High Penetrance of Pheochromocytoma Associated with the Novel C634Y/Y791F Double Germline Mutation in the<i>RET</i>Protooncogene

Toledo, Rodrigo A.; Wagner, Simona; Coutinho, Flavia L.; Lourenço, Delmar M.; Azevedo, Juliana Aires Paiva de; Longuini, Viviane C.; Reis, Mariana Tenorio Antunes; Siqueira, Sheila Aparecida Coelho; Lucon, Antônio Marmo; Tavares, Marcos Roberto; Fragoso, Maria Candida Barisson Villares; Pereira, Ana Cláudia Costa; Dahia, Patricia L.M.; Mulligan, Lois M.; Toledo, S. P. A.

doi:10.1210/jc.2009-1355

Cited by 43 publications

(40 citation statements)

References 32 publications

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“…As the advent of RET mutation diagnosis, genotype-phenotype relationships have affected clinical management (4,5). Specific agerelated neoplastic risk profiles and penetrance estimations of PHEO have been reported in MEN2A caused by germ line RET mutations in C634W, C634Y/Y791F, and C609S (6,7,8). Precise codon-specific development of PHEO has been reported, although no figures on penetrance were provided (9).…”

Section: Introductionmentioning

confidence: 99%

High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients

Imai

Uchino

Okamoto

et al. 2013

European Journal of Endocrinology

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Objective: The precise penetrance of pheochromocytoma (PHEO) in multiple endocrine neoplasia type 2 (MEN2) has not been reported in a large cohort. In this study, we aimed to clarify the codon-specific penetrance of PHEO in MEN2. Design: We established a study group designated the 'MEN Consortium of Japan' in 2008 and asked physicians and surgeons to provide clinical and genetic information on patients they had treated up to 2011. Methods: Data were collected on patients identified as carriers of the RET mutation or diagnosed with medullary thyroid carcinoma (MTC) and/or PHEO with family history from 52 institutions all over Japan. Results: Of 493 registered MEN2 patients, RET mutation data were available for 390. Of these, 144 developed PHEOs, while 246 did not. The penetrance of PHEO was 25% by age 30 years, 52% by age 50 years, and 88% by age 77 years in RET mutation carriers with a codon 634 mutation. All patients with a codon 918 mutation (MEN2B) developed PHEO by age 56 years. Less than 32% penetrance of PHEO was seen in patients with mutations at codons other than 634 and 918. Conclusions: Most patients with a codon 634 mutation develop PHEOs as well as MTC during their lifetime.

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Section: Introductionmentioning

confidence: 99%

High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients

Imai

Uchino

Okamoto

et al. 2013

European Journal of Endocrinology

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“…However, more recent findings question pathogenicity of an isolated Y791F RET mutation in MTC (Erlic et al 2010). More likely, Y791F RET is a modifying mutation acting together with some other synchronous mutations (Toledo et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

Virtanen

Pukkala

Kivisaari

et al. 2013

Endocrine-Related Cancer

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The objective of this study was to assess the occurrence of thyroid cancer and co-occurring RET mutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950-1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer, RET mutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52-1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer without RET mutations was detected by clinical screening. Four subjects (aged 31-50 years) with co-occurring RET mutations in exons 10 (C609R; nZ1) and 13 (Y791F, nZ3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associated RET mutations were restricted to exons 10 and 13 affecting w5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease.

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“…Крайне ред-ко у пациента обнаруживают одновременно две и более мутации [6,[8][9][10][11][12][13]. У членов описанной семьи выявлено три мутации.…”

Section: Discussionunclassified

“…Вторая мутация может быть получена от второго родителя (разные RET мутации у членов одной семьи) или возникать de novo. 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.…”

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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High Penetrance of Pheochromocytoma Associated with the Novel C634Y/Y791F Double Germline Mutation in theRETProtooncogene

Cited by 43 publications

References 32 publications

High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients

High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients

Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

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

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