A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A

Bethanis, Sotirios; Koutsodontis, George; Palouka, Theodosia; Avgoustis, Christos; Yannoukakos, Drakoulis; Bei, Thalia; Papadopoulos, Stavros; Linos, Dimitrios; Tsagarakis, Stylianos

doi:10.14310/horm.2002.1111011

Cited by 42 publications

(28 citation statements)

References 19 publications

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“…Codon 533 is located in exon 8 of the RET proto-oncogene, a region that is not routinely sequenced in most commercial laboratories in the United States offering RET analysis; therefore, patients with this mutation could easily be missed, which might account for its apparent rarity. Even though the majority of the 71 codon 533 patients came from a single large Brazilian family or from one of 5 different families of Greek ancestry (10,16,33,47), our data argue in favor of routinely sequencing exon 8, given that it is now a well-characterized and clearly deleterious mutation.…”

Section: Figmentioning

confidence: 80%

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

Rich

Feng

Busaidy

et al. 2014

Thyroid

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Background: Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy. Methods: From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs. no MTC after thyroidectomy or no clinical evidence of MTC if thyroid intact). Data were used to estimate the cumulative prevalence of MTC and/or assess likelihood of MTC stratified by codon. After exclusion of cases with missing data or small representation, 503 patients with mutations in codons 533, 609, 611, 618, 620, 791, and 804 were analyzed. Results: 236 patients had MTC. Cumulative prevalence and median time to MTC varied by codon and within ATA risk levels ( p < 0.0001). Patients with a codon 620 mutation were 2.8-6.9 times more likely to have MTC than other level B mutation carriers, and 5.1-21.7 times more likely than level A mutation carriers included in our focus population. The youngest median time to MTC was 19 years for codon 620 and the oldest was 56 years for codon 611. Cumulative prevalence of MTC by age 20 was 10% or lower for codons 533, 609, 611, 791, and 804. By age 50, it ranged from 18% for codon 791 to 95% for codon 620. An elevated preoperative calcitonin level strongly predicted MTC on final pathology, though false-negative rates varied by codon ( p < 0.0001). Positive predictive values ranged from 76% to 100% by codon with an overall positive predictive value of 87% across codons. Conclusions: This study offers a better understanding of the age-related development of MTC in lower risk RET mutation carriers, provides evidence of further distinctions between lower risk mutations within ATA subgroups, and clarifies the clinical significance of codon 791 mutations. The data support individualized ''codon-based'' management approaches coupled with clinical data such as calcitonin levels.

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Section: Figmentioning

confidence: 80%

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

Rich

Feng

Busaidy

et al. 2014

Thyroid

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“…FMTC (OMIM*155240) is associated with mutations either in the extracellular or in the intracellular domain of RET, mostly affecting exons 10, 11, 13, 14 and 15 and never involving exon 16. Mutations in exons 5 and 8 have been reported respectively in one Czech family (8) and in five families originating from Brazil (9), Italy (10) and Greece (11)(12)(13). Nevertheless, the genetic analysis of these exons is routinely performed only in few centres, consistent with the very recent ATA guidelines for the management of MTCs (14), which include among the relevant exons of RET to be screened only exons 10 …”

Section: Introductionmentioning

confidence: 79%

“…It is also tempting to speculate that the high in vitro transforming potential found for this variant could be responsible for the aggressive behaviour of MTC with lung metastases found in patient 2. It is worth noting that another non-cysteine variant in RET exon 8 (Gly533Cys) has been described previously, but not functionally characterized, in five Greek families, three with MEN2A (11,13) and two with FMTC (12), and in one large Brazilian multigenerational family with FMTC (9). On the basis of all these data, exon 8 appears to be an underestimated hotspot of RET variants with an oncogenic potential.…”

Section: Discussionmentioning

confidence: 98%

Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro

Muzza¹,

Cordella²,

Bombled³

et al. 2010

European Journal of Endocrinology

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Context: Most germline-activating mutations of the RET proto-oncogene associated with inherited medullary thyroid cancer (MTC) are localized in exons 10, 11 and 13-15. Four novel RET variants, located in the extracellular domain (p.A510V, p.E511K and p.C531R) coded by exon 8 and in the intracellular juxtamembrane region (p.K666N) coded by exon 11, were identified on the leukocyte DNA from apparently sporadic cases. Methods: Plasmids carrying Ret9-wild-type (Ret9-WT), Ret9-C634R and all Ret9 variants were transfected, and the phosphorylation levels of RET and ERK were evaluated by western blot analyses. The transforming potentials were assessed by the focus formation assay. Results: The p.A510V, p.E511K and p.C531R variants were found to generate RET and ERK phosphorylation levels and to have a transforming activity higher than that of Ret9-WT variant, but lower than that of Ret9-C634R variant. Differently, the p.K666N variant, located immediately downstream of the transmembrane domain, and involving a conserved residue, displayed high kinase and transforming activities. Computational analysis predicted non-conservative alterations in the mutant proteins consistent with putative modifications of the receptor conformation. Conclusions: The molecular analyses revealed an oncogenic potential for all the novel germline RET variants. Therefore, the prevalence of exon 8 genomic variations with an oncogenic potential may be higher than previously thought, and the analysis of this exon should be considered after the exclusion of mutations in the classical hotspots. In addition, on the basis of these functional data, it is advisable to extend the genetic screening to all the first-degree relatives of the MTC patients, and to perform a strict follow-up of familial carriers.

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“…RET mutations with low clinical expression, involving codons 321, 533, 768, 790, 791, 804, and 891, are usually found in these families (Eng et al 1996, Hofstra et al 1997, Berndt et al 1998, Fattoruso et al 1998, Pigny et al 1999, Antinolo et al 2002, Da Silva et al 2003, Dvorakova et al 2005, Kouvaraki et al 2005, Raue & Frank-Raue 2007, Castellone et al 2009). Occasionally, patients with these mutations may also develop the MEN2A phenotype (Berndt et al 1998, Jimenez et al 2004, Bethanis et al 2007, Pinna et al 2007). In addition, up to 10% of patients presenting with apparently sporadic MTC (AS-MTC) reveal occult RET germ line mutations (Prazeres et al 2006).…”

Section: Introductionmentioning

confidence: 99%

In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp

Prazeres

Couto

Rodrigues

et al. 2011

Endocrine-Related Cancer

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Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (RET ) proto-oncogene. RET encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS-RAF-ERK1/2, PIK3-AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the RET variants and measured the number of NIH3T3 transformation foci and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1/2, STAT1, STAT3, and TCF4), and the extent of ERK1/2 inhibition on sorafenib treatment. We found that RET variants Arg886Trp and Glu511Lys have shown increased in vitro transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and Arg886Trp showed 10-and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5-and 3-fold versus 1.2-and 2-fold in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens.

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A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A

Cited by 42 publications

References 19 publications

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro

In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp

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