Germany (10%) (17, 31, 32, 38, 39, 42). A high prevalence of the p.Val804Met variant was primarily reported in a Sardinian study (59% prevalence), and this finding was explained as an outcome of the role of genetic drift and the founder effect in the history of that population, who lived isolated for several centuries (59). Nevertheless, this explanation is not true for continental Italy, since the pattern of RET gene single-nucleotide polymorphisms in index cases harboring p.Val804Met is different (31).

Another interesting observation in these series is that the pathogenic variant p.Ser891Ala is more prevalent in Italy (9.7%) than in Germany or France (4.7 and 4.6%, respectively). This is apparently due to a founder effect in an isolated mountainous region in northern Italy (58). The authors noticed an impressive percentage of patients harboring the p.Ser891Ala variant in their local series (54.9%) when compared with the percentage found in Italy for p.Val804Met (13.7%). The hypothesis of a common ancestor was then investigated, and a common haplotype identified, as demonstrated by accurate research on church and municipal archives and regional clustering of mutations in kindreds in two areas, the Seriana Valley, in the province of Bergamo, and the Plain of Brescia. The reconstruction of the genealogical tree confirmed that family residents in Brescia were descendants of immigrants from the Seriana Valley in the 1600s, supporting the hypothesis that the p.Ser891Ala variant was most likely introduced by a founder pathogenic variant (58). Recent studies from Italy (not included in Table 1) from two distinct centers have shed light on these observations. The first one, from Pisa, including 353 patients, identified 42 different germline missense variants with a distribution of affected codons similar to those found in previous reports; in addition, some rare variants, among them Ala883Thr, were found in nine patients (17). The second study, from Bologna and Parma, analyzed 72 MTC patients and identified a likely pathogenic variant, p.Ser904Phe, found in eight carriers in a kindred (60).

On the other hand, p.Leu790Phe is more common in Germany (11.6–13.6%) and France (9.9%) than in Italy (3.4%). Machens et al. addressed this issue in a fascinating study that disclosed European ancestral heritage, showing the differences among these abovementioned RET variants in present-day Germany (36). The authors analyzed the RET data from 189 German families and observed that variants p.Val804Met and p.Leu790Phe are distributed in different historical German regions: RET p.Val804Met families are located mainly in the so-called ‘Roman’ historic settlement area, whereas RET p.Leu790Phe families are more prevalent outside than inside the historic ‘Roman’ settlement area. Because the RET p.Leu790Phe variant was found in at least 19 families from France and 8 families from Italy, studies from these countries may be ideally suited to elucidate the European ancestry of the RET p.Leu790Phe variant. The authors also showed that the benign RET variant p.Tyr791Phe shows a significant association with the ‘Slavic’ historic settlement area in present-day Germany. Notably, some pathogenic RET variants have been transmitted for centuries, as demonstrated for the p.Cys634Tyr variant in the fascinating first description of PHEO in Germany in 1886 (61) and the p.Cys611Phe variant in a study from Germany in 1876 (39).

Comparing the data of France, Italy, and Germany with those from Brazil, we observe similarities as well as differences. While variants p.Met918Thr, p.Cys620X, p.Glu768Asp, and p.Ser891Ala present similar proportion in these countries, the p.Leu790Phe variant is more frequent in Germany and France (P < 0.01), the p.Val804Met mutation is more frequent in Italy and France (P < 0.05), and p.Ser891Ala in Italy. On the other hand, pathogenic RET variants p.Gly533Cys and p.Met918Val are mainly found in Brazil. For codon 634 mutations, the relative frequency in Brazil (47.0%) was higher than those found in France, Germany, Italy, UK, Japan, or USA (P < 0.05) (Table 1). One potential explanation could be the fact that RET screening in Brazil is not yet comprehensive, and patients with variants at codon 634 develop the disease earlier, a scenario comparable with that of the early European data on RET variants causing MEN2, when codon 634 variants were found in between 63 and 67.6% of MEN2 patients (11, 62). Nevertheless, it should be noted that codon 634 mutations are found in nearly 90% of MEN2 patients in southern Brazil, where molecular diagnosis has been performed for over two decades. Another interesting observation is that p.Cys634Arg is the most frequent variant in Italy, France, and Germany, whereas in Brazil, the most frequent is p.Cys634Tyr. In the German database, among 184 patients harboring codon 634 variants, 84 (45.6%) had p.Cys634Arg and 52 (28.2%) had p.Cys634Tyr. In the French database, among 144 patients with codon 634 variants, 53 (36%) had p.Cys634Arg and 46 (32%) had p.Cys634Tyr. In the Italian database, among 86 patients with codon 634 variants, 34 (40%) had p.Cys634Arg and 28 (33%) had p.Cys634Tyr (17, 39, 41, 42). On the other hand, among 262 Brazilian patients affected by a variant at codon 634, 166 had Cys634Tyr (63.4%), whereas 74 (28.2%) had Cys634Arg. Interestingly, the Tyr791Phe variant co-occurred with the Cys634Arg (Cys634arg/Tyr791Phe) in 47 patients (44).

The findings that RET pathogenic variants in Brazil display similarities as well as differences from those observed in Europe might be justified by the genomic ancestry of Brazilians, presenting individual proportions of European, African, and Amerindian ancestry in their mosaic genome (63, 64, 65).

The p.Gly533Cys RET pathogenic variant was firstly described in the largest MEN2A family studied so far; they emigrated from Barcelona, Spain, to Brazil at the end of the 19th century (66, 67, 68). Some years after this report, Greek researchers found that p.Gly533Cys was the most prevalent RET variant in Greece (69, 70, 71), a fact that has been anticipated, since the Mediterranean Sea has always been a place of frequent migratory currents (66, 73). This variant has also been described in a family with Greek ancestors living in the USA (74), in a patient from Slovenia living in Ireland (75) and, more recently, in gene carriers in France (39, 41), Germany (9), and the UK (43). It has been hypothesized that these families would have a common ancestor, as several Greek city states were scattered throughout the Mediterranean since ancient times (73). Cunha et al. endorsed this hypothesis by showing that Brazilian (originally from Spain) and Greek patients have a common ancestor (35). This interesting finding suggests that, historically, the most likely origin of this variant was Greece and that the Greek migratory currents have taken the variant to the Iberian Peninsula.

Another finding of the Brazilian series was the identification of the p.Met918Val variant (33). Codon 918 is typically related to MEN2B when the first mutation caused by a methionine substitution by threonine at this codon (p.Met918Thr) was described (4, 5, 6). However, the clinical presentation of MTC related to p.Met918Val and the results of in silico and in vitro analyses (76) indicate that this is a moderate-risk variant (24, 33). At first, it was supposed that these families were isolated, but the haplotype study showed that all affected patients had a common ancestor, and through historical and mathematical studies, the existence of a pioneer who emigrated from Portugal to Brazil in 1700 was confirmed, corroborating the hypothesis that this variant accompanied the population of this region for approximately 350–400 years and that these supposedly different families belong to a single family fragmented over the centuries (33). There are now reports of the p.Met918Val variant in Italy, France, and Russia (31, 41, 77).

Recently, a large study of the RET genotypes and MEN2-related clinical features of 1,058 index MTC patients from the UK was published (Table 1) (43). The authors found RET pathogenic variants in 110 patients (10.2%), the majority occurring at codon 634 (n = 32, being 11 p.Cys634Arg; 11 p.Cys634Thyr; 6 p.Cys634Gly; 2 p.Cys634Ser; 1 p.Cys634Phe, and 1 p.Cys634Trp). Fifteen MEN2B patients presented the pathogenic variant p.Met918Thyr. Variants p.Gly533Cys and p.Ala883Phe were also reported (43). A retrospective review of prophylactic thyroidectomy in children who underwent genetic testing confirmed the high prevalence of codon 634 variants (78).

As mentioned, differently from France, Germany, Italy, UK, Brazil, and Japan where the results of RET variants were consolidated by national studies, the results of RET variants from USA represent our compilation of published reports (45, 46, 47, 48, 49, 50, 51, 52, 74) (Table 1). Actually, patients from USA with MEN2 have been included in the International RET Mutation Consortium since the first studies on RET genotyping (7). In our compilation, we have included the following studies: the first publications on RET variants in American patients reporting the outcome of thyroidectomy from MD Anderson Cancer Center (47); the series of 50 MEN2A patients with variants at codons 634 (38%), 620 (32%), 618 (22%), 609 (6%), and 611 (2%) from Duke University (48); a large series including 262 MEN2A patients from the MD Anderson Cancer Center, showing variants at codon 634 (52%), codon 609 (14%), codon 618 (12%), codon 620 (8%), p.Val804Met (6%), codon 891 (4%), and codon 611 (3%) (49). We have also included a small series of 29 patients with medullary microcarcinoma and C-cell hyperplasia from the Massachusetts General Hospital showing a higher prevalence of p.Val804Met (48%) (50) and a series of 38 children and adolescents from NIH presenting MEN 2B caused by the variant p.Met918Thr (46).

There are also interesting observations on rare variants causing MTC, such as p.Gly533Cys (74) and p.Lys666Arg (51). Another interesting paper shows 12 rare germline RET variants in a large series of 6700 cases from the Mayo Clinic and Quest Diagnostics; segregation within families suggests that p.Lys666Glu (MTC and PHEO) and Thr636insGlu-Leu-Cys-Arg; Thr636Pro, a 13bp insertion and 1bp deletion (MTC), respectively, are disease-causing variants (45). Finally, it is important to cite that Arup Laboratories, University of Utah, has developed and maintains a database of the 199 RET variants found worldwide, with genotype, codon change, protein change, classification according to pathogenicity, MEN 2 phenotype, first reference, and comments (www.arup.utah.edu/database/MEN2/MEN2_welcome.php); however, the database does not specify the number of affected patients for each variant or their geographical origin (52).

In the largest MEN2 patient series from Japan, Imai et al. (53) showed the distribution of RET variants in 390 patients with MEN2. Codon 634 was the most affected (37%), followed by codon 618 (17.4%) and 620 (10%). RET pathogenic variants at codons 609, 610, 611, 620, 768, 790, 804, and 891 have also been reported among Japanese (Table 1). Other studies have shown similar RET codon variant distribution (54, 55). Interestingly, Japan presents the lowest rate of MEN2B patients among the countries. A newly described mutation at codon 666, p.Lys666Arg, has also been recently found in Japan. Codon 666, located in the RET intracellular juxta-membrane domain, is a highly conserved residue among species (56). Some missense variants at RET codon 666 have been reported in MTC patients: p.Lys666Glu in the USA and Italy (45, 79), p.Lys666Met in Italy (31), and p.Lys666Asn in Italy and the USA (45, 80). Interestingly, Japanese researchers have described a novel combination of tandem RET variant (p.Gln781Arg/p.Val804Met) in an MEN2B-like patient; in silico analysis showed a high prediction score, which was compatible with the patient’s clinical phenotype (57).

The MEN2B phenotype, caused mainly by the variant p.Met918Thr, was equally distributed in all larger series, corresponding to 4.6 to 13.5% of affected patients (Table 1). The categorization of variant p.Ala883Phe as carrying ‘very high’ risk is no longer current, since an international cohort study has demonstrated that these patients, even presenting MEN2B phenotype, have a more indolent natural course when compared with that of p.Met918Thr (81).

Comprehensive RET database incidence and prevalence in Norway and Denmark

Norway and Denmark have a complete cancer registry database, which includes the number of MEN2 patients and their respective RET genotypes. In addition to providing relevant information on RET variants in geographic areas, these studies further illustrate that the prevalence of the distinct RET variants might be particular for every country, even in those that are very close geographically, linguistically, and historically, such as Norway and Denmark. Indeed, it may be worthwhile mentioning that the kingdoms of Norway, Sweden, and Denmark once were united under one single Danish monarch (Kalmar Union, from 1397 to 1523, until the Kingdom of Sweden broke away).

Norway has a population of 5.1 million inhabitants and 237 patients with MTC (4.2% of all thyroid cancer patients), of whom 67 have MEN2A. The incidence of MTC grew from 0.18 to 0.25 for every 100 000 inhabitants/year between 1994 and 2016, or 1/66 438 live births per year (27). The prevalence of MEN2A is estimated to be between 1:73 786 and 1:79 462 (27, 82). The affected RET codons in Norwegian MEN2A patients are, in order of frequency, 634 (50%), 611, 804, 781, 790, 618, and 620 (27, 82).

Interestingly, Denmark, shows differences in the incidence, prevalence, and distribution of MTC-related RET variants when compared with Norway. Hence, Denmark, for a population of 5.7 million inhabitants, has approximately 476 patients with MTC, 25% of whom have hereditary MTC (34, 83, 84, 85, 86, 87). The incidence is 28 per million live births per year, and the prevalence is 24 per million. The most prevalent RET variant is p.Cys611Tyr (68%; founder effect, see below), followed by p.Cys618Tyr (6%), p.Cys611Trp (5%), p.Cys620Arg (4%), p.Asp631Tyr (4%), p.Cys634Arg (2%), p.Val804Met (2%), p.Leu790Phe (2%), p.Cys618Phe (1%), and p.Cys634Tyr (1%) (34, 83, 84, 85, 86).

Regarding the founder effect of RET variant p.Cys611Tyr in Denmark, Mathiesen et al. studied 12 apparently unrelated families and demonstrated that all shared a common haplotype, suggesting a recent common ancestor (86). Carriers of the p.Cys611Tyr variant have also been reported in Germany, the Netherlands, Portugal, the Czech Republic, Hungary, Brazil, China, Japan, Iran, and the USA. Although unclear, one might speculate that some of these carriers, especially those from countries in proximity to Denmark, might be related to Danish families. Of interest, recently, in Denmark the first case of a European family harboring a RET variant (p.Cys620Arg) with children born after a preimplantation genetic test for monogenic disorders (85) was reported.

A complete database of MEN2B patients is also available in Denmark. In the period from 1941 to 2014, 12 patients were included, 7 of whom harbored the Met918Thr mutation and 1 harbored the Ala883Phe mutation (4 patients died before RET testing was available) (81, 87). The prevalence in 2015 was 1.06 patients/million; the incidence from 1970 to 2000 was 2.6 per million live births per year.

Summary of other published RET genotype data from countries across the 5 continents

Table 2 summarizes published data of RET pathogenic variants from countries across the five continents. The majority of studies includes a relatively small number of patients and analyzes only exons 10, 11, and 13–16. Nevertheless, some interesting observations about founder effects, uncommon RET variants, or disease phenotype described in some countries deserve to be highlighted.

Table 2

RET pathogenic variants from countries across five continents (excluding Brazil, Denmark, France, Germany, Italy, Japan, Norway, UK, and USA).

ContinentCountryRET pathogenic variants reportedReferences
AfricaMoroccop.Cys634Arg/Phe/Trp107, 108
South Africap.Cys634Ser/Phe/Arg, p.Cys620Trp/Arg109, 110
AmericasArgentinap.Cys634Arg/Thr/Phe (79%), p.Met918Thr, p.Cys611Thr111, 112
Canadap.Met918Thr113
Chilep.Cys634Arg/Trp (55%), p.Cys618Arg, p.Cys620Arg, p.Val804Met, p.Ser891Ala, p.Met918Thr114
Mexicop.Cys634Phe, p.Met918Thr115
AsiaChinap.Val292Met, p.Ser409Tyr, p.Tyr606Cys, p.Cys618Tyr/Arg/Ser, p.Cys620Tyr, p.Cys634Tyr (75%), p.Asp707Glu, p.Leu790Phe, p.Ser891Ala, p.Met918Thr96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106
Indiap.Cys609Arg, p.Cys611Tyr, p.Cys618Gly, p.Asp631Tyr, p.Cys634Arg/Tyr/Gly/Ser/Thr (most prevalent), p.Val804Met, p.Ser891Ala, p.Leu790Phe, p.Met918Thr116, 117, 118, 119, 120
Iranp.Cys618Tyr/Arg/Phe/Ser, p.Cys620Arg/Phe, p.Cys630, p.Cys634Arg/Tyr, p.Val804Met, p.Met918Thr121, 122, 123, 124
Israelp.Cys618Arg, p.Cys634Arg, p.Val804Met, p.Met918Thr125, 126
South Koreap.Cys618Arg, p.Cys634Tyr/Arg (37.1%), p.Met918Thr, p.Cys 611*, p.Cys618*, P.Cys620*, p.Glu768Asp, p.Leu790Phe, p.Val804Met127, 128
Saudi Arabiap.Cys 611*, p.Cys618*(46.6%) , p.Cys634*, p.Cys620Ser, p.Met918Thr129, 130
EuropeAustriap.Cys611Tyr/Trp, p.Cys618Ser, p.Cys620Tyr, p.Cys634Tyr/Arg/Ser/Trp, p.Leu790Phe, p.Val804Leu, p.Ser891Ala131, 132
Cyprusp.Cys618Arg (69.2%), p.Cys634Phe, p.Met918Thr88
Czech Republicp.Cys634Arg/Ser/Trp/Tyr (>50% cases), p.Cys609Tyr, p.Cys611Tyr, p.Glu768Asp, p.Tyr791Phe, p.Val804Met, p.Met918Thr133
Greecep.Gly533Cys (36.3%), p.Cys618Arg/Tyr/Ser (32.8%), p.Cys620Tyr/Arg/Phe, p.Cys634Arg/Tyr/Phe, p.Leu804Met, p.Met18Thr35, 69, 70, 71, 72, 134
Irelandp.Gly533Cys, p.Cys634Arg75, 135
Northern Irelandp.Met18Thr136
Polandp.Cys609Phe/Arg/Tyr, p.Cys618/Gly/Phe, p.Cys620Arg, p.Cys634Arg p.Glu768asp, p.Val804Leu, p.Met918Thr137, 138, 139
Portugalp.Cys515Trp, p.Cys531Arg, p.Cys609Arg, p.Cys611Tyr, p.Cys620Arg, p.Cys634Arg/Tyr, p.Thr636Met, p.Val804Leu, p.Met918Thr140, 141, 142, 143, 144
Russiap.Cys634Arg, p.Ser891Ala, p.Ala639Gly, p.Ala641Arg, p.Arg886Gln, p.Ser922Phe, p.Met918Val77, 145, 146, 147, 148
Serbiap.Cys634Phe/Trp/Tyr/Arg (66.7%), p.Val804Met, p.Cys618Arg, p.Leu790Phe149
Sloveniap.Cys634Tyr, p.Cys634Arg, p.Cys634Gly, p.Cys618Arg, p.Cys618Ser, p.Leu790Phe, p.Ala639Thr150, 151
Spainp.Cys609Ser, p.Cys611Phe, p.Cys618Arg, p.Cys620Ser, p.Ser589Cys, p.Cys634Tyr/Arg, p.Glu768Asp, p.Val804Met, p.Ser891Ala, p.Met918Thr90, 91, 92, 93, 94, 95
Swedenp.Cys618Arg89, 152
Switzerlandp.Cys618Ser, p.Cys630Phe, p.Cys634Tyr/Arg/Ser/Phe, p.Met918Thr62, 153, 154
Turkeyp.Cys634Arg (54.9%), p.Val804Met (25.4%)155, 156
OceaniaAustraliap.533, p.Cys618*, p.Cys620*, p.Cys634*, p.Val804Met, p.Met918Thr157, 158

*Amino acid exchanged not specified.

In Cyprus, the p.Cys618Arg is by far the most prevalent pathogenic variant due to a possible founder effect (88). There is also a fascinating description of a Swedish family harboring the p.Cys618Arg mutation, which was mapped over six generations with differences in tumor aggressiveness (89).

In the last 25 years, there have been several isolated publications on RET pathogenic variants in Spain but not a comprehensive review. It seems to be a preponderance of mutations at codon 634, with the majority of families harboring the p.Cys634Tyr variant instead of p.Cys634Arg (90, 91, 92, 93, 94), which is different from the rest of Europe. Interestingly, a study comparing both variants demonstrated that p.Cys634Arg is more aggressive than p.Cys634Thy (93), a finding previously reported in a Brazilian cohort (12). The rare pathogenic variant p.Ser589Cys has been reported in a Spanish family, now categorized as a moderate risk of the disease (95).

Interestingly, the first paper on RET genotyping from China indicated that pathogenic variants are restricted to those occurring at codon 634, causing MEN 2A syndrome in 75% of patients (with a preponderance of p.Cys634Tyr), and p.Met918Thr, resulting in MEN2B syndrome (96). Nevertheless, the widespread use of molecular diagnosis reported other variants, such as p.Tyr606Cys, p.Cys618Tyr, p.Cys618Arg, p.Cys618Ser, p.Cys620Tyr, p.Leu790Phe, and p.Ser891Ala (97, 98, 99, 100, 101, 102). Recently, there have been reports indicating the double pathogenic variants in the same patient, as in a large pedigree of 33 patients harboring p.Cys634/p.Asp707Glu, with a probably modifying effect in the age of onset and disease severity (103). In addition, investigators have described that the compound p.Cys634Tyr/p.Val292Met transmutation was associated with a more aggressive disease than either p.Cys634Thyr or p.Val292Met variants, indicating a synergic effect of compound nonsynonymous germline RET pathogenic variants (104). A novel germline RET variant, Ser409Tyr, likely pathogenic, has also been recently reported (105). Notably, a Chinese group reported the first preimplantation genetic diagnosis in a patient harboring a RET pathogenic variant (p.Cys634Tyr); one healthy baby was born after 38 gestational weeks (106).

Of note, a rare case of an Arabic patient with bilateral PHEO and a ganglioneuroma component associated with MEN2A has been reported in Morocco (107).

Conclusion

Molecular epidemiology evaluates the influence of genetic risk factors in the etiology, diagnosis, and prevention of a genetic disease. The increasing number of patients and geographies studied has demonstrated heterogeneity on the disease presentation even among gene carriers of the same kindred. This heterogeneity justifies a global effort to describe families with MEN2 to help on clarifying the genetic or environmental circumstances that might impact on disease phenotypes. Here, we show that a large spectrum of RET variants is observed worldwide. The codon 634 variants seem to be the most prevalent (Fig. 2 and Table 2), but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants.

Figure 2
Figure 2

Relative frequency of p.Cys634 variants among all RET carriers identified in the respective countries. NA, data not available or insufficient data to calculate the frequency.

Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0753

Some hypotheses may be postulated to explain the variability in the RET variant profiles among the countries. Studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. An important drawback of these observations resides in the limited amount or lack of data from many countries, which was somewhat disappointing considering that the causative role of RET germline variants in MEN2 syndrome has been demonstrated almost 30 years ago. Moreover, the reports from several countries used different sequence techniques over time; in addition, at the beginning, the goal was on analyzing only RET exons 10, 11, and 16; after some years, researchers have extended the search to exons 5, 8, 8–16. Finally, it is important to call attention that the recommendation for the molecular diagnosis of the RET has changed from clinically affected MEN2 patients in the early years to all patients with MTC and PHEO nowadays. These changes over time might have resulted in different distribution of RET variants. Hopefully, the advent of next-generation sequencing and comprehensive analysis of the RET exome, or the entire locus, extended to a larger number of MEN2 patients, shed light on the geographic distribution of RET variants and environmental circumstances that might affect genotype–phenotype correlations.

Declaration of interest

A L M has served as principal investigator in multicenter studies for Astra-Zeneca, Exelixis, and Lilly within the past 2 years. R M B M has nothing to disclose.

Funding

This work was supported by research grants from the Sao Paulo State Research Foundation (FAPESP), numbers 2006/60402-1, 2010/51547-1, 2013/01476-9, and 2014/06570-6 to RMBM and by a research grant from the Programa de Apoio a Núcleos de Excelência (PRONEX)/Rio Grande do Sul Research Foundation (FAPERGS), 16/2551-0000482-2, to A L M. A L M and R M B M are recipients of scholarships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

References

  • 1

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hedge M, Lyon E & Spector E et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015 17 405424. (https://doi.org/10.1038/gim.2015.30)

    • Search Google Scholar
    • Export Citation
  • 2

    Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Morley JF, Goodfellow P, Wells SA. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics 1993 2 851856. (https://doi.org/10.1093/hmg/2.7.851)

    • Search Google Scholar
    • Export Citation
  • 3

    Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993 363 458460. (https://doi.org/10.1038/363458a0)

    • Search Google Scholar
    • Export Citation
  • 4

    Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells Jr SA, Goodfellow PJ, Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. PNAS 1994 91 15791583. (https://doi.org/10.1073/pnas.91.4.1579)

    • Search Google Scholar
    • Export Citation
  • 5

    Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994 367 375376. (https://doi.org/10.1038/367375a0)

    • Search Google Scholar
    • Export Citation
  • 6

    Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Lackson CE, Tunnaclife A. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Human Molecular Genetics 1994 3 237241. (https://doi.org/10.1093/hmg/3.2.237)

    • Search Google Scholar
    • Export Citation
  • 7

    Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HKP, Lips CJM, Nishisho I & Takai SI et al.The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996 276 15751579.

    • Search Google Scholar
    • Export Citation
  • 8

    Mulligan LM RET revisited: expanding the oncogenic portfolio. Nature Reviews: Cancer 2014 14 173186. (https://doi.org/10.1038/nrc3680)

  • 9

    Raue F, Bruckner T, Frank-Raue K. Long-term outcomes and aggressiveness of hereditary medullary thyroid carcinoma: 40 years of experience at one center. Journal of Clinical Endocrinology and Metabolism 2019 104 42644272. (https://doi.org/10.1210/jc.2019-00516)

    • Search Google Scholar
    • Export Citation
  • 10

    Ceolin L, Duval MADS, Benini AF, Ferreira CV, Maia AL. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocrine-Related Cancer 2019 26 R499R518. (https://doi.org/10.1530/ERC-18-0574)

    • Search Google Scholar
    • Export Citation
  • 11

    Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F & Conte-Devolx B et al.Early malignant progression of hereditary medullary thyroid cancer. New England Journal of Medicine 2003 349 15171525. (https://doi.org/10.1056/NEJMoa012915)

    • Search Google Scholar
    • Export Citation
  • 12

    Puñales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. Journal of Clinical Endocrinology and Metabolism 2003 88 26442649. (https://doi.org/10.1210/jc.2002-021422)

    • Search Google Scholar
    • Export Citation
  • 13

    Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs A, Robledo M, Biarnes J, Barontini M & Links TP et al.Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocrine-Related Cancer 2008 15 10351041. (https://doi.org/10.1677/ERC-08-0105)

    • Search Google Scholar
    • Export Citation
  • 14

    Scapineli JO, Ceolin L, Puñales MK, Dora JM, Maia AL. MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics. Familial Cancer 2016 15 625633. (https://doi.org/10.1007/s10689-016-9892-6)

    • Search Google Scholar
    • Export Citation
  • 15

    Coyle D, Friedmacher F, Puri P. The association between Hirschsprung’s disease and multiple endocrine neoplasia type 2A: a systematic review. Pediatric Surgery International 2014 30 751756. (https://doi.org/10.1007/s00383-014-3538-2)

    • Search Google Scholar
    • Export Citation
  • 16

    Leboulleux S, Baudin E, Travagli JP, Schlumberger M. Medullary thyroid carcinoma. Clinical Endocrinology 2004 61 299310. (https://doi.org/10.1111/j.1365-2265.2004.02037.x)

    • Search Google Scholar
    • Export Citation
  • 17

    Elisei R, Tacito A, Ramone T, Ciampi R, Bottici V, Cappagli V, Viola D, Matrone A, Lorusso L & Valerio L et al.Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations. Genes 2019 10 698. (https://doi.org/10.3390/genes10090698)

    • Search Google Scholar
    • Export Citation
  • 18

    Sponziello M, Benvenuti S, Gentile A, Pecce V, Rosignolo F, Virzì AR, Milan M, Comoglio PM, Londin E & Fortina P et al.Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer. Human Mutation 2018 39 371377. (https://doi.org/10.1002/humu.23378)

    • Search Google Scholar
    • Export Citation
  • 19

    Castinetti F, Waguespack SG, Machens A, Uchino S, Lazaar K, Sanso G, Else T, Dvorakova S, Qi XP & Elisei R et al.Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet: Diabetes and Endocrinology 2019 7 213220. (https://doi.org/10.1016/S2213-8587(18)30336-X)

    • Search Google Scholar
    • Export Citation
  • 20

    Machens A, Lorenz K, Dralle H. Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Annals of Surgery 2009 250 305310. (https://doi.org/10.1097/SLA.0b013e3181ae333f)

    • Search Google Scholar
    • Export Citation
  • 21

    Elisei R, Romei C, Renzini G, Bottici V, Cosci B, Molinaro E, Agate L, Cappagli V, Miccoli P & Berti P et al.The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. Journal of Clinical Endocrinology and Metabolism 2012 97 426435. (https://doi.org/10.1210/jc.2011-2046)

    • Search Google Scholar
    • Export Citation
  • 22

    Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG & Libroia A et al.Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism 2001 86 56585671. (https://doi.org/10.1210/jcem.86.12.8070)

    • Search Google Scholar
    • Export Citation
  • 23

    American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F & Ringel MD et al.Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009 19 565612. (https://doi.org/10.1089/thy.2008.0403)

    • Search Google Scholar
    • Export Citation
  • 24

    Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF & Pacini F et al.Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015 25 567610. (https://doi.org/10.1089/thy.2014.0335)

    • Search Google Scholar
    • Export Citation
  • 25

    Maia AL, Siqueira DR, Kulcsar MA, Tincani AJ, Mazeto GM, Maciel LM. Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arquivos Brasileiros de Endocrinologia e Metabologia 2014 58 667700. (https://doi.org/10.1590/0004-2730000003427)

    • Search Google Scholar
    • Export Citation
  • 26

    Machens A, Lorenz K, Sekulla C, Höppner W, Frank-Raue K, Raue F, Dralle H. Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium. European Journal of Endocrinology 2013 168 307314. (https://doi.org/10.1530/EJE-12-0919)

    • Search Google Scholar
    • Export Citation
  • 27

    Opsahl EM, Brauckhoff M, Schlichting E, Helset K, Svartberg J, Brauckhoff K, Maehle L, Engebretsen LF, Sigstad E & Groholt KK et al.A nationwide study of multiple endocrine neoplasia type 2A in Norway: predictive and prognostic factors for the clinical course of medullary thyroid carcinoma. Thyroid 2016 26 12251238. (https://doi.org/10.1089/thy.2015.0673)

    • Search Google Scholar
    • Export Citation
  • 28

    Slatkin M Allele age and a test for selection on rare alleles. Philosophical Transactions of the Royal Society of London: Series B, Biological Sciences 2000 355 16631668. (https://doi.org/10.1098/rstb.2000.0729)

    • Search Google Scholar
    • Export Citation
  • 29

    Machens A, Elwerr M, Lorenz K, Weber F, Dralle H. 100-year evolution of precision medicine and surgery for multiple endocrine neoplasia type 2A. Endocrine 2020 68 368376. (https://doi.org/10.1007/s12020-020-02232-5)

    • Search Google Scholar
    • Export Citation
  • 30

    Niccoli-Sire P, Murat A, Rohmer V, Gibelin H, Chabrier G, Conte-Devolx B, Visset J, Ronceray J, Jaeck D & Henry JF et al.When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery 2003 134 10291036; discussion 1036. (https://doi.org/10.1016/j.surg.2003.07.019)

    • Search Google Scholar
    • Export Citation
  • 31

    Romei C, Mariotti S, Fugazzola L, Taccaliti A, Pacini F, Opocher G, Mian C, Castellano M, degli Uberti E & Ceccherini I et al.Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. European Journal of Endocrinology 2010 163 301308. (https://doi.org/10.1530/EJE-10-0333)

    • Search Google Scholar
    • Export Citation
  • 32

    Romei C, Casella F, Tacito A, Bottici V, Valerio L, Viola D, Cappagli V, Matrone A, Ciampi R & Piaggi P et al.New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. Journal of Medical Genetics 2016 53 729734. (https://doi.org/10.1136/jmedgenet-2016-103833)

    • Search Google Scholar
    • Export Citation
  • 33

    Martins-Costa MC, Cunha LL, Lindsey SC, Camacho CP, Dotto RP, Furuzawa GK, Sousa MSA, Kasamatsu TS, Kunii IS & Martins MM et al.M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds. Endocrine-Related Cancer 2016 23 909920. (https://doi.org/10.1530/ERC-16-0141)

    • Search Google Scholar
    • Export Citation
  • 34

    Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Gaustadnes M, Ørntoft TF & van Overeem Hansen T et al.Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994–2014: a nationwide study. Thyroid 2017 27 215223. (https://doi.org/10.1089/thy.2016.0411)

    • Search Google Scholar
    • Export Citation
  • 35

    Cunha LL, Lindsey SC, França MIC, Sarika L, Papathoma A, Kunii IS, Cerutti JM, Dias-da-Silva MR, Alevizaki M, Maciel RMB. Evidence for the founder effect of RET533 as the common Greek and Brazilian ancestor spreading multiple endocrine neoplasia 2A. European Journal of Endocrinology 2017 176 515519. (https://doi.org/10.1530/EJE-16-1021)

    • Search Google Scholar
    • Export Citation
  • 36

    Machens A, Lorenz K, Weber F, Dralle H. Geographic epidemiology of medullary thyroid cancer families: unearthing European ancestral heritage. Endocrine-Related Cancer 2018 25 L27L30. (https://doi.org/10.1530/ERC-17-0514)

    • Search Google Scholar
    • Export Citation
  • 37

    Castinetti F, Maia AL, Peczkowska M, Barontini M, Hasse-Lazar K, Links TP, Toledo RA, Dvorakova S, Mian C & Bugalho MJ et al.The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations. Endocrine-Related Cancer 2017 24 L63L67. (https://doi.org/10.1530/ERC-17-0189)

    • Search Google Scholar
    • Export Citation
  • 38

    Machens A, Lorenz K, Weber F, Dralle H. Genotype-specific progression of hereditary medullary thyroid cancer. Human Mutation 2018 39 860869. (https://doi.org/10.1002/humu.23430)

    • Search Google Scholar
    • Export Citation
  • 39

    Machens A, Dralle H. Long-term outcome after DNA-based prophylactic neck surgery in children at risk of hereditary medullary thyroid cancer. Best Practice and Research: Clinical Endocrinology and Metabolism 2019 33 101274. (https://doi.org/10.1016/j.beem.2019.04.008)

    • Search Google Scholar
    • Export Citation
  • 40

    Rohmer V, Vidal-Trecan G, Bourdelot A, Niccoli P, Murat A, Wemeau JL, Borson-Chazot F, Schvartz C, Tabarin A & Chabre O et al.Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d’Etude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism 2011 96 E509E518. (https://doi.org/10.1210/jc.2010-1234)

    • Search Google Scholar
    • Export Citation
  • 41

    Lebeault M, Pinson S, Guillaud-Bataille M, Gimenez-Roqueplo AP, Carrie A, Barbu V, Pigny P, Bezieau S, Rey JM & Delvincourt C et al.Nationwide French study of RET variants detected from 2003 to 2013 suggests a possible influence of polymorphisms as modifiers. Thyroid 2017 27 15111522. (https://doi.org/10.1089/thy.2016.0399)

    • Search Google Scholar
    • Export Citation
  • 42

    Romei C, Tacito A, Molinaro E, Agate L, Bottici V, Viola D, Matrone A, Biagini A, Casella F & Ciampi R et al.Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clinical Endocrinology 2015 82 892899. (https://doi.org/10.1111/cen.12686)

    • Search Google Scholar
    • Export Citation
  • 43

    Fussey JM, Smith JA, Cleaver R, Bowles C, Ellard S, Vaidya B, Owens M. Diagnostic RET genetic testing in 1,058 index patients: a UK centre perspective. Clinical Endocrinology 2021 95 295302. (https://doi.org/10.1111/cen.14395)

    • Search Google Scholar
    • Export Citation
  • 44

    Maciel RMB, Camacho CP, Assumpção LVM, Bufalo NE, Carvalho AL, de Carvalho GA, Castroneves LA, de Castro FM, Ceolin L & Cerutti JM et al.Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocrine Connections 2019 8 289298. (https://doi.org/10.1530/EC-18-0506)

    • Search Google Scholar
    • Export Citation
  • 45

    Ahmed SA, Snow-Bailey K, Highsmith WE, Sun W, Fenwick RG, Mao R. Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. Journal of Molecular Diagnostics 2005 7 283288. (https://doi.org/10.1016/S1525-1578(10)60556-9)

    • Search Google Scholar
    • Export Citation
  • 46

    Makri A, Akshintala S, Derse-Anthony C, Del Rivero J, Widemannn B, Stratakis CA, Glod J, Lodish M. Pheochromocytoma in children and adolescentes with multiple endocrine neoplasia type 2B. Journal of Clinical Endocrinology and Metabolism 2019 104 712. (https://doi.org/10.1210/jc.2018-00705)

    • Search Google Scholar
    • Export Citation
  • 47

    Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, Sherman SI, Gagel RF, Lee JE, Evans DB. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Archives of Surgery 2003 138 409416; discussion 416. (https://doi.org/10.1001/archsurg.138.4.409)

    • Search Google Scholar
    • Export Citation
  • 48

    Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. New England Journal of Medicine 2005 353 11051113. (https://doi.org/10.1056/NEJMoa043999)

    • Search Google Scholar
    • Export Citation
  • 49

    Voss RK, Feng L, Lee JE, Perrier ND, Graham PH, Hyde SM, Nieves-Munoz F, Cabanillas ME, Waguespack SG & Cote GJ et al.Medullary thyroid carcinoma in MEN2A: ATA moderate- or high-risk RET mutations do not predict disease aggressiveness. Journal of Clinical Endocrinology and Metabolism 2017 102 28072813. (https://doi.org/10.1210/jc.2017-00317)

    • Search Google Scholar
    • Export Citation
  • 50

    Etit D, Faquin WC, Gaz R, Randolph G, DeLellis RA, Pilch BZ. Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Archives of Pathology and Laboratory Medicine 2008 132 17671773. (https://doi.org/10.5858/132.11.1767)

    • Search Google Scholar
    • Export Citation
  • 51

    Jaber T, Hyde SM, Cote GJ, Grubbs EG, Giles WH, Stevens CA, Dadu R. A homozygous RET K666N genotype with an MEN2A phenotype. Journal of Clinical Endocrinology and Metabolism 2018 103 12691272. (https://doi.org/10.1210/jc.2017-02402)

    • Search Google Scholar
    • Export Citation
  • 52

    Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, Mao R. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Human Mutation 2009 30 548556. (https://doi.org/10.1002/humu.20928)

    • Search Google Scholar
    • Export Citation
  • 53

    Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T, Sakurai A & MEN Consortium of Japan. High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. European Journal of Endocrinology 2013 168 683687. (https://doi.org/10.1530/EJE-12-1106)

    • Search Google Scholar
    • Export Citation
  • 54

    Kameyama K, Takami H. Medullary thyroid carcinoma: nationwide Japanese survey of 634 cases in 1996 and 271 cases in 2002. Endocrine Journal 2004 51 453456. (https://doi.org/10.1507/endocrj.51.453)

    • Search Google Scholar
    • Export Citation
  • 55

    Matsushita R, Nagasaki K, Ayabe T, Miyoshi Y, Kinjo S, Haruna H, Ihara K, Hasegawa T, Ida S & Ozono K et al.Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997–2017. Journal of Pediatric Endocrinology and Metabolism 2019 32 585595. (https://doi.org/10.1515/jpem-2018-0444)

    • Search Google Scholar
    • Export Citation
  • 56

    Yamazaki M, Hanamura T, Ito K, Uchino S, Sakurai A, Komatsu M. A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma. Endocrine Journal 2014 61 11411144. (https://doi.org/10.1507/endocrj.ej14-0334)

    • Search Google Scholar
    • Export Citation
  • 57

    Nakao KT, Usui T, Ikeda M, Mori Y, Yamamoto T, Kawashima ST, Namba K, Yuno A, Tamanaha T & Tagami T et al.Novel tandem germline RET proto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: report of a case and a literature review of tandem RET mutations with in silico analysis. Head and Neck 2013 35 E363E368. (https://doi.org/10.1002/hed.23241)

    • Search Google Scholar
    • Export Citation
  • 58

    Giacché M, Panarotto A, Tacchetti MC, Tosini R, Campana F, Mori L, Cappelli C, Pirola I, Lombardi D & Pezzola DC et al.p.Ser891Ala RET gene mutations in medullary thyroid cancer: phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy. Human Mutation 2019 40 926937. (https://doi.org/10.1002/humu.23754)

    • Search Google Scholar
    • Export Citation
  • 59

    Pinna G, Orgiana G, Riola A, Ghiani M, Lai ML, Carcassi C, Mariotti S. RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid 2007 17 101104. (https://doi.org/10.1089/thy.2006.0198)

    • Search Google Scholar
    • Export Citation
  • 60

    Innella G, Rossi C, Romagnoli M, Repaci A, Bianchi D, Cantarini ME, Martorana D, Godino L, Pession A & Percesepe A et al.Results and clinical interpretation of germline RET analysis in a series of patients with medullary thyroid carcinoma: the challenge of the variants with uncertain significance. Cancers 2020 12 3268. (https://doi.org/10.3390/cancers12113268)

    • Search Google Scholar
    • Export Citation
  • 61

    Neumann HPH, Vortmeyer A, Schmidt D, Werner M, Erlic Z, Cascon A, Bausch B, Januszewicz A, Eng C. Evidence of MEN-2 in the original description of classic pheochromocytoma. New England Journal of Medicine 2007 357 13111315. (https://doi.org/10.1056/NEJMoa071407)

    • Search Google Scholar
    • Export Citation
  • 62

    Szinnai G, Meier C, Komminoth P, Zumsteg UW. Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 2003 111 E132E139. (https://doi.org/10.1542/peds.111.2.e132)

    • Search Google Scholar
    • Export Citation
  • 63

    Pena SD, Bastos-Rodrigues L, Pimenta JR, Bydlowski SP. DNA tests probe the genomic ancestry of Brazilians. Brazilian Journal of Medical and Biological Research 2009 42 870876. (https://doi.org/10.1590/s0100-879x2009005000026)

    • Search Google Scholar
    • Export Citation
  • 64

    Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy Fde S, Kohlrausch F, Magno LA, Montenegro RC & Moraes MO et al.The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE 2011 6 e17063. (https://doi.org/10.1371/journal.pone.0017063)

    • Search Google Scholar
    • Export Citation
  • 65

    Ongaro L, Scliar MO, Flores R, Raveane A, Marnetto D, Sarno S, Gnecchi-Ruscone GA, Alancón-Riquelme ME, Patin E & Wangkumhang P et al.The genomic impact of European colonization of the Americas. Current Biology 2019 29 3974.e43986.e4.

    • Search Google Scholar
    • Export Citation
  • 66

    Da Silva AM, Maciel RMB, Da Silva MR, Toledo SR, De Carvalho MB, Cerutti JM. A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2003 88 54385443. (https://doi.org/10.1210/jc.2003-030997)

    • Search Google Scholar
    • Export Citation
  • 67

    Oliveira MN, Hemerly JP, Bastos AU, Tamanaha R, Latini FR, Camacho CP, Impellizzeri A, Maciel RMB, Cerutti JM. The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. Thyroid 2011 21 975985. (https://doi.org/10.1089/thy.2010.0190)

    • Search Google Scholar
    • Export Citation
  • 68

    Signorini PS, França MI, Camacho CP, Lindsey SC, Valente FO, Kasamatsu TS, Machado AL, Salim CP, Delcelo R & Hoff AO et al.A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. Clinical Endocrinology 2014 80 235245. (https://doi.org/10.1111/cen.12264)

    • Search Google Scholar
    • Export Citation
  • 69

    Bethanis S, Koutsodontis G, Palouka T, Avgoustis C, Yannoukakos D, Bei T, Papadopoulos S, Linos D, Tsagarakis S. A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. Hormones 2007 6 152156. (https://doi.org/10.14310/horm.2002.1111011)

    • Search Google Scholar
    • Export Citation
  • 70

    Peppa M, Boutati E, Kamakari S, Pikounis V, Peros G, Panayiotides IG, Economopoulos T, Raptis SA, Hadjidakis D. Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. European Journal of Endocrinology 2008 159 767771. (https://doi.org/10.1530/EJE-08-0476)

    • Search Google Scholar
    • Export Citation
  • 71

    Sarika HL, Papathoma A, Garofalaki M, Vasileiou V, Vlassopoulou B, Anastasiou E, Alevizaki M. High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece. Clinical Endocrinology 2012 77 857862. (https://doi.org/10.1111/j.1365-2265.2012.04462.x)

    • Search Google Scholar
    • Export Citation
  • 72

    Sarika HL, Papathoma A, Garofalaki M, Saltiki K, Pappa T, Pazaitou-Panayiotou K, Anastasiou E, Alevizaki M. Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades. European Journal of Endocrinology 2015 172 501509. (https://doi.org/10.1530/EJE-14-0817)

    • Search Google Scholar
    • Export Citation
  • 73

    Braudel F The Mediterranean Anda the Mediterranean World in the Age of Philip II, 1st ed. University of California Press Books: Berkeley, CA, USA 1996.

    • Search Google Scholar
    • Export Citation
  • 74

    Castro MR, Thomas BC, Richards ML, Zhang J, Morris JC. Multiple endocrine neoplasia type 2A due to an exon 8 (G533C) mutation in a large North American kindred. Thyroid 2013 23 15471552. (https://doi.org/10.1089/thy.2012.0599)

    • Search Google Scholar
    • Export Citation
  • 75

    Casey R, Prendeville S, Joyce C, O’Halloran D. First reported case in Ireland of MEN2A due to a rare mutation in exon 8 of the RET oncogene. Endocrinology, Diabetes and Metabolism Case Reports 2013 2013 130044. (https://doi.org/10.1530/EDM-13-0044)

    • Search Google Scholar
    • Export Citation
  • 76

    Cosci B, Vivaldi A, Romei C, Gemignani F, Landi S, Ciampi R, Tacito A, Molinaro E, Agate L & Bottici V et al.In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocrine-Related Cancer 2011 18 603612. (https://doi.org/10.1530/ERC-11-0117)

    • Search Google Scholar
    • Export Citation
  • 77

    Amosenko FA, Khvostovoy VV, Shchagina OA, Polyakov AV. A rare germline mutation c.2752 A>G (p.M918V) in the RET protooncogene in a patient with medullary and papillary thyroid carcinomas in cervical lymph node metastases: a case report and review of the literature. Clinical and Experimental Thyroidology 2016 12 4652. (https://doi.org/10.14341/ket2016146-52)

    • Search Google Scholar
    • Export Citation
  • 78

    Prete FP, Abdel-Aziz T, Morkane C, Brain C, Kurzawinski TR & MEN2 in Children UK Collaborative Group. Prophylactic thyroidectomy in children with multiple endocrine neoplasia type 2. British Journal of Surgery 2018 105 13191327. (https://doi.org/10.1002/bjs.10856)

    • Search Google Scholar
    • Export Citation
  • 79

    Borrello MG, Aiello A, Peissel B, Rizzetti MG, Mondellini P, Degl’Innocenti D, Catalano V, Gobbo M, Collini P & Bongarzone I et al.Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. Endocrine-Related Cancer 2011 18 519527. (https://doi.org/10.1530/ERC-10-0306)

    • Search Google Scholar
    • Export Citation
  • 80

    Muzza M, Cordella D, Bombled J, Bressac-de Paillerets B, Guizzardi F, Francis Z, Beck-Peccoz P, Schlumberger M, Persani L, Fugazzola L. Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro. European Journal of Endocrinology 2010 162 771777. (https://doi.org/10.1530/EJE-09-0929)

    • Search Google Scholar
    • Export Citation
  • 81

    Mathiesen JS, Habra MA, Bassett JHD, Choudhury SM, Balasubramanian SP, Howlett TA, Robinson BG, Gimenez-Roqueplo AP, Castinetti F & Vestergaard P et al.Risk profile of the RET A883F germline mutation: an international collaborative study. Journal of Clinical Endocrinology and Metabolism 2017 102 20692074. (https://doi.org/10.1210/jc.2016-3640)

    • Search Google Scholar
    • Export Citation
  • 82

    Opsahl EM, Akslen LA, Schlichting E, Aas T, Brauckhoff K, Hagen AI, Rosenlund AF, Sigstad E, Groholt KK & Maehle L et al.Trends in diagnostics, surgical treatment, and prognostic factors for outcomes in medullary thyroid carcinoma in Norway: a nationwide population-based study. European Thyroid Journal 2019 8 3140. (https://doi.org/10.1159/000493977)

    • Search Google Scholar
    • Export Citation
  • 83

    Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Schytte S, Londero SC & Pedersen HB et al.Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960–2014: a nationwide study. Endocrine Connections 2018 7 829839. (https://doi.org/10.1530/EC-18-0157)

    • Search Google Scholar
    • Export Citation
  • 84

    Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Schytte S, Londero SC & Pedersen HB et al.Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997–2013: a nationwide study. Clinical Epidemiology 2019 11 9399. (https://doi.org/10.2147/CLEP.S183268)

    • Search Google Scholar
    • Export Citation
  • 85

    Hansen AW, Roos LKS, Lossl K, Goodbale C, Mathiesen JS. Preimplantation genetic testing of multiple endocrine neoplasia type 2A. Frontiers in Endocrinology 2020 11 572151.

    • Search Google Scholar
    • Export Citation
  • 86

    Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Gaustadnes M, Orntoft TF & Rossing M et al.Founder effect of the RET C611Y mutation in multiple Endocrine Neoplasia 2A in Denmark: a nationwide study. Thyroid 2017 27 15051510. (https://doi.org/10.1089/thy.2017.0404)

    • Search Google Scholar
    • Export Citation
  • 87

    Mathiesen JS, Kroustrup JP, Vestergaard P, Madsen M, Stochholm K, Poulsen PL, Rasmussen Å, Feldt-Rasmussen U, Schytte S & Pedersen HB et al.Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark: a nationwide study. Endocrine-Related Cancer 2017 24 L39L42. (https://doi.org/10.1530/ERC-17-0122)

    • Search Google Scholar
    • Export Citation
  • 88

    Fanis P, Skordis N, Frangos S, Christopoulos G, Spanou-Aristidou E, Andreou E, Manoli P, Mavrommatis M, Nicolaou S & Kleanthous M et al.Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect. Journal of Endocrinological Investestigation 2018 41 11491157. (https://doi.org/10.1007/s40618-018-0841-0)

    • Search Google Scholar
    • Export Citation
  • 89

    Lindskog S, Nilsson O, Jansson S, Nilsson B, Illerskog AC, Ysander L, Ahlman H, Tisell LE. Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a RET mutation at codon 618. British Journal of Surgery 2004 91 713718. (https://doi.org/10.1002/bjs.4457)

    • Search Google Scholar
    • Export Citation
  • 90

    Sánchez B, Robledo M, Biarnes J, Sáez ME, Volpini V, Benítez J, Navarro E, Ruiz A, Antiñolo G, Borrego S. High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain. Journal of Medical Genetics 1999 36 6870.

    • Search Google Scholar
    • Export Citation
  • 91

    Fernández RM, Navarro E, Antiñolo G, Ruiz-Ferrer M, Borrego S. Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients. International Journal of Molecular Medicine 2006 17 575581. (https://doi.org/10.3892/ijmm.17.4.575)

    • Search Google Scholar
    • Export Citation
  • 92

    Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J, Parrilla P. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World Journal of Surgery 2008 32 25202526. (https://doi.org/10.1007/s00268-008-9734-2)

    • Search Google Scholar
    • Export Citation
  • 93

    Valdés N, Navarro E, Mesa J, Casterás A, Alcázar V, Lamas C, Tebar J, Cataño L, Gaztambide S & Forga L et al.RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. European Journal of Endocrinology 2015 172 301307. (https://doi.org/10.1530/EJE-14-0818)

    • Search Google Scholar
    • Export Citation
  • 94

    Febrero B, Rodríguez JM, Ríos A, Segura P, Pérez-Sánchez B, Torregrosa N, Hernandez AM, Parrilla P. Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: a long-term follow-up in a large single-center cohort. European Journal of Surgical Oncology 2019 45 625630. (https://doi.org/10.1016/j.ejso.2018.09.002)

    • Search Google Scholar
    • Export Citation
  • 95

    Oriola J, Sanchez A, Paniello B, de la Bellacasa JP, Biarnés J. A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid carcinoma. Familial Cancer 2021 20 253256. (https://doi.org/10.1007/s10689-020-00214-0)

    • Search Google Scholar
    • Export Citation
  • 96

    Zhou Y, Zhao Y, Cui B, Gu L, Zhu S, Li J, Liu J, Yin M, Zhao T & Yin Z et al.RET proto-oncogene mutations are restricted to codons 634 and 918 in mainland Chinese families with MEN2A and MEN2B. Clinical Endocrinology 2007 67 570576. (https://doi.org/10.1111/j.1365-2265.2007.02927.x)

    • Search Google Scholar
    • Export Citation
  • 97

    Qi XP, Chen XL, Ma JM, Du ZF, Fei J, Yang CP, Cheng J, Song QZ, Han JS & Jin HY et al.RET proto-oncogene genetic screening of families with multiple endocrine neoplasia type 2 optimizes diagnostic and clinical management in China. Thyroid 2012 22 12571265. (https://doi.org/10.1089/thy.2012.0134)

    • Search Google Scholar
    • Export Citation
  • 98

    Qi XP, Zhao JQ, Du ZF, Yang RR, Ma JM, Fei J, Cheng J, Han JS, Jin HY & Chen ZG et al.Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China. European Journal of Surgical Oncology 2013 39 10071012. (https://doi.org/10.1016/j.ejso.2013.06.015)

    • Search Google Scholar
    • Export Citation
  • 99

    Wang J, Zhang B, Liu W, Zhang Y, Di X, Yang Y, Yan D. Screening of RET gene mutations in Chinese patients with medullary thyroid carcinoma and their relatives. Familial Cancer 2016 15 99104. (https://doi.org/10.1007/s10689-015-9828-6)

    • Search Google Scholar
    • Export Citation
  • 100

    Zhang X, Yan D, Wang J, Wan H, Zhang Y, Zhang Y, He Y, Liu W, Zhang B. Is new American Thyroid Association risk classification for hereditary medullary thyroid carcinoma applicable to Chinese patients? A single-center study. Chinese Journal of Cancer Research 2017 29 223230. (https://doi.org/10.21147/j.issn.1000-9604.2017.03.08)

    • Search Google Scholar
    • Export Citation
  • 101

    Zhao JQ, Chen ZG, Qi XP. Molecular diagnosis and comprehensive treatment of multiple endocrine neoplasia type 2 in Southeastern Chinese. Hereditary Cancer in Clinical Practice 2015 13 5. (https://doi.org/10.1186/s13053-015-0026-1)

    • Search Google Scholar
    • Export Citation
  • 102

    Huang Q, Hu A, Zhang M. Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: implications for RET oncogene detection. BMC Endocrine Disorders 2020 20 64. (https://doi.org/10.1186/s12902-020-0544-3)

    • Search Google Scholar
    • Export Citation
  • 103

    Lu F, Chen X, Bai Y, Feng Y, Wu J. A large Chinese pedigree of multiple endocrine neoplasia type 2A with a novel C634Y/D707E germline mutation in RET exon 11. Oncology Letters 2017 14 35523558. (https://doi.org/10.3892/ol.2017.6583)

    • Search Google Scholar
    • Export Citation
  • 104

    Yang Z, Qi X, Gross N, Kou X, Bai Y, Feng Y, Wang B, Zafereo ME, Li G & Sun C et al.The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A. Journal of Cellular and Molecular Medicine 2020 24 1316313170. (https://doi.org/10.1111/jcmm.15922)

    • Search Google Scholar
    • Export Citation
  • 105

    Qi XP, Jin BY, Li PF, Wang S, Zhao YH, Cao ZL, Yu XH, Cheng J, Fang XD & Zhao JQ et al.RET S409Y germline mutation and associated medullary thyroid carcinoma. Thyroid 2019 29 14471456. (https://doi.org/10.1089/thy.2018.0385)

    • Search Google Scholar
    • Export Citation
  • 106

    Chen S, Li S, Zhang J, Zhang L, Chen Y, Wang L, Jin L, Hu Y, Qi X & Huang H et al.Preimplantation genetic diagnosis of multiple endocrine neoplasia type 2A using informative markers identified by targeted sequencing. Thyroid 2018 28 281287. (https://doi.org/10.1089/thy.2017.0200)

    • Search Google Scholar
    • Export Citation
  • 107

    Efared B, Atsame-Ebang G, Tahirou S, Mazaz K, Hammas N, El Fatemi H, Chbani L. Bilateral pheochromocytoma with ganglioneuroma component associated with multiple neuroendocrine neoplasia type 2A: a case report. Journal of Medical Case Reports 2017 11 208. (https://doi.org/10.1186/s13256-017-1364-6)

    • Search Google Scholar
    • Export Citation
  • 108

    Abdelhakim A, Barlier A, Kebbou M, Benabdeljalil N, Timinouni M, Taoufiq F, Roche C, El Antri S. RET genetic screening in patients with medullary thyroid cancer: the Moroccan experience. Journal of Cancer Research and Therapeutics 2009 5 198202. (https://doi.org/10.4103/0973-1482.57126)

    • Search Google Scholar
    • Export Citation
  • 109

    Moore SW, Zaahl MG. Chasing the ubiquitous RET proto-oncogene in South African MEN2 families--implications for the surgeon. South African Journal of Surgery 2010 48 127131.

    • Search Google Scholar
    • Export Citation
  • 110

    Moore SW, Zaahl M. Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 ‘Janus’ genetic variation. Journal of Pediatric Surgery 2010 45 393396. (https://doi.org/10.1016/j.jpedsurg.2009.10.080)

    • Search Google Scholar
    • Export Citation
  • 111

    Califano I, Deutsch S, Castro Jozami L, Fassi J, Lowenstein A, Balzaretti M, Novelli JL, Figari M, Olstein G & Sansó G et al.Medullary thyroid carcinoma: clinical presentation and outcome in 219 patients. Revista Argentina de Endocrinologia y Metabolismo 2013 50 6370.

    • Search Google Scholar
    • Export Citation
  • 112

    Sansó GE, Domene HM, Garcia R, Pusiol E, de M, Roque M, Ring A, Perinetti H, Elsner B & Iorcansky S et al.Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 2002 94 323330. (https://doi.org/10.1002/cncr.10228)

    • Search Google Scholar
    • Export Citation
  • 113

    Bussières V, Roy S, Deladoey J, Rousseau É, St-Vil D, Piché N. Prophylactic thyroidectomies in MEN2 syndrome: management and outcomes. Journal of Pediatric Surgery 2018 53 283285. (https://doi.org/10.1016/j.jpedsurg.2017.11.015)

    • Search Google Scholar
    • Export Citation
  • 114

    Diaz RE, Wohllk N. Multiple endocrine neoplasia: the Chilean experience. Clinics 2012 67 (Supplement 1) 711. (https://doi.org/10.6061/clinics/2012(sup01)03)

    • Search Google Scholar
    • Export Citation
  • 115

    González B, Salcedo M, Medrano ME, Mantilla A, Quiñónez G, Benítez-Bribiesca L, Rodrigues-Cuevas S, Cabrera L, de León B & Altamirano N et al.RET oncogene mutations in medullary thyroid carcinoma in Mexican families. Archives of Medical Research 2003 34 4149. (https://doi.org/10.1016/s0188-4409(02)00461-7)

    • Search Google Scholar
    • Export Citation
  • 116

    Sharma BP, Saranath D. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients. Journal of Biosciences 2011 36 603611. (https://doi.org/10.1007/s12038-011-9095-0)

    • Search Google Scholar
    • Export Citation
  • 117

    Mahesh DM, Nehru AG, Seshadri MS, Thomas N, Nair A, Pai R, Rajaratnam S. RET mutations in a large Indian family with medullary thyroid carcinoma. Indian Journal of Endocrinology and Metabolism 2014 18 516520. (https://doi.org/10.4103/2230-8210.137508)

    • Search Google Scholar
    • Export Citation
  • 118

    Cherian AJ, Ramakant P, Pai R, Manipadam MT, Elanthenral S, Chandramohan A, Hephzibah J, Mathew D, Naik D & Paul TV et al.Outcome of treatment for medullary thyroid carcinoma-a single centre experience. Indian Journal of Surgical Oncolology 2018 9 5258. (https://doi.org/10.1007/s13193-017-0718-2)

    • Search Google Scholar
    • Export Citation
  • 119

    Valiveru RC, Agarwal G, Agrawal V, Mayilvaganan S, Chand G, Mishra A, Agarwal A, Mishra SK, Bhatia E. Hereditary medullary thyroid carcinoma: genotype, phenotype and outcomes in a North Indian cohort. World Journal of Surgery 2021 45 17851793. (https://doi.org/10.1007/s00268-021-05993-w)

    • Search Google Scholar
    • Export Citation
  • 120

    Vijayan R, Nair V, Menon U, Kumar H. A rare RET mutation in an Indian pedigree with familial medullary thyroid carcinoma. Indian Journal of Cancer 2021 58 98100. (https://doi.org/10.4103/ijc.IJC_639_19)

    • Search Google Scholar
    • Export Citation
  • 121

    Alvandi E, Akrami SM, Chiani M, Hedayati M, Nayer BN, Tehrani MR, Nakhjavani M, Pedram M. Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population. Thyroid 2011 21 373382. (https://doi.org/10.1089/thy.2010.0267)

    • Search Google Scholar
    • Export Citation
  • 122

    Hedayati M, Zarif Yeganeh M, Sheikhol Eslami S, Rezghi Barez S, Hoghooghi Rad L, Azizi F. Predominant RET germline mutations in Exons 10, 11, and 16 in Iranian patients with hereditary medullary thyroid carcinoma. Journal of Thyroid Research 2011 2011 264248. (https://doi.org/10.4061/2011/264248)

    • Search Google Scholar
    • Export Citation
  • 123

    Yeganeh MZ, Sheikholeslami S, Dehbashi Behbahani G, Farashi S, Hedayati M. Skewed mutational spectrum of RET proto-oncogene Exon10 in Iranian patients with medullary thyroid carcinoma. Tumour Biology 2015 36 52255231. (https://doi.org/10.1007/s13277-015-3179-7)

    • Search Google Scholar
    • Export Citation
  • 124

    Hedayati M, Zarif Yeganeh M, Sheikholeslami S, Afsari F. Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer. Critical Reviews in Clinical Laboratory Sciences 2016 53 217227. (https://doi.org/10.3109/10408363.2015.1129529)

    • Search Google Scholar
    • Export Citation
  • 125

    Al-Kurd A, Gross DJ, Zangen D, Atlan K, Mazeh H, Grozinsky-Glasberg S. Bilateral medullary thyroid carcinoma in a 3-year-old female patient with multiple endocrine neoplasia 2A syndrome undergoing prophylactic thyroidectomy: should current guidelines be revised? European Thyroid Journal 2018 7 267271. (https://doi.org/10.1159/000489170)

    • Search Google Scholar
    • Export Citation
  • 126

    Grozinsky-Glasberg S, Benbassat CA, Tsvetov G, Feinmesser R, Peretz H, Shimon I, Lapidot M. Medullary thyroid cancer: a retrospective analysis of a cohort treated at a single tertiary care center between 1970 and 2005. Thyroid 2007 17 549556. (https://doi.org/10.1089/thy.2006.0229)

    • Search Google Scholar
    • Export Citation
  • 127

    Chung YJ, Kim HH, Kim HJ, Min YK, Lee MS, Lee MK, Kim KW, Ki CS, Kim JW, Chung JH. RET proto-oncogene mutations are restricted to codon 634 and 618 in Korean families with multiple endocrine neoplasia 2A. Thyroid 2004 14 813818. (https://doi.org/10.1089/thy.2004.14.813)

    • Search Google Scholar
    • Export Citation
  • 128

    Jung KY, Kim SM, Kim MJ, Cho SW, Kim BW, Lee YS, Jeong JJ, Nam KH, Chung WY & Lee KE et al.Genotypic characteristics and their association with phenotypic characteristics of hereditary medullary thyroid carcinoma in Korea. Surgery 2018 164 312318. (https://doi.org/10.1016/j.surg.2018.03.018)

    • Search Google Scholar
    • Export Citation
  • 129

    Qari F RET codon 618 mutations in Saudi families with multiple endocrine neoplasia Type 2A and familial medullary thyroid carcinoma. Annals of Saudi Medicine 2013 33 155158. (https://doi.org/10.5144/0256-4947.2013.155)

    • Search Google Scholar
    • Export Citation
  • 130

    Schulten HJ, Al-Maghrabi J, Al-Ghamdi K, Salama S, Al-Muhayawi S, Chaudhary A, Hamour O, Abuzenadah A, Gari M, Al-Qahtani M. Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. Anticancer Research 2011 31 41794183.

    • Search Google Scholar
    • Export Citation
  • 131

    Fink M, Weinhüsel A, Niederle B, Haas OA. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. ‘Study Group Multiple Endocrine Neoplasia Austria (SMENA)’. International Journal of Cancer 1996 69 312316. (https://doi.org/10.1002/(SICI)1097-0215(19960822)69:4<312::AID-IJC13>3.0.CO;2-7)

    • Search Google Scholar
    • Export Citation
  • 132

    Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle B, Kaserer K, Waldhaus W, Vierhapper H. Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? Journal of Clinical Endocrinology and Metabolism 2005 90 62326236. (https://doi.org/10.1210/jc.2005-1278)

    • Search Google Scholar
    • Export Citation
  • 133

    Jindrichová S, Vcelák J, Vlcek P, Neradilová M, Nemec J, Bendlová B. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. Journal of Endocrinology 2004 183 257265. (https://doi.org/10.1677/joe.1.05838)

    • Search Google Scholar
    • Export Citation
  • 134

    Kaldrymides P, Mytakidis N, Anagnostopoulos T, Vassiliou M, Tertipi A, Zahariou M, Rampias T, Koutsodontis G, Konstantopoulou I & Ladopoulou A et al.A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clinical Endocrinology 2006 64 561566. (https://doi.org/10.1111/j.1365-2265.2006.02509.x)

    • Search Google Scholar
    • Export Citation
  • 135

    Casey R, Bell M, Keane M, Smyth A. An unusual presentation of MEN2A. BMJ Case Reports 2013 2013.doi:10.1136/bcr-2012-007171.

  • 136

    Znaczko A, Donnelly DE, Morrison PJ. Epidemiology, clinical features, and genetics of multiple endocrine neoplasia type 2B in a complete population. Oncologist 2014 19 12841286. (https://doi.org/10.1634/theoncologist.2014-0277)

    • Search Google Scholar
    • Export Citation
  • 137

    Paszko Z, Sromek M, Czetwertynska M, Skasko E, Czapczak D, Wisniewska A, Prokurat A, Chruoek M, Jagielska A, Kozlowicz-Gudzinska I. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred’s from Central Poland. Cancer Investigation 2007 25 742749. (https://doi.org/10.1080/07357900701518735)

    • Search Google Scholar
    • Export Citation
  • 138

    Sromek M, Czetwertyńska M, Tarasińska M, Janiec-Jankowska A, Zub R, Ćwikła M, Nowakowska D, Chechlinska M. Analysis of newly identified and rare synonymous genetic variants in the RET gene in patients with medullary thyroid carcinoma in polish population. Endocrine Pathology 2017 28 198206. (https://doi.org/10.1007/s12022-017-9487-2)

    • Search Google Scholar
    • Export Citation
  • 139

    Kaczmarek-Ryś M, Ziemnicka K, Pławski A, Budny B, Michalak M, Hryhorowicz S, Hoppe-Golebiewska J, Borun P, Golab M & Czetwertynska M et al.Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course. Endocrine-Related Cancer 2018 25 421436. (https://doi.org/10.1530/ERC-17-0452)

    • Search Google Scholar
    • Export Citation
  • 140

    Bugalho MJ, Domingues R, Sobrinho L. MEN 2A families: from hot spots to hot regions. International Journal of Molecular Medicine 2003 11 7174. (https://doi.org/10.3892/ijmm.11.1.71)

    • Search Google Scholar
    • Export Citation
  • 141

    Bugalho MJ, Domingues R, Santos JR, Catarino AL, Sobrinho L. Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre. Surgery 2007 141 9095. (https://doi.org/10.1016/j.surg.2006.03.025)

    • Search Google Scholar
    • Export Citation
  • 142

    Silva AL, Carmo F, Moura MM, Domingues R, Espadinha C, Leite V, Cavaco B, Bugalho MJ. Identification and characterization of two novel germline RET variants associated with medullary thyroid carcinoma. Endocrine 2015 49 366372. (https://doi.org/10.1007/s12020-015-0559-0)

    • Search Google Scholar
    • Export Citation
  • 143

    Prazeres HJ, Rodrigues F, Figueiredo P, Naidenov P, Soares P, Bugalho MJ, Lacerda M, Campos B, Martins TC. Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal. Clinical Endocrinology 2006 64 659666. (https://doi.org/10.1111/j.1365-2265.2006.02524.x)

    • Search Google Scholar
    • Export Citation
  • 144

    Martins AF, Martins JM, do Vale S, Dias T, Silveira C, da Silva IR, Carmo-Fonseca M. A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A. Hormones 2016 15 435440. (https://doi.org/10.14310/horm.2002.1691)

    • Search Google Scholar
    • Export Citation
  • 145

    Amosenko FA, Pushkash K, Frilling A, Kozlova VN, Liubchenko LN, Kazubskaia TP, Brelysh KE, Garkavtseva RF, Kalinin VN. Molecular diagnosis of multiple type 2 endocrine neoplasia. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk 2001 2 3437.

    • Search Google Scholar
    • Export Citation
  • 146

    Kalinin VN, Amosenko FA, Puskas C, Frilling A, Broelsch CE. A new inherited RET proto-oncogene mutation associated with familial medullary thyroid carcinoma and polymorphisms in adjacent regions. Genetika 1998 34 11571159.

    • Search Google Scholar
    • Export Citation
  • 147

    Kalinin VN, Amosenko FA, Shabanov MA, Lubchenko LN, Hosch SB, Garkavtseva RF, Izbicki JR. Three novel mutations in the RET proto-oncogene. Journal of Molecular Medicine 2001 79 609612. (https://doi.org/10.1007/s001090100250)

    • Search Google Scholar
    • Export Citation
  • 148

    Amosenko FA, Ryadninskaya NV, Loginova AN, Polyakov AV. A rare germline allelic variant с.2657 G>A (p.Arg886Gln) in the RET protooncogene in a patient with medullary thyroid carcinoma. Medical Genetics 2018 17 5355.

    • Search Google Scholar
    • Export Citation
  • 149

    Rovcanin B, Damjanovic S, Zivaljevic V, Diklic A, Jovanovic M, Paunovic I. The results of molecular genetic testing for RET proto-oncogene mutations in patients with medullary thyroid carcinoma in a referral center after the two decade period. Hippokratia 2016 20 187191.

    • Search Google Scholar
    • Export Citation
  • 150

    Bergant D, Hocevar M, Besic N, Glavac D, Korosec B, Caserman S. Hereditary medullary thyroid cancer in Slovenia – genotype-phenotype correlations. Wiener Klinische Wochenschrift 2006 118 411416. (https://doi.org/10.1007/s00508-006-0636-8)

    • Search Google Scholar
    • Export Citation
  • 151

    Zupan A, Glavač D. The development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes. Experimental and Molecular Pathology 2015 99 416425. (https://doi.org/10.1016/j.yexmp.2015.08.017)

    • Search Google Scholar
    • Export Citation
  • 152

    Zedenius J, Larsson C, Bergholm U, Bovée J, Svensson A, Hallengren B, Grimelius L, Backdahl M, Weber G, Wallin G. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 1995 80 30883090. (https://doi.org/10.1210/jcem.80.10.7559902)

    • Search Google Scholar
    • Export Citation
  • 153

    Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer 1995 76 479489. (https://doi.org/10.1002/1097-0142(19950801)76:3<479::aid-cncr2820760319>3.0.co;2-m)

    • Search Google Scholar
    • Export Citation
  • 154

    Komminoth P, Muletta-Feurer S, Soltermann A, Gemsenjäger E, Bürgi H, Staub JJ, Schönle E, Fried M, Vetter W & Spinas GA et al.Detection of RET-proto-oncogene mutations in the diagnosis of Type 2 endocrine neoplasia (MEN 2). Schweizerische Medizinische Wochenschrift 1996 126 13291338.

    • Search Google Scholar
    • Export Citation
  • 155

    Basaran MN, Tuna MM, Karakılıç E, Doğan BA, İmga NN, Berker D, Guler S. Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. Journal of Endocrinological Investigation 2015 38 541546. (https://doi.org/10.1007/s40618-014-0224-0)

    • Search Google Scholar
    • Export Citation
  • 156

    Aydoğan , Yüksel B, Tuna MM, Navdar Başaran M, Akkurt Kocaeli A, Ertörer ME, Aydin K, Guldiken S, Simsek Y & Karaca ZC et al.Distribution of RET mutations and evaluation of treatment approaches in hereditary medullary thyroid carcinoma in turkey. Journal of Clinical Research in Pediatric Endocrinology 2016 8 1320. (https://doi.org/10.4274/jcrpe.2219)

    • Search Google Scholar
    • Export Citation
  • 157

    Abraham DT, Low TH, Messina M, Jackson N, Gill A, Chou AS, Delbridge L, Learoyd D, Robinson BG & Sidhu S et al.Medullary thyroid carcinoma: long-term outcomes of surgical treatment. Annals of Surgical Oncology 2011 18 219225. (https://doi.org/10.1245/s10434-010-1339-y)

    • Search Google Scholar
    • Export Citation
  • 158

    Jayakody S, Reagh J, Bullock M, Aniss A, Clifton-Bligh R, Learoyd D, Robinson B, Delbridge L, Sidhu S & Gill AJ et al.Medullary thyroid carcinoma: survival analysis and evaluation of mutation-specific immunohistochemistry in detection of sporadic disease. World Journal of Surgery 2018 42 14321439. (https://doi.org/10.1007/s00268-018-4551-8)

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology