Atypical MEN Type 2B Associated with Two Germline RET Mutations on the Same Allele Not Involving Codon 918

Menko, Fred H.; Luijt, Rob B. van der; Valk, Irene A. J. de; Toorians, Arno W. F. T.; Sepers, Jan M.; Diest, Paul J. van; Lips, Cornelis J.M.

doi:10.1210/jcem.87.1.8136

Cited by 78 publications

(31 citation statements)

References 17 publications

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“…We reasoned that the effect of tandem substitutions in RET, including RET V804M/E805K , should similarly correlate with aggregate physicochemical change. To substantiate this, we identified, from the literature, four additional reports of tandem mutations in RET: (a) RET V804M/Y806C (25) and (b) RET V804M/S904C (27) in MEN 2B, and (c) RET…”

Section: Resultsmentioning

confidence: 99%

“…However, the V804M mutation has only been reported in patients with MEN 2B when it is present on the same RET allele with a missense mutation at either codon 806 (25) or codon 904 (27). Neither germ line nor somatic mutations of codon 805 have been reported previously in MEN 2 or FMTC.…”

Section: Discussionmentioning

confidence: 98%

“…These mutations were then shown to be transforming (26). Subsequently, germ line missense mutations at valine 804 and serine 904 were shown to cosegregate with MTC and mucosal neurilemomas in a family with MEN 2B (27). Interestingly, mutation of codon 805 either singly or in combination with codon 804 has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B

et al. 2006

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Constitutive activation of the RET receptor tyrosine kinase underlies the genesis and progression of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although kinase activation represents a common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained a patient with classical features of MEN 2B, but lacking either of the classical mutations in RET (M918T or A883F). Instead, the patient harbors a novel pair of germ line missense mutations in cis at codons 804 and 805. We evaluated the potential physiochemical effects of these substitutions in silico, predicting both to be moderately deleterious in isolation, but severely deleterious in combination. Consistent with this postulate, we show that the identified tandem mutations (V804M/E805K) are biologically active, transforming cells in culture and that their transforming capacity in combination is distinctly synergistic. Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations. To address this question, we used homology molecular modeling in silico to model the active site of RET. We predict that RET804 constitutes a critical gatekeeper residue that, when mutated in combination with RET805, induces a conformational change in the hinge region that locks the active site in a position permissive for ATP hydrolysis. Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B

et al. 2006

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“…Немногочисленные сообщения о двойных мутациях противоречивы в отношении по-тенциирующего влияния второй мутации на клини-ческие проявления, в том числе на возраст манифе-стации наследственного МРЩЖ и синдрома МЭ-Н2А [8,9,[11][12][13]. В ряде работ [6,9,13,[18][19][20][21][22][23] со-общается о более агрессивном течении МРЩЖ, более высокой пенетрантности феохромоцитомы, появлении ганглионейроматоза, характерного для синдрома МЭН2Б, эктопической продукции АКТГ опухолью (МРЩЖ или феохромоцитомой) у боль-ных с множественными RET мутациями. Поэтому, хотя в данном случае роль каждой мутации в отдель-ности позволяла придерживаться тактики активно-го наблюдения, наличие одновременно двух мута-ций послужило аргументом в пользу профилактиче-ской тиреоидэктомии.…”

Section: Discussionunclassified

Three RET germ-line mutations in a family with multiple endocrine neoplasia type 2A syndrome

Severskaya

Викторовна²,

Polyakov

et al. 2017

Probl Endokrinol (Mosk)

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Multiple mutations in RET proto-oncogene are not common findings in patients with multiple endocrine neoplasia type 2A syndrome (MEN2A). Screening for RET mutation in MEN2A family members is usually limited by the known affected exon. However the second unrevealed mutation in RET proto-oncogene can coexist and modify the phenotype of MEN2 patients, including age of onset of medullary thyroid carcinoma, penetrance of pheochromocytoma etc. We here describe a family with MEN 2A syndrome with combination of three different germ-line RET mutations in its members (RET codon C634R, C634R+I852M, I852M+Y791F, Y791F). The earliest onset of medullary thyroid carcinoma was in a patient harboring the C634R+I852M double mutation at age 24 years. A 49-y.o.patient with C634R mutation has persistent medullary thyroid carcinoma after thyroidectomy at 35 years old. A carrier of Y791F mutation had no clinical evidence of disease at age of 28 years. In a child with compound I852M+Y791F mutation preventive thyroidectomy revealed C-cell hyperplasia at age of 4 years. The clinical significance of double RET mutation in the described family is not clear. Literature data of multiple germ-line RET mutations in patients with multiple endocrine neoplasia type 2A syndrome are presented.

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“…Instead, the patients presented with compound RET mutations including a common mutation in codon 804 in combination with a second substitution mutation in codon 781, 806, 904 or 905 (Miyauchi et al 1999, Menko et al 2002, Cranston et al 2006, Nakao et al 2013. In all these cases, the patient presented with MTC, extra-endocrine features suggesting MEN2B, but no pheochromocytoma.…”

Section: The Specific Features Of Patients Carrying Tandem Ret Mutationsmentioning

confidence: 99%

A comprehensive review on MEN2B

Castinetti¹,

Moley²,

Mulligan³

et al. 2018

Endocrine-Related Cancer

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MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are de novo, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B.

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Atypical MEN Type 2B Associated with Two Germline RET Mutations on the Same Allele Not Involving Codon 918

Cited by 78 publications

References 17 publications

RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B

RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B

Three RET germ-line mutations in a family with multiple endocrine neoplasia type 2A syndrome

A comprehensive review on MEN2B

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