Risk and Penetrance of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A Families with Mutations at Codon 634 of the RET Proto-Oncogene

Schuffenecker, Isabelle

doi:10.1210/jc.83.2.487

Cited by 122 publications

(93 citation statements)

References 24 publications

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“…This risk was estimated twice as high (19.1% by age 34 years) based on the data from a national MEN2 registry going back to 1984 (Schuffenecker et al 1998) or more than fourfold greater in an earlier institutional series (Asari et al 2006). The penetrance of primary hyperparathyroidism was rated using these MEN2 registry data at 14% by age 30 years; 26% by age 40 years; 48% by age 60 years and 81% by age 70 years (Schuffenecker et al 1998). …”

Section: Transformation Of the Parathyroid Glandsmentioning

confidence: 99%

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

Machens¹,

Dralle²

2018

Endocrine-Related Cancer

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Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a 'window of opportunity', within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal 'tissue-sparing' adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

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Section: Transformation Of the Parathyroid Glandsmentioning

confidence: 99%

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

Machens¹,

Dralle²

2018

Endocrine-Related Cancer

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“…Sporadic MTC forms are related to somatic mutations in the RET gene in 30-50% of these tumors (Uchino et al 1999), while the vast majority of FMTC forms carry inherited mutations of RET (Schuffenecker et al 1998, Randolph & Maniar 2000, Nagy et al 2004. These are gainof-function mutations and activate the kinase activity of RET, which provides mitogenic and survival signals to the calcitonin-producing C-cells.…”

Section: Introductionmentioning

confidence: 99%

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Rodríguez‐Antona

Pallarés²,

Montero‐Conde³

et al. 2010

Endocrine-Related Cancer

118

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Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, PZ0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (PZ0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (PZ2.8!10 K8 ). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.

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“…Studies on white populations with hereditary MTC showed different RET proto-oncogene mutations in various populations and ethnic groups, for example, the largely main mutation in Spain and France was at codon 634 (Schuffenecker et al, 1998;Robledo et al, 2003). In Italy the highest and the lowest mutation rates of RET proto-oncogene mutation were belong to codons 804 and 634 in familial MTC, respectively, and in sporadic from was mutation at codon 918 (Pinna et al, 2007;Saggiorato et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Wild-Type and Mutated RET Proto-Oncogene Associated with Familial Medullary Thyroid Cancer

Masbi¹,

Mohammadi-Asl²,

Galehdari³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: We aimed to assess RET proto-oncogene polymorphisms in three different Iranian families with medullary thyroid cancer (MTC), and performed molecular dynamics simulations and free energy stability analysis of these mutations. Materials and Methods: This study consisted of 48 patients and their first-degree relatives with MTC confirmed by pathologic diagnosis and surgery. We performed molecular dynamics simulations and free energy stability analysis of mutations, and docking evaluation of known RET proto-oncogene inhibitors, including ZD-6474 and ponatinib, with wild-type and mutant forms. Results: The first family consisted of 27 people from four generations, in which nine had the C.G2901A (P.C634Y) mutation; the second family consisted of six people, of whom three had the C.G2901T (P.C634F) mutation, and the third family, who included 12 individuals from three generations, three having the C.G2251A (P.G691S) mutation. The automated 3D structure of RET protein was predicted using I-TASSER, and validated by various protein model verification programs that showed more than 96.3% of the residues in favored and allowed regions. The predicted instability indices of the mutated structures were greater than 40, which reveals that mutated RET protein is less thermo-stable compared to the wild-type form (35.4). Conclusions: Simultaneous study of the cancer mutations using both in silico and medical genetic procedures, as well as onco-protein inhibitor binding considering mutation-induced drug resistance, may help in better overcoming chemotherapy resistance and designing innovative drugs.

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Risk and Penetrance of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A Families with Mutations at Codon 634 of the RET Proto-Oncogene

Cited by 122 publications

References 24 publications

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Characterization of Wild-Type and Mutated RET Proto-Oncogene Associated with Familial Medullary Thyroid Cancer

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