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      Variability in Medullary Thyroid Carcinoma in RET L790F Carriers: A Case Comparison Study of Index Patients

      case-report

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          Abstract

          Background: Previous studies have suggested that the variability in age of onset and aggressiveness of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN 2A) carrying the same REarranged during Transfection ( RET) mutation may be caused by additional RET germline variants or somatic variants.

          Methods: This study was a retrospective case comparison study of all MEN 2A index patients ( n = 2) with the RET L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for RET germline variants and other somatic variants (>500), respectively.

          Results: Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline RET germline variants nor other variants were found to explain this MTC variability.

          Conclusions: We could not confirm the previously reported finding of a somatic RET variant as likely responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Also, we found no RET germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic FLT3 R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in RET L790F carriers.

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          Most cited references51

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          Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

          Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.
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            Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

            Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
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              A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

              Multiple endocrine neoplasia type 2 (MEN 2) comprises three clinically distinct, dominantly inherited cancer syndromes. MEN 2A patients develop medullary thyroid carcinoma (MTC) and phaeochromocytoma. MEN 2B patients show in addition ganglioneuromas of the gastrointestinal tract and skeletal abnormalities. In familial MTC, only the thyroid is affected. Germ-line mutations of the RET proto-oncogene have recently been reported in association with MEN 2A and familial MTC. All mutations occurred within codons specifying cysteine residues in the transition point between the RET protein extracellular and transmembrane domains. We now show that MEN 2B is also associated with mutation of the RET proto-oncogene. A mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated MEN 2B patients studied. The same mutation was found in six out of 18 sporadic tumours.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                28 April 2020
                2020
                : 11
                : 251
                Affiliations
                [1] 1Department of ORL Head and Neck Surgery and Audiology, Odense University Hospital , Odense, Denmark
                [2] 2Department of Clinical Research, University of Southern Denmark , Odense, Denmark
                [3] 3Department of Medical Endocrinology, Copenhagen University Hospital , Copenhagen, Denmark
                [4] 4Department of Pathology, Copenhagen University Hospital , Copenhagen, Denmark
                [5] 5Department of Clinical Genetics, Copenhagen University Hospital , Copenhagen, Denmark
                [6] 6Department of Endocrinology, Odense University Hospital , Odense, Denmark
                [7] 7Department of Pathology, Odense University Hospital , Odense, Denmark
                [8] 8Department of Clinical Genetics, Odense University Hospital , Odense, Denmark
                [9] 9Department of Clinical Genetics, Aalborg University Hospital , Aalborg, Denmark
                [10] 10Center for Genomic Medicine, Copenhagen University Hospital , Copenhagen, Denmark
                Author notes

                Edited by: Wen Zhou, Case Western Reserve University, United States

                Reviewed by: Maria Alevizaki, National and Kapodistrian University of Athens, Greece; Daniela Pasquali, University of Campania Luigi Vanvitelli, Italy

                *Correspondence: Jes Sloth Mathiesen jes_mathiesen@ 123456yahoo.dk

                This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2020.00251
                7198720
                78fd1141-d371-44b8-b704-0e168264837c
                Copyright © 2020 Mathiesen, Nielsen, Rasmussen, Kiss, Wadt, Hermann, Nielsen, Larsen, Brusgaard, Frederiksen, Godballe and Rossing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 January 2020
                : 06 April 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 58, Pages: 7, Words: 5118
                Categories
                Endocrinology
                Case Report

                Endocrinology & Diabetes
                multiple endocrine neoplasia type 2,medullary thyroid carcinoma,rearranged during transfection,l790f,variability,gene variants,flt3 r387q

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