A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid car
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A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid carcinoma Josep Oriola1,2 · Aurora Sanchez1 · Blanca Paniello1 · Jordi Puig de la Bellacasa3 · Josefina Biarnés4 Received: 24 July 2020 / Accepted: 14 October 2020 © Springer Nature B.V. 2020
Abstract Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited disease, characterized by germ-line variants in RET proto-oncogene. Variants are frequently located in the RET extracellular cysteine-rich region domain, mainly affecting cysteines which are replaced by an alternative amino acid, resulting in a mispaired cysteine and the generation of RET dimers. We describe a novel c.1765A > T variant of RET proto-oncogene in a family with medullary thyroid carcinoma (MTC) that predicts the creation of an additional cysteine p.(Ser589Cys) in the cysteine-rich domain. In this site only three other punctual variants have been described, giving rise to extra cysteines. We have characterized the clinical phenotype of this family. The index case was a 79-year-old woman with MTC in both thyroid lobes. This variant co-segregates in this family in four affected members. One member was operated on at 31 years of age and already presented MTC, indicating that prophylactic thyroidectomy was appropriated. Variants predicting additional cysteines are not frequent in RET, and when present, they allow us to understand their implication in the disease. According to clinical data obtained in this family, this variant could be categorized as a moderate-risk of the disease. Keywords Cancer · Endocrine · Medullary thyroid carcinoma · RET proto-oncogene
Introduction Medullary thyroid carcinoma (MTC) arises from parafollicular cells of the thyroid gland, with calcitonin being its major secretory product. MTC covers around 3–6% of thyroid carcinomas and it can occur sporadically or as a hereditary form in 25% of cases. Activating germline point variants of the RET proto-oncogene (MIM*164761) are responsible for the hereditary cases resulting in three dominantly inherited cancer syndromes: Multiple Endocrine Neoplasia type 2A (MEN2A), MEN2B and familial MTC (FMTC), this * Josep Oriola [email protected] 1
Servei de Bioquímica i Genètica Molecular, CDB, Hospital Clínic, Barcelona, Spain
2
Departament de Biomedicina, University of Barcelona, Barcelona, Spain
3
Servei d’Endocrinologia i Nutrició, IDIBELL, Hospital Universitari de Bellvitge, Barcelona, Spain
4
Diabetis i Nutrició (UDENTG), Unitat d’Endocrinologia, CIBEROBN,Hospital Universitari Dr. Josep Trueta, Girona, Spain
last type sometimes considered a subgroup of the MEN2A syndrome with low penetrance of pheochromocytoma and primary hyperparathyroidism [1]. The RET proto-oncogene encodes a receptor tyrosine kinase. This receptor has a large extracellular domain containing a cysteine-rich region, a transmembrane domain and an intracellular tyrosine kinase domain. Cysteines in the cysteine-rich region contribute to the tert
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