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RET codon 609 mutations: a contribution for better clinical managing
Caterina MianI, Paola SartoratoII, Susi BarolloI, Mariangela ZaneII, Giuseppe OpocherI,II,
Corresponding author
giuseppe.opocher@unipd.it

Tel.: +39 0498215569
I University of Padova, Department of Medicine, Via Gattamelata, 64 35128 Padova, Italy.
II Veneto Institute of Oncology, Via Gattamelata, 64 35128 Padova, Italy.
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Pedigree analysis&#46; The proband is indicated by the black arrow&#46; Deceased patients are identified by diagonal lines&#46; Subjects with signs of MEN2A syndrome are indicated by black shading&#44; which covers half of the pedigree symbol for patients with MTC alone and three-quarters of the symbol for patients with MTC plus PHEO&#46; All patients who underwent genetic testing are marked with an asterisk&#46; After genotyping&#44; gene mutation carriers are identified by the square shape of their respective pedigree symbols&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Medullary thyroid carcinoma &#40;MTC&#41; currently accounts for 5&#8211;8&#37; of all thyroid cancers&#46; It arises from the parafollicular C-cells originating from the neural crest that are incorporated into the thyroid during fetal development&#46; The clinical course of MTC varies from extremely indolent tumors that can go unchanged for years to extremely aggressive variants that are associated with a high mortality rate&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">The relationship between proto-oncogene <span class="elsevierStyleItalic">RET</span> mutations and MTC is one of the best examples of translational medicine&#46; <span class="elsevierStyleItalic">RET</span> mutations predispose an individual to the development of parafollicular C-cell hyperplasia and&#44; subsequently&#44; to the onset of MTC&#46; Most of the sporadic MTC cases harbor a somatic <span class="elsevierStyleItalic">RET</span> mutation that can be correlated with disease aggressiveness&#46; Up to 20&#8211;30&#37; of the subjects with an apparently sporadic MTC have a germline mutation &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Hereditary MTC can occur as three major subtypes&#58; multiple endocrine neoplasia type 2A &#40;MEN2A&#41;&#44; multiple endocrine neoplasia type 2B &#40;MEN2B&#41;&#44; or familial MCT &#40;FMTC&#41;&#46; When the <span class="elsevierStyleItalic">RET</span> mutation presents at the germline level&#44; the disease&#44; either FMTC or MEN2&#44; is transmitted as an autosomal-dominant trait with complete penetrance&#46; In MEN2A&#44; in addition to MTC &#40;100&#37; of cases&#41;&#44; patients develop pheochromocytoma &#40;PHEO&#41; and primary hyperparathyroidism &#40;HPT&#41; in approximately 50&#37; and 20&#37; of cases&#44; respectively&#46; The MEN2B phenotype is characterized by the presence of mucosal neuromas and marfanoid habitus as well as MTC &#40;100&#37; of cases&#41; and PHEO &#40;50&#37; of cases&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">In this syndrome&#44; the phenotype-genotype correlation is strong&#46; Thus&#44; different codon mutations along the <span class="elsevierStyleItalic">RET</span> oncogene predispose individuals to different ages of onset and disease aggressiveness&#46; Also&#44; the specific <span class="elsevierStyleItalic">RET</span> codon mutation can influence decisions about surgical prophylactic thyroid intervention&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">Complete penetrance&#44; autosomal-dominant transmission&#44; strong phenotype-genotype correlation&#44; and a relatively simple genomic structure are the key points of the success of <span class="elsevierStyleItalic">RET</span>&#44; as an example&#44; in translational medicine&#46; For these reasons&#44; the detection of germline <span class="elsevierStyleItalic">RET</span> mutations is now broadly accepted for the clinical evaluation of subjects with MTC&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">RET</span> gene is localized on chromosome 10&#44; band 10q11&#46;2&#59; it is comprised of 21 exons and encodes for the RET transmembrane receptor with intrinsic tyrosine kinase &#40;TK&#41; activity and is stimulated by interaction with different growth factors belonging to the glial-derived neurotrophic factor family&#46; In animal models&#44; RET is essential for the development of the sympathetic and parasympathetic enteric nervous systems and the kidneys&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">In 98&#37; of MEN2A families&#44; germline mutations affect the cysteine-rich extracellular domain by converting a cysteine into another amino acid&#44; and by determining RET spontaneous dimerization and activation&#46; These mutations are located in codon 634 &#40;exon 11&#41; or codons 609&#44; 611&#44; 618&#44; and 620 &#40;exon 10&#41;&#46; The most common mutation&#44; accounting for 80&#37; of MEN2A families&#44; affects codon 634&#44; and in this codon a particular point mutation&#44; when a cysteine is substituted for an arginine&#44; accounts for 50&#37; of all MEN2A cases&#46; Approximately half of FMTC kindred are due to germline mutations in exon 10 &#40;codon 618 and 620&#41;&#44; but some FMTC families are caused by mutations in exon 11 &#40;codons 630&#44; 631 or 634&#41;&#46; Interestingly&#44; the cysteine-arginine substitution in the <span class="elsevierStyleItalic">RET</span> 634 codon has never been found in FMTC families&#46; In an increasing number of FMTC cases&#44; germline mutations have been reported in exons 13 &#40;codons 768&#44; 790 and 791&#41;&#44; 14 &#40;codon 804 and 844&#41;&#44; and 15 &#40;codon 891&#41;&#44; which are located in the TK domain&#44; thereby interfering with intracellular ATP binding&#46; In approximately 95&#37; of patients with MEN2B&#44; a single mutation that converts methionine to threonine at codon 918 &#40;exon 16&#41; has been identified &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; This mutation causes alterations in the substrate recognition pocket of the TK catalytic core&#46; Other rare intracellular mutations that are associated with MEN2B involve codon 882 &#40;exon 15&#41;&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">There is a close relationship between genotype and phenotype&#46; Thus&#44; more aggressive phenotypes have been noticed in cases carrying mutations in the extracellular portion of RET rather than the intracellular portion&#46; Furthermore&#44; the average age at diagnosis for MEN2 patients with C-cell hyperplasia and RET extracellular domain mutations is 8&#46;3 years&#44; whereas the average age at diagnosis is of 11&#46;2 years in patients with RET intracellular domain mutations&#46; In patients with node-negative MTC&#44; the average age at diagnosis is 10&#46;2 years for patients with the associated extracellular domain mutations and 16&#46;6 years for patients harboring intracellular domain mutations &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">The strong genotype-phenotype correlation and the age-related progression of MTC based on the type of <span class="elsevierStyleItalic">RET</span> mutation has enabled researchers to identify different classes of risk regarding MTC penetrance and aggressiveness&#46; Thus&#44; a &#8220;codon-directed&#8221; appropriate timing for surgery in <span class="elsevierStyleItalic">RET</span> mutation carriers has been defined&#46; Patients with level 3 mutations &#40;codons 883&#44; 918 and 922&#41; are at the highest risk of developing aggressive MTC&#44; while patients with level 2 mutations &#40;codons 611&#44; 618&#44; 620 and 634&#41; are at intermediate risk and patients with level 1 mutations &#40;codons 768&#44; 790&#44; 791&#44; 804 and 891&#41; are at the lowest risk &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46;</p><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">The <span class="elsevierStyleItalic">RET</span> codon 609 mutation</span><p id="para100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">RET</span> mutations in codon 609 are extremely rare genetic events in patients with MEN2A &#40;&#60;1&#37; of all reported cases&#41; and were initially considered as level 1 mutations &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; However&#44; after the publication of a family pedigree carrying the <span class="elsevierStyleItalic">RET</span> 609 cysteine-to-glycine substitution&#44; in which a <span class="elsevierStyleItalic">RET</span> mutation carrier was diagnosed with MTC at 5 years of age &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#44; some authors shifted the <span class="elsevierStyleItalic">RET</span> codon 609 mutations from risk level 1 to risk level 2 &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">One way to overcome the relatively poor information available regarding the genotype-phenotype correlation in patients with the <span class="elsevierStyleItalic">RET</span> codon 609 mutation is to take into account descriptions of large&#44; affected families and registry studies with sufficiently large numbers of individuals with the <span class="elsevierStyleItalic">RET</span> 609 codon mutation&#46;</p><p id="para120" class="elsevierStylePara elsevierViewall">Several large families with <span class="elsevierStyleItalic">RET</span> codon 609 mutations have been reported in the literature&#46; In the family reported by Kinlaw et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#44; carriers of the <span class="elsevierStyleItalic">RET</span> codon 609 cysteine-to-serine substitution were characterized by the low penetrance of MTC and the high penetrance of PHEO&#46; Calva et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41; described 16 affected patients belonging to a 38-member genealogy with a RET Cys609Tyr mutation&#46; The phenotype of these subjects was characterized by MTC in nine out of 16 affected cases&#44; lymph node metastasis in six out of nine cases&#44; parathyroid adenoma in one out of 16 cases&#59; however&#44; PHEO was not found in this family&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">We have also described a 5-generation&#44; 48-member family with MEN2A syndrome that also harbored the RET Cys609Tyr mutation &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46; Furthermore&#44; a large registry study of individuals carrying <span class="elsevierStyleItalic">RET</span> exon 10 mutations&#44; which also includes this family&#44; was published by Frank-Raue et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">Description of the Italian RET C609S pedigree</span><p id="para140" class="elsevierStylePara elsevierViewall">The proband was a 36-year-old man&#46; He had a 12-mm hypoechogenic&#44; highly vascularized thyroid node of indeterminate cytology and a serum calcitonin &#40;CT&#41; level of 76 pg&#47;ml&#46; His family history was remarkable in terms of MTC and PHEO&#44; but a previous genetic test on one of his affected relatives had failed to identify known any <span class="elsevierStyleItalic">RET</span> mutations&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">Urinary metanephrines and adrenal computed tomography revealed no biochemical or radiological signs of PHEO&#59; serum PTH&#44; calcium and phosphorus levels were also within the normal ranges&#46; The patient underwent a total thyroidectomy and central neck dissection&#44; and the histological diagnosis was MTC without lymph node involvement &#40;T1mN0Mx&#41;&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">His genealogy included five already diagnosed cases of MTC&#46; Two subjects had isolated MTC&#44; three had lymph-node-positive MTC&#44; and one had liver metastasis&#46; Two out of five patients had PHEO &#40;which was the first clinical sign of MEN2A syndrome in one case&#41;&#46;</p><p id="para170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">RET</span> analysis&#44; which was reconsidered in the proband&#44; revealed a codon 609 mutation &#40;TGC609TCC&#41; that lead to a cysteine-to-serine substitution&#44; Cys609Ser&#46; This mutation was also confirmed in the members of his family already known to be affected&#46; Another 24 family members underwent genetic testing for this <span class="elsevierStyleItalic">RET</span> mutation&#44; revealing nine carriers &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#46; Two at-risk individuals refused genetic investigations&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Phenotypic characterization of the gene mutation carriers</span><p id="para180" class="elsevierStylePara elsevierViewall">In short&#44; clinical investigation revealed that none of the patients had a palpable thyroid node&#46; None of the nodes were larger than 10 mm in diameter&#44; presented with a suspected echographic pattern on ultrasound or had hypertension&#59; one patient had two episodes of nephrolithiasis as the first clinical sign of the syndrome&#46; Serum CT measurements revealed that the older subjects&#44; one of whom was an 86-year-old woman&#44; had the highest basal CT levels&#44; while those of the younger subjects were low or unresponsive to pentagastrin&#46; None of the patients had biochemical or radiological evidence of PHEO&#46; All patients who underwent thyroid surgery demonstrated isolated MTC and&#47;or C-cell hyperplasia&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">Phenotype-genotype correlations in RET 609 carriers and recommendations</span><p id="para190" class="elsevierStylePara elsevierViewall">The 1999 consensus statement on MEN recommended that codon 609 <span class="elsevierStyleItalic">RET</span> mutations should be considered as risk level 1&#44; for which there are no unequivocal clinical management guidelines&#46; Some clinicians recommend a prophylactic total thyroidectomy by the age of 5 years&#44; others by the age of 10 years&#44; whereas others advocate surgery as soon as routine pentagastrin-stimulated test findings become abnormal &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">Indeed&#44; 609 <span class="elsevierStyleItalic">RET</span> mutations are quite rare genetic events at the onset of MEN2A and few affected families have been described in the literature &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46; One family was comprised a 5-year-old boy who harbored a Cys609Gly substitution that is associated with an invasive MTC at final histology and warranting the inclusion of such mutations in the intermediate risk category &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; On the other hand&#44; <span class="elsevierStyleItalic">in vitro</span> data obtained from transfected NIH3T3 cells seem to suggest that 609 mutations have a smaller capacity for neoplastic transformation than other level 2 <span class="elsevierStyleItalic">RET</span> mutations &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Only one large family carrying a Cys609Ser mutation was reported by Kinlaw et al&#46; and&#44; regarding its clinical aspects&#44; this genealogy revealed an unusual phenotype characterized by a scarcely penetrant&#44; non-aggressive MTC &#40;20&#37;&#41; and a tendency for cases to present with PHEO rather than MTC &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46; We described a kindred with the same <span class="elsevierStyleItalic">RET</span> mutation&#46; Based on the large number of affected subjects with this specific mutation in this family who had undergone total thyroidectomy&#44; we agree that the Cys609Ser mutation carries a level 1 risk&#58; we saw no MTC develop before the age of 17 years&#44; no lymph node metastases up to 30 years of age and no distant metastases up to 60 years of age&#46; There was also an 86-year-old mutation carrier who did not undergo surgery&#46; Moreover&#44; we saw no anticipation effect&#44; which is by no means rare in MEN2A kindreds carrying level 1 mutations&#44; leading to MTC onset at an earlier age in each successive generation &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">MTC was highly penetrant in our family &#40;75&#37; of cases&#41; and was the first sign of disease in all but two cases &#40;one presented with PHEO and another presented with the clinical consequences of primary HPT&#41;&#59; the penetrance of PHEO and primary HPT was low&#46; Furthermore&#44; the paper by Frank-Raue et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41; was a very large registry study on <span class="elsevierStyleItalic">RET</span> exon 10 mutations&#46; In this study&#44; the 45 carriers of <span class="elsevierStyleItalic">RET</span> codon 609 mutations&#44; each with different cysteine substitutions &#40;including 15 individuals belonging to the Italian C609S pedigree&#41;&#44; demonstrated a less aggressive MTC but a 50&#37; penetrance of PHEO &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">In conclusion&#44; the results obtained in this study of large genealogies may be very helpful for establishing a better genotype-phenotype correlation&#46; In particular&#44; the results we obtained by analyzing this very large MEN2 kindred suggest that carriers of the Cys609Ser <span class="elsevierStyleItalic">RET</span> mutation can be considered as risk level 1&#44; for which non-aggressive clinical management may be indicated&#46; Thus&#44; as also reported by Frank-Raue et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#44; in these cases&#44; prophylactic total thyroidectomy may be postponed until after 5 years of age if careful yearly monitoring of stimulated calcitonin levels is implemented&#46;</p></span></span></span>"
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          "titulo" => "INTRODUCTION"
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              "identificador" => "cesec20"
              "titulo" => "The RET codon 609 mutation"
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            1 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "Description of the Italian RET C609S pedigree"
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            2 => array:2 [
              "identificador" => "cesec40"
              "titulo" => "Phenotypic characterization of the gene mutation carriers"
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            3 => array:2 [
              "identificador" => "cesec50"
              "titulo" => "Phenotype-genotype correlations in RET 609 carriers and recommendations"
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            0 => "Pheochromocytoma"
            1 => "MEN2A"
            2 => "Medullary Thyroid Carcinoma"
            3 => "Hereditary Thyroid Cancer"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Medullary thyroid carcinoma currently accounts for 5&#8211;8&#37; of all thyroid cancers&#46; The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate&#46; As many as 75&#37; of all medullary thyroid carcinomas are sporadic&#44; with an average age at presentation reported as 60 years&#44; and the remaining 25&#37; are hereditary with an earlier age of presentation&#44; ranging from 20 to 40 years&#46;</p><p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Germline <span class="elsevierStyleItalic">RET</span> proto-oncogene mutations are the genetic causes of multiple endocrine neoplasia type 2 and a strong genotype-phenotype correlation exists&#44; particularly between a specific <span class="elsevierStyleItalic">RET</span> codon mutation and the &#40;a&#41; age-related onset and &#40;b&#41; thyroid tumor progression&#44; from C-cell hyperplasia to medullary thyroid carcinoma and&#44; ultimately&#44; to nodal metastases&#46; <span class="elsevierStyleItalic">RET</span> mutations predispose an individual to the development of medullary thyroid carcinomas and can also influence the individual response to RET protein receptor-targeted therapies&#46;</p><p id="spara40" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">RET</span> codon 609-point mutations are rare genetic events belonging to the intermediate risk category for the onset of medullary thyroid carcinoma&#46; A large genealogy resulting in a less aggressive form of medullary thyroid carcinoma is associated with the high penetrance of pheochromocytoma and has been reported in the literature&#46; In this short review article&#44; we comment on our previous report of a large multiple endocrine neoplasia type 2A kindred with the same Cys609Ser germline <span class="elsevierStyleItalic">RET</span> mutation in which&#44; conversely&#44; the syndrome was characterized by a slightly aggressive&#44; highly penetrant form of medullary thyroid carcinoma that was associated with low penetrance of pheochromocytoma and primary hyperparathyroidism&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p> <p class="elsevierStyleNotepara" id="cenpara20">Mian C has actively contributed to the clinical and molecular studies on patients and to the drafting of the article&#46; Sartorato P has contributed to the review of the literature on the topic and to the drafting of the article&#46; Barollo S and Zane M have performed the genetic studies&#46; Opocher G has coordinated the clinical and molecular studies conducted on patients and planned the drafting of the review&#46;</p>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Pedigree analysis&#46; The proband is indicated by the black arrow&#46; Deceased patients are identified by diagonal lines&#46; Subjects with signs of MEN2A syndrome are indicated by black shading&#44; which covers half of the pedigree symbol for patients with MTC alone and three-quarters of the symbol for patients with MTC plus PHEO&#46; All patients who underwent genetic testing are marked with an asterisk&#46; After genotyping&#44; gene mutation carriers are identified by the square shape of their respective pedigree symbols&#46;</p>"
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