Familial prevalence and age of RET germline mutations: implications for screening

Machens, Andreas; Dralle, Henning

doi:10.1111/j.1365-2265.2007.03153.x

Cited by 54 publications

(34 citation statements)

References 39 publications

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“…With an estimated prevalence of only 9% (13 of 141 RET families), germ-line mutations in exon 10 represent a rare condition, especially when they involve codon 609 or 611 (Machens & Dralle 2008). This has rendered it difficult to accrue carriers of exon 10 RET mutations, which confer moderate transforming activity in vitro (Ito et al 1997, Chappuis-Flament et al 1998; Fig.…”

Section: Discussionmentioning

confidence: 99%

Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10

Machens¹,

Hauptmann²,

Dralle³

2009

Endocrine-Related Cancer

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Rearranged during transfection (RET) germ-line mutations in exon 10 are peculiar because they produce both gain-of-function multiple endocrine neoplasia 2A and loss-of-function Hirschsprung's disease phenotypes. Drawing on 38 medullary thyroid cancer patients harboring germline mutations in codon 620 (nZ8), 618 (nZ19), 611 (nZ10), and 609 (nZ1), this study aimed to test the hypothesis that closer proximity of RET germ-line mutations in exon 10 to the cell membrane may translate into earlier or more advanced disease. The closer mutations in codon 620, 618, and 611 were located to the transmembrane domain (codons 657-636) of the RET receptor, the greater were mean primary tumor diameters (23.5, 18.7, and 7.5 mm, PZ0.020), the frequency of lymph node metastasis (75, 68, and 30%, PZ0.11) and pheochromocytoma (38, 16, and 0%, PZ0.11). Periods of observation were broadly comparable for these groups (mean age 33.4-39.3 years; PZ0.71). When mutations in adjoining codons were collapsed (codons 620/618 vs 611/609), the differences in mean primary tumor diameter (20.1 vs 7.4 mm, PZ0.005) and lymph node metastasis (70 vs 36%; PZ0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, nZ78; codon 630, nZ2), the 38 carriers of exon 10 mutations, which are rarer and confer a weaker transforming activity in vitro than exon 11 mutations, required significantly more time to develop fewer tumors. Although limited in numbers, these data suggested that membrane proximity is an important determinant of tumor development in carriers of RET mutations in exon 10.

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Section: Discussionmentioning

confidence: 99%

Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10

Machens¹,

Hauptmann²,

Dralle³

2009

Endocrine-Related Cancer

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“…6 Owing to the rarity of the MEN2 syndromes, the prevalence of different RET mutations in distinct geographic areas is not well defined. [7][8][9] As a rule, the clinical presentation of MEN2 syndromes will be more variable when the transforming activity of RET mutation is low. 2,10,11 Genetic analysis of the RET proto-oncogene can be performed in those families affected by MEN2A and MEN2B, in cases of sporadic MTC or HSCR, and allows exact molecular diagnosis of the disease.…”

Section: Introductionmentioning

confidence: 99%

Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A

Aghdam

Abbaszadegan

Tafazoli

et al. 2015

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PuRPose: Multiple endocrine neoplasia type 2A (Men2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (Mtc), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germ line Ret (Rearranged in transfection) mutation is required to make the diagnosis and initiate genetic counseling. MetHods: we analyzed blood dnA from three Iranian families with three generations of Men2A including 20 affected individuals with Mtc and four with pheochromocytoma. RET hotspots were amplified in probands and sequenced for mutation detection. ResuLt: the causative mutation in all families was found to be the cys634tyr missense substitution. the presence of a functional snP resulting in Gly691ser was also detected in exon 11 of 15 affected cases. four patients showed both of these RET variations. concLusIon: our study shows that the cys634tyr missense substitution and the Gly691ser polymorphism are recurrent in Iranian patients, since our families are unrelated. All asymptomatic carriers of the cys634tyr high-risk activating mutation were referred for prophylactic thyroidectomy.

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“…Drs Machens and Dralle and others reported the relationship between RET germline mutations and hyperparathyroidism [5,6]. In future, for RET mutation carriers, total parathyroidectomy and autotransplantation may be restricted only for the patients who have mutation-based high risk profiles of developing HPT.…”

Section: Dear Sir;mentioning

confidence: 99%

Reply to Drs. Machens and Dralle

2009

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Familial prevalence and age of RET germline mutations: implications for screening

Abstract: These data reveal the potential of DNA-based screening of all relevant RET exons, especially for index patients with solitary, seemingly sporadic disease.

Cited by 54 publications

References 39 publications

Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10

Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10

Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A

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