595 results on '"RET mutation"'
Search Results
2. Targeting RET mutation in medullary thyroid cancer.
- Author
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Assi T, Tikriti Z, Shayya A, and Ibrahim R
- Subjects
- Humans, Mutation genetics, Proto-Oncogene Proteins c-ret genetics, Carcinoma, Neuroendocrine genetics, Thyroid Neoplasms genetics
- Published
- 2024
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3. Real-world clinical profile, RET mutation testing, treatments, and PROs for MTC in Europe.
- Author
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Segall G, Singh R, Jen MH, Sanderson I, Rider A, Lewis K, and Kiiskinen U
- Abstract
Objective: This study aimed to describe real-world patient and physician characteristics, rearranged during transfection (RET) mutation testing and results, treatment patterns, and patient-reported outcomes (PROs) in advanced or metastatic medullary thyroid cancer (aMTC) across five populous European countries., Methods: Cross-sectional physician and patient surveys were used to collect quantitative and qualitative data in France, Germany, Italy, Spain, and the UK from July to December 2020, prior to the introduction of selective RET inhibitors in Europe. Physicians completed patient record forms and a survey about their specialty and practice site. Patients were asked to provide PRO data using four validated instruments, including the EuroQol 5 Dimension (EQ-5D) questionnaire., Results: The physician-reported sample included 275 patients with aMTC, including 79 patients with RET mutation-positive disease; median age was 60 and 56 years, respectively. Overall, 75% were tested for RET mutation (35% germline only, 21% somatic only, 44% both). Common physician-cited barriers to RET mutation testing included high cost, difficulty accessing latest tests, and time delay for results. First-line systemic therapy (most commonly vandetanib or cabozantinib) was prescribed for 69% of patients overall and 82% of the RET mutation-positive subgroup. Second-line therapy was prescribed for 12% of patients who received first-line therapy; most patients remained on first-line therapy at data capture. PROs revealed substantial disease/treatment burden., Conclusions: Patients with aMTC report substantial disease/treatment burden. Outcomes could be improved by identifying patients eligible for treatment with selective RET inhibitors through more optimal RET mutation testing.
- Published
- 2024
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4. Clinical characteristics of a large familial cohort with Medullary thyroid cancer and germline Cys618Arg RET mutation in an Israeli multicenter study.
- Author
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Rosenblum RC, Hirsch D, Grozinsky-Glasberg S, Benbassat C, Yoel U, Ishay A, Zolotov S, Bachar G, Banne E, Levy S, and Twito O
- Subjects
- Humans, Adult, Israel epidemiology, Retrospective Studies, Proto-Oncogene Proteins c-ret genetics, Mutation, Carcinoma, Medullary surgery, Multiple Endocrine Neoplasia Type 2a diagnosis, Thyroid Neoplasms pathology, Adrenal Gland Neoplasms
- Abstract
Objective: To determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study., Methods: Retrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups., Results: Genetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01)., Conclusion: This is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rosenblum, Hirsch, Grozinsky-Glasberg, Benbassat, Yoel, Ishay, Zolotov, Bachar, Banne, Levy and Twito.)
- Published
- 2023
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5. The protean role of Val804Met RET mutation in thyroid neoplasms: An example of a "MEN2C" syndrome?
- Author
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Miani C, Locatello LG, Rugiu MG, Antonio JK, Di Loreto C, and Pegolo E
- Subjects
- Male, Female, Humans, Proto-Oncogene Proteins c-ret genetics, Mutation genetics, Multiple Endocrine Neoplasia Type 2a genetics, Multiple Endocrine Neoplasia Type 2a pathology, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Adrenal Gland Neoplasms
- Abstract
Background: Val804Met RET is one of the most common genetic alterations in Multiple Endocrine Neoplasia 2 and is considered to confer only a moderate risk for familial medullary thyroid carcinoma (MTC). The associated phenotype can however be much more complex in some cases., Methods: A clinical, genetic, and pathological analysis was conducted on a family cluster of thyroid neoplasms associated with Val804Met RET mutation., Results: All the kindreds who are carriers of the mutated RET received total thyroidectomy + /- VI level dissection. The proband presented with a pT1bN0 MTC, her 29-yo brother showed a concomitant papillary thyroid carcinoma (PTC) and MTC, their father had a pT1a PTC plus a follicular adenoma, while the uncle of the proband showed C-cell hyperplasia. None had clinical or biochemical evidence of parathyroid disorders or pheochromocytoma., Conclusions: In the presence of Val804Met RET several types of thyroid premalignant and malignant should be screened for, and without limiting to MTC., (Copyright © 2023 Elsevier GmbH. All rights reserved.)
- Published
- 2023
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6. A Single RET Mutation in Hirschsprung Disease Induces Intestinal Aganglionosis Via a Dominant-Negative Mechanism.
- Author
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Sunardi M, Ito K, Sato Y, Uesaka T, Iwasaki M, and Enomoto H
- Subjects
- Animals, Mice, Proto-Oncogene Proteins c-ret genetics, Proto-Oncogene Proteins c-ret metabolism, Mutation genetics, Neurons metabolism, Hirschsprung Disease genetics, Enteric Nervous System metabolism
- Abstract
Background & Aims: Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of the enteric nervous system (ENS). HSCR potentially involves multiple gene aberrations and displays complex patterns of inheritance. Mutations of the RET gene, encoding the RET receptor tyrosine kinase, play a central role in the pathogenesis of HSCR. Although a wide variety of coding RET mutations have been identified, their pathogenetic significance in vivo has remained largely unclear., Methods: We introduced a HSCR-associated RET missense mutation, RET(S811F), into the corresponding region (S812) of the mouse Ret gene. Pathogenetic impact of Ret(S812F) was assessed by histologic and functional analyses of the ENS and by biochemical analyses. Interactions of the Ret(S812F) allele with HSCR susceptibility genes, the RET9 allele and the Ednrb gene, were examined by genetic crossing in mice., Results: Ret
S812F/+ mice displayed intestinal aganglionosis (incidence, 50%) or hypoganglionosis (50%), impaired differentiation of enteric neurons, defecation deficits, and increased lethality. Biochemical analyses revealed that Ret(S811F) protein was not only kinase-deficient but also abrogated function of wild-type RET in trans. Moreover, the Ret(S812F) allele interacted with other HSCR susceptibility genes and caused intestinal aganglionosis with full penetrance., Conclusions: This study demonstrates that a single RET missense mutation alone induces intestinal aganglionosis via a dominant-negative mechanism. The RetS812F/+ mice model HSCR displays dominant inheritance with incomplete penetrance and serves as a valuable platform for better understanding of the pathogenetic mechanism of HSCR caused by coding RET mutations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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7. The correlation between the expression of ATF4 and procalcitonin combined with the detection of RET mutation and the pathological stage and clinical prognosis of medullary thyroid carcinoma.
- Author
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Ma S, Wang H, Li W, Yan Z, Luo X, and Lu P
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- Adult, Carcinoma, Neuroendocrine mortality, DNA Mutational Analysis methods, Female, Humans, Male, Middle Aged, Neoplasm Staging, Prognosis, Risk Factors, Survival Rate, Thyroid Neoplasms mortality, Activating Transcription Factor 4 genetics, Activating Transcription Factor 4 metabolism, Carcinoma, Neuroendocrine genetics, Carcinoma, Neuroendocrine pathology, Gene Expression genetics, Genetic Association Studies, Mutation, Procalcitonin genetics, Procalcitonin metabolism, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology
- Abstract
To explore the correlation between the activating transcription factor 4 (ATF4) and procalcitonin (PCT) expressions combined with RET mutation and the pathological staging and clinical prognosis of sporadic medullary thyroid carcinoma (SMTC). Fifty cases (tumor tissue) of SMTC diagnosed by clinicopathology were collected and the patients with nodular goiter were selected as normal control. The RET mutation site was analyzed by detection kit and expressions of PCT and ATF4 in SMTC were analyzed by Western blot and immunohistochemistry. Multiple linear regression was used to analyze the correlation of risk factors (PCT or ATF4 expression, RET mutation, tumor differentiation, SMTC stage, lymphatic metastasis) for 5-year recurrence and survival of SMTC. The ATF4 and PCT expressions were significantly decreased and increased, respectively, with the increase of the SMTC stage. The most frequent mutation of RET gene in cancer tissue was M 22458A in exon 16. The ATF4 and PCT expressions, as well as RET mutation, were significantly associated with a 5-year recurrence, while the ATF4 expression was significantly related to better 5-year survival. ATF4 and PCT expressions combined with RET mutation are related to the clinical prognosis of SMTC and can predict SMTC staging.
- Published
- 2022
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8. The RET gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and RET mutation results in Hirschsprung's disease.
- Author
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Bhattarai C, Poudel PP, Ghosh A, and Kalthur SG
- Abstract
Enteric neurons and ganglia are derived from vagal and sacral neural crest cells, which undergo migration from the neural tube to the gut wall. In the gut wall, they first undergo rostrocaudal migration followed by migration from the superficial to deep layers. After migration, they proliferate and differentiate into the enteric plexus. Expression of the Rearranged During Transfection ( RET ) gene and its protein RET plays a crucial role in the formation of enteric neurons. This review describes the molecular mechanism by which the RET gene and the RET protein influence the development of enteric neurons. Vagal neural crest cells give rise to enteric neurons and glia of the foregut and midgut while sacral neural crest cells give rise to neurons of the hindgut. Interaction of RET protein with its ligands (glial cell derived neurotrophic factor (GDNF), neurturin (NRTN), and artemin (ARTN)) and its co-receptors (GDNF receptor alpha proteins (GFRα1-4)) activates the Phosphoinositide-3-kinase-protein kinase B (PI3K-PKB/AKT), RAS mitogen-activated protein kinase (RAS/MAPK) and phospholipase Cγ (PLCγ) signaling pathways, which control the survival, migration, proliferation, differentiation, and maturation of the vagal and sacral neural crest cells into enteric neurons. Abnormalities of the RET gene result in Hirschsprung's disease., Competing Interests: Conflict of interest: The authors declare that there are no conflicts of interest., (© 2022 the Author(s), licensee AIMS Press.)
- Published
- 2022
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9. Functional impact of a germline RET mutation in alveolar rhabdomyosarcoma.
- Author
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Berlow NE, Crawford KA, Bult CJ, Noakes C, Sloma I, Rudzinski ER, and Keller C
- Subjects
- Animals, Cell Line, Tumor, DNA Mutational Analysis, Genotype, Humans, Mice, Multiple Endocrine Neoplasia Type 2a genetics, Multiple Endocrine Neoplasia Type 2a pathology, Phenotype, Rhabdomyosarcoma, Alveolar drug therapy, Xenograft Model Antitumor Assays, Germ Cells physiology, Germ-Line Mutation, Proto-Oncogene Proteins c-ret genetics, Proto-Oncogene Proteins c-ret metabolism, Rhabdomyosarcoma, Alveolar genetics
- Abstract
Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. Although tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to several genetically similar cell models, which were transformed to express the same mutant RET as the index case and used to explore potential therapeutic options for mutant RET -bearing alveolar rhabdomyosarcoma. We also determined whether the RET mutation associated with the index case caused synthetic lethality to select clinical agents. From our investigation, we did not identify synthetic lethality associated with the expression of that patient's RET variant, and overall we did not find experimental evidence for the role of RET in rhabdomyosarcoma progression., (© 2021 Berlow et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2021
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10. Multiple endocrine neoplasia 2A with RET mutation p.Cys611Tyr: A case report.
- Author
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Li Y, Tan YQ, Tang ZX, Liao QH, Guo ZQ, Lai KB, Wang R, and Chen YH
- Subjects
- Adolescent, Aftercare, Asian People ethnology, Carcinoma, Neuroendocrine complications, Carcinoma, Neuroendocrine diagnosis, Carcinoma, Neuroendocrine surgery, Exons, Female, Gene Rearrangement genetics, Humans, Interdisciplinary Communication, Lymphatic Metastasis pathology, Male, Middle Aged, Multiple Endocrine Neoplasia Type 2a diagnosis, Multiple Endocrine Neoplasia Type 2a pathology, Mutation, Nuclear Family ethnology, Pedigree, Pituitary Neoplasms complications, Pituitary Neoplasms diagnosis, Thyroid Neoplasms complications, Thyroid Neoplasms diagnosis, Thyroid Neoplasms surgery, Thyroidectomy methods, Treatment Outcome, Adrenal Gland Neoplasms pathology, Carcinoembryonic Antigen metabolism, Multiple Endocrine Neoplasia Type 2a genetics, Pheochromocytoma surgery, Proto-Oncogene Proteins c-ret genetics
- Abstract
Rationale: Multiple endocrine neoplasia 2A (MEN2A) is a rare autosomal-dominant genetic syndrome, frequently misdiagnosed or neglected clinically, resulting in delayed therapy to patients., Patient Concerns: A 47-year-old Chinese male patient underwent laparoscopic right adrenal tumorectomy, and postoperative pathology confirmed the tumor as pheochromocytoma (PHEO). He was readmitted to the department of endocrinology and metabolism due to constant increase in carcinoembryonic antigen (CEA) at 5 months after the operation., Diagnosis: The patient was confirmed with medullary thyroid carcinoma (MTC), multiple neck lymph node metastasis, and pituitary microadenoma. The p.Cys611Tyr (c.1832G>A, C611Y) mutation was detected. Therefore, he was diagnosed with MEN2A., Interventions: He underwent total thyroidectomy. The gene-sequencing analysis of his family was conducted, and the C611Y mutation was detected in his daughter., Outcomes: The level of carcinoembryonic antigen decreased significantly after thyroidectomy in this patient. Long-term follow-up management was conducted. Elevated serum calcitonin and bilateral thyroid nodules were found in his 13-year-old daughter. Thus, MEN2A was highly suspected and she was suggested to undergo total thyroidectomy., Conclusion: Patients with MEN2A should be screened regularly and managed by a multidisciplinary team., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2021
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11. Crude annual incidence rate of medullary thyroid cancer and RET mutation frequency.
- Author
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Milićević S, Bergant D, Žagar T, and Perić B
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- Carcinoma, Neuroendocrine, Germ-Line Mutation, Humans, Incidence, Mutation, Mutation Rate, Proto-Oncogene Mas, Proto-Oncogene Proteins c-ret genetics, Retrospective Studies, Slovenia epidemiology, Multiple Endocrine Neoplasia Type 2a, Thyroid Neoplasms epidemiology, Thyroid Neoplasms genetics
- Abstract
Aim: To determine the frequency and type of RET mutation in Slovenian medullary thyroid cancer (MTC) patients and estimate the crude annual incidence of MTC in Slovenia., Methods: This referral-center retrospective analysis involved 186 MTC patients diagnosed between 1995 and 2015 and their relatives who underwent genetic counseling and testing. The crude incidence rate of MTC was estimated with the joinpoint regression analysis. Genomic DNA was isolated, and exons 10, 11, 13, 14, 15, and 16 of the RET proto-oncogene were amplified with polymerase chain reaction. Point mutations of the RET gene were detected by single-strand conformation analysis and DNA sequencing. Detected mutations were confirmed by restriction enzymes., Results: The average crude annual incidence rate of MTC in Slovenia was 0.34/100,000. A germline mutation in the RET proto-oncogene was identified in 25.9% of MTC patients. The most frequently altered codons were codons 634 and 618, followed by codon 790, codon 804, and codon 918., Conclusions: Annual incidence increase and nation-specific frequency of RET mutations justify the future use of genetic counseling and testing of MTC patients in Slovenia.
- Published
- 2021
12. A rare RET mutation in an Indian pedigree with familial medullary thyroid carcinoma.
- Author
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Vijayan R, Nair V, Menon U, and Kumar H
- Subjects
- Adult, Carcinoma, Medullary genetics, Female, Humans, India, Mutation, Carcinoma, Medullary congenital, Multiple Endocrine Neoplasia Type 2a genetics, Proto-Oncogene Proteins c-ret metabolism, Thyroid Neoplasms genetics
- Abstract
Familial medullary thyroid carcinoma (FMTC) is a variant of multiple endocrine neoplasia type 2 (MEN2) associated with the RET gene mutation. We report a rare RET mutation of c.2671T>G; p.Ser891Ala in Exon 15 of the RET gene in an Indian pedigree where seven family members out of 14 screened were found to be positive for the same. RET genetic analysis should be considered as an early approach in the diagnosis of medullary thyroid carcinoma (MTC) since it improves the prognosis and permits surveillance of other family members., Competing Interests: None
- Published
- 2021
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13. Novel Causative RET Mutation in a Japanese Family with Hirschsprung's Disease: Case Report and Factors Impacting Disease Severity.
- Author
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Higuchi T, Yoshizawa K, Hatata T, Yoshizawa K, Takamizawa S, Kobayashi J, Kubota N, and Hidaka E
- Abstract
RET gene variances confer susceptibility to Hirschsprung's disease (HSCR) with pathogenetic mutations being identified in half of familial cases. This investigation of familial HSCR was aimed to clarify the relationship between genetic mutations and clinical phenotype using next-generation sequencing. A novel c2313C > G(D771E) RET mutation was identified in all three affected family members. The mutation involved the kinase domain, which is believe to impair RET activity and intestinal function. A second RET mutation, c1465G > A(D489N), was found only in the extensive aganglionosis case. We conclude that the novel c2313C > A(D771E) mutation in RET may be pathogenic for HSCR, while the c1465C > G(D489N) mutation may be related to phenotype severity., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)
- Published
- 2020
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14. Case report for an adolescent with germline RET mutation and alveolar rhabdomyosarcoma.
- Author
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Crawford KA, Berlow NE, Tsay J, Lazich M, Mancini M, Noakes C, Huang T, and Keller C
- Subjects
- Adolescent, Alleles, Amino Acid Substitution, Biopsy, DNA Mutational Analysis, Genotype, Humans, Immunohistochemistry, Male, Phenotype, Positron-Emission Tomography, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-ret metabolism, Radiography, Thoracic, Rhabdomyosarcoma, Alveolar drug therapy, Rhabdomyosarcoma, Alveolar metabolism, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Proto-Oncogene Proteins c-ret genetics, Rhabdomyosarcoma, Alveolar diagnosis, Rhabdomyosarcoma, Alveolar genetics
- Abstract
In this case report we evaluate the genetics of and scientific basis of therapeutic options for a 14-yr-old male patient diagnosed with metastatic PAX3-FOXO1 fusion positive alveolar rhabdomyosarcoma. A distinguishing genetic feature of this patient was a germline RET C634F mutation, which is a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. Through sequential DNA and RNA sequencing analyses over the patient's clinical course, a set of gene mutations, amplifications, and overexpressed genes were identified and biological hypotheses generated to explore the biology of RET and coexisting signaling pathways in rhabdomyosarcoma. Somatic genetic abnormalities identified include CDK4 amplification and FGFR4 G388R polymorphism. Because of the initial lack of patient-derived primary cell cultures, these hypotheses were evaluated using several approaches including western blot analysis and pharmacological evaluation with molecularly similar alveolar rhabdomyosarcoma cell lines. Once a primary cell culture became available, the RET inhibitor cabozantinib was tested but showed no appreciable efficacy in vitro, affirming with the western blot negative for RET protein expression that RET germline mutation could be only incidental. In parallel, the patient was treated with cabozantinib without definitive clinical benefit. Parallel chemical screens identified PI3K and HSP90 as potential tumor-specific biological features. Inhibitors of PI3K and HSP90 were further validated in drug combination synergy experiments and shown to be synergistic in the patient-derived culture. We also evaluated the use of JAK/STAT pathway inhibitors in the context of rhabdomyosarcomas bearing the FGFR4 G388R coding variant. Although the patient succumbed to his disease, study of the patient's tumor has generated insights into the biology of RET and other targets in rhabdomyosarcoma., (© 2020 Crawford et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2020
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15. Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: implications for RET oncogene detection.
- Author
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Huang Q, Hu A, and Zhang M
- Subjects
- Carcinoma, Medullary diagnostic imaging, Carcinoma, Medullary genetics, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia Type 2a diagnostic imaging, Pedigree, Positron Emission Tomography Computed Tomography methods, Proto-Oncogene Mas, Thyroid Neoplasms diagnostic imaging, Asian People genetics, Carcinoma, Medullary congenital, Multiple Endocrine Neoplasia Type 2a genetics, Mutation genetics, Oncogenes genetics, Proto-Oncogene Proteins c-ret genetics, Siblings, Thyroid Neoplasms genetics
- Abstract
Background: Hereditary medullary thyroid carcinoma (MTC) is mainly caused by germline mutations in the RET proto-oncogene, which accounts for 20-30% of all MTC according to foreign studies. However, no English literatures have reported Chinese hereditary MTC. Here, we reported two Chinese brothers with MTC that caused by germline RET mutation., Case Presentation: The younger brother was diagnosed with MTC at 29 years ago and suffered recurrence more than 10 years. For elder brother, the diagnosis of MTC was made by postoperative pathological examination at age 61. Both patients received total thyroidectomy and lymph node dissection. Since they had a significant family history for MTC, genetic detection was performed and identified a germline mutation in RET exon 10 (p.C620Y). This mutation was also detected in their offspring, indicating a moderate risk of MTC., Conclusions: This is the first report presenting a Chinese family with hereditary MTC caused by the RET p.C620Y variant. This case series emphasize the importance of genetic detection of RET proto-oncogene for MTC patients, and bring out managements for individuals after detection of RET mutations.
- Published
- 2020
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16. A case of Warthin-like papillary thyroid carcinoma with diffuse sclerosing stroma and a novel RET mutation: a new entity or a combined tumour?
- Author
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Maffini F, Lorenzini D, Lepanto D, De Fiori E, Fumagalli C, Rappa A, Tagliabue M, and Barberis M
- Abstract
Activating mutations of the RET gene have been described for both papillary (chromosomal rearrangement) and medullary (missense mutations) thyroid carcinomas. Here, we describe a case of a Warthin-like variant of papillary thyroid carcinoma displaying some morphological aspects that mimic the diffuse sclerosing variant. The tumour harboured BRAF V600E mutation and a novel germline point mutation in the RET gene, with unknown clinical and pathological meaning., Competing Interests: The authors declare that they have no conflicts of interest., (© the authors; licensee ecancermedicalscience.)
- Published
- 2019
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17. Unique association of multiple endocrine neoplasia 2A and congenital anomalies of the kidney and urinary tract in a child with a RET mutation.
- Author
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Wood OR, Else T, and Sampson MG
- Subjects
- Adult, Female, Humans, Infant, Newborn, Mutation, Pedigree, Kidney abnormalities, Multiple Endocrine Neoplasia Type 2a genetics, Proto-Oncogene Proteins c-ret genetics, Urinary Tract abnormalities
- Abstract
Pathogenic variants in the RET gene can cause isolated and multi-system diseases. We report a patient diagnosed prenatally with unilateral multicystic dysplastic kidney and genitourinary abnormality whose mother had multiple endocrine neoplasia type 2A (MEN2A). Targeted RET sequencing found the same pathogenic variant p.C618S in the child as her mother. The child is followed by paediatric nephrology for congenital anomalies of the kidney and urinary tract (CAKUT) and by endocrine oncology for surveillance for MEN2A-related endocrine tumours. While implicated in each of these conditions individually, RET variants have never been reported to cause MEN2A and CAKUT together. This child's family history prompted RET sequencing, resulting in presymptomatic, personalised care for MEN2A. However, this case supports the idea that genetic screening of RET (and many other genes) in patients with CAKUT may lead to molecular diagnoses that potentially improve their health through precision care., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2019
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18. Identification of a secondary RET mutation in a pediatric patient with relapsed acute myeloid leukemia leads to the diagnosis and treatment of asymptomatic metastatic medullary thyroid cancer in a parent: a case for sequencing the germline.
- Author
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Pendrick DM, Oberg JA, Hsiao SJ, Chung WK, Koval C, Sireci A, Kuo JH, Satwani P, Glasser CL, Sulis ML, Mansukhani MM, and Glade Bender JL
- Subjects
- Carcinoma, Neuroendocrine genetics, Child, Preschool, Fathers, Humans, Incidental Findings, Male, Neoplasm Metastasis, Pedigree, Sequence Analysis, DNA, Thyroid Neoplasms genetics, Carcinoma, Neuroendocrine diagnosis, Germ-Line Mutation, Leukemia, Myeloid, Acute genetics, Neoplasm Recurrence, Local genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms diagnosis
- Abstract
The incorporation of tumor-normal genomic testing into oncology can identify somatic mutations that inform therapeutic measures but also germline variants associated with unsuspected cancer predisposition. We describe a case in which a RET variant was identified in a 3-yr-old male with relapsed leukemia. Sanger sequencing revealed the patient's father and three siblings carried the same variant, associated with multiple endocrine neoplasia 2A (MEN2A). Evaluation of the father led to the diagnosis and treatment of metastatic medullary thyroid carcinoma. Detection of RET mutations in families with hereditary MTC allows for genetic risk stratification and disease surveillance to reduce morbidity and mortality., (© 2019 Pendrick et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2019
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19. Current surgical management in RET mutation carriers [Aktualne postępowanie chirurgiczne u nosicieli mutacji proto-onkogenu RET].
- Author
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Czarniecka A, Oczko-Wojciechowska M, Hajduk A, Zeman M, and Jarzab B
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- Calcitonin blood, Carcinoma, Medullary blood, Carcinoma, Medullary genetics, Carcinoma, Medullary surgery, Disease Management, Humans, Multiple Endocrine Neoplasia Type 2a blood, Multiple Endocrine Neoplasia Type 2a genetics, Practice Guidelines as Topic, Proto-Oncogene Mas, Thyroid Neoplasms blood, Thyroid Neoplasms genetics, Carcinoma, Medullary congenital, Multiple Endocrine Neoplasia Type 2a surgery, Mutation, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms surgery, Thyroidectomy
- Abstract
Medullary thyroid carcinoma (MTC) still remains a rare endocrine tumor. 20-25% of MTC cases are genetically determined. The detection of the RET proto-oncogene mutation in 1993 allowed to understand the unique genotype-phenotype relationships in hereditary medullary thyroid carcinoma (HMTC) and formed the basis for therapeutic decisions based on the molecular results. Currently, prophylactic thyroidectomy is a commonly adopted and accepted therapeutic method. The decision on the time and extent of surgery should be made based on the results of molecular examination, the assessment of calcitonin (Ct) concentration and family history. Treatment of patients with HMTC requires the cooperation of a multidisciplinary team of experts and should be done in specialized centers only. The study is a review of the current guidelines for surgical management in the MEN2 syndrome.
- Published
- 2019
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20. Sporadic minute medullary thyroid carcinoma with a double RET mutation: A case report.
- Author
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Yamamoto H, Ishii J, Chiba T, Nakazato Y, Hirano K, and Kamma H
- Subjects
- Aged, Carcinoma, Neuroendocrine pathology, Humans, Male, Mutation, Proto-Oncogene Mas, Thyroid Neoplasms pathology, Carcinoma, Neuroendocrine genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
We describe a 74-year-old man with a nodular goiter accompanied by an incidental sporadic minute medullary thyroid carcinoma (MTC). Histopathologically, the MTC was a well-defined 1.7 mm tumor in the upper one-third right lobe, with solid cell nests (SCNs) adjacent to the MTC. C-cells were scattered mainly around the SCNs, but C-cell hyperplasia was not evident in the background thyroid. The MTC cell phenotype was immunohistochemically identical to background C-cells, but was completely different from the SCN main cells. Direct DNA analyses of isolated MTC paraffin-embedded specimens revealed two RET proto-oncogene missense point mutations in exon 11 (i.e., C630R and C634W). The non-tumor thyroid tissue did not reveal any mutations. This study reports the smallest case of sporadic MTC with a double RET somatic mutation, substantiating that RET mutations can occur during a very early stage of carcinogenesis. The combined presence of C630R and C634W represent a novel somatic mutation in sporadic MTC. The present case indicates that the sporadic MTC originated from the surrounding C-cells of the SCNs without C-cell hyperplasia and that the SCN main cells may not be able to develop into an MTC., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)
- Published
- 2017
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21. Establishment of an induced pluripotent stem cell model of Hirschsrpung disease, a congenital condition of the enteric nervous system, from a patient carrying a novel RET mutation.
- Author
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Wang Y, Lai X, Huang L, Liu G, Zai Z, Zhu D, Zhang Y, Liang Z, Yao Z, Chen Y, Wen Z, and Xia H
- Subjects
- Animals, Cells, Cultured, Enteric Nervous System pathology, Hirschsprung Disease pathology, Humans, Induced Pluripotent Stem Cells pathology, Mice, Mice, Nude, Enteric Nervous System physiology, Hirschsprung Disease genetics, Induced Pluripotent Stem Cells physiology, Mutation genetics, Proto-Oncogene Proteins c-ret genetics
- Abstract
Hirschsprung disease (HSCR) is a complex genetic disorder of the enteric nervous system that is characterized by a complete loss of the neuronal ganglion cells in the intestinal tract. It is one of the most frequent causes of congenital intestinal obstruction and more than 80% of the causative mutations are in RET. Here, we identified a new RET mutation in a patient and established a cell model that can be used to elucidate the pathogenesis of HSCR. Peripheral blood was collected from a patient who was clinically and pathologically diagnosed with HSCR with a heterozygous deletion mutation (c.180delT; p.Glu61ArgfsX163) in exon 2 of RET. Patient-derived induced pluripotent stem cell (iPSC) lines were generated from dermal fibroblasts. Using immunofluorescence staining and RT-PCR, we showed that the generated iPSCs expressed the pluripotency markers OCT4, SSEA4, SOX2, TRA-1-60, and NANOG. We also showed that the HSCR-iPSCs could differentiate into cells from all three germ layers by spontaneous in-vitro differentiation. In addition, 3 months after the administration of a subcutaneous injection of these iPSCs into nude mice, teratomas with all three germ layers were observed. We identified a new RET gene mutation causing HSCR and successfully established a human iPSC line from an HSCR patient carrying this novel RET mutation, which could be useful in pathogenesis studies of HSCR.
- Published
- 2018
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22. A secondary RET mutation in the activation loop conferring resistance to vandetanib.
- Author
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Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, and Goto K
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Middle Aged, Piperidines pharmacology, Proto-Oncogene Proteins c-ret antagonists & inhibitors, Quinazolines pharmacology, Adenocarcinoma genetics, Drug Resistance, Neoplasm genetics, Lung Neoplasms genetics, Mutation, Missense, Piperidines therapeutic use, Proto-Oncogene Proteins c-ret genetics, Quinazolines therapeutic use
- Abstract
Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects.
- Published
- 2018
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23. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases.
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Romei C, Ciampi R, Casella F, Tacito A, Torregrossa L, Ugolini C, Basolo F, Materazzi G, Vitti P, and Elisei R
- Abstract
Purpose: Medullary Thyroid Cancer (MTC) whose pathogenesis is strictly related to RET proto-oncogene alterations, has been shown to have a heterogenic RET mutation profile in subpopulations of MTC. The aim of our study was to investigate the RET somatic mutation profile in primary MTC and in the corresponding metastatic tissues in a series of advanced metastatic cases., Results: This study demonstrated that in about 20% of cases a different RET mutation profile can be found when comparing primary tumor and its corresponding metastases. Furthermore in 8% of tumors, RET intratumor heterogeneity was observed We also showed that in some cases an imbalance of RET copy number was present. We confirmed a high prevalence (90%) of RET somatic mutations in advanced tumors., Materials and Methods: Fifty-six MTC patients (50 somatic and 6 hereditary cases) have been included in the study and a total of 209 specimens have been analysed by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) has been used to investigate amplification/deletion of RET alleles., Conclusions: In conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity., Competing Interests: CONFLICTS OF INTEREST The authors declare that there is no conflicts of interest that could affect the impartiality of the reported research.
- Published
- 2018
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24. Detection of early stage medullary thyroid carcinoma by measuring serum calcitonin using an electro chemiluminescence immuno-assay: A case report of a young Japanese woman with a high-risk RET mutation.
- Author
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Abe Y and Tsukano S
- Abstract
Medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder caused by the mutation of the RET proto-oncogene, that shows nearly complete penetration. The American Thyroid Association guidelines recommend prophylactic thyroidectomy for patients with high-risk RET mutations. However, in Japan, ethical and medical issues may preclude prophylactic treatment in young patients. Hence, an early diagnosis of MTC is necessary to ensure a favorable outcome. Here, we report the case of a young Japanese girl with a high-risk RET mutation, diagnosed with very early stage MTC using serum calcitonin (Ctn) values measured using an electro chemiluminescence immuno-assay (ECLIA). The Japanese girl with a family history of MEN2 had been followed at our hospital since she was 5-mo-old. RET analysis revealed that she displayed a Cys634Gly mutation. The patient underwent annual neck ultrasonography and calcium infusion testing. When she was 8-yr-old, the Ctn level, measured using ECLIA, dramatically increased with calcium stimulation, from a baseline of 11.3 pg/mL to 333 pg/mL. She subsequently underwent total thyroidectomy and was diagnosed with stage I MTC. Detecting early stage MTC by monitoring serum Ctn measured by ECLIA, may represent a useful strategy for patients with high-risk RET mutations.
- Published
- 2017
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25. M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds.
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Martins-Costa MC, Cunha LL, Lindsey SC, Camacho CP, Dotto RP, Furuzawa GK, Sousa MS, Kasamatsu TS, Kunii IS, Martins MM, Machado AL, Martins JR, Dias-da-Silva MR, and Maciel RM
- Subjects
- Adolescent, Adult, Aged, 80 and over, Brazil, Carcinoma, Medullary genetics, Child, Family, Female, Founder Effect, Germ-Line Mutation, Humans, Male, Methionine genetics, Middle Aged, Pedigree, Valine genetics, Young Adult, Amino Acid Substitution, Carcinoma, Medullary congenital, Multiple Endocrine Neoplasia Type 2a genetics, Mutation, Missense, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Germline mutations in codon 918 of exon 16 of the RET gene (M918T) are classically associated with multiple endocrine neoplasia type 2B (MEN 2B) with highly aggressive medullary thyroid cancer (MTC), pheochromocytoma and a unique phenotype. The objectives of this study are to describe the rare M918V RET mutation discovered in 8 MTC kindreds from Brazil lacking the MEN 2B phenotype classically observed in M918T patients and to investigate the presence of a founder effect for this germline mutation. Eight apparently sporadic MTC cases were diagnosed with the germline M918V RET mutation. Subsequently, their relatives underwent clinical and genetic assessment (n = 113), and M918V was found in 42 of them. Until today, 20/50 M918V carriers underwent thyroidectomy and all presented MTC/C-cell hyperplasia; the remainder carriers are on clinical follow-up. None of the M918V carriers presented clinical features of MEN 2B. Their clinical presentation was heterogeneous, and the age at tumor diagnosis ranged from 24 to 59 years. Lymph node metastases were present in 12/20 patients, and presumable distant metastases in 2/20; in contrast, we observed a carrier of up to 87 years of age without evidence of MTC. Ethnographic fieldwork and haplotype analyses suggested that the founder mutation first settled in that area fifteen generations ago and originated from Portugal. Our study is the first to demonstrate the RET M918V mutation co-segregating in 8 familial MTC kindreds with validated evidence of a founder effect. We suggest that M918V MTC should be clinically considered an American Thyroid Association (ATA) moderate-risk category., (© 2016 Society for Endocrinology.)
- Published
- 2016
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26. Clinical Features of a Family with Multiple Endocrine Neoplasia Type 2A Caused by the D631Y RET Mutation.
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Ospina NS, Maraka S, Donegan D, and Morris JC
- Subjects
- Adrenal Gland Neoplasms pathology, Adult, Aged, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia Type 2a pathology, Pheochromocytoma pathology, Thyroid Neoplasms pathology, Young Adult, Adrenal Gland Neoplasms genetics, Multiple Endocrine Neoplasia Type 2a genetics, Pheochromocytoma genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
We describe a family with multiple endocrine neoplasia type 2A (MEN2A) caused by the D631Y RET mutation resulting in an atypical phenotype. The index case was a 24-year-old man with history of recurrent anaplastic ependymoma incidentally found to have the D631Y RET mutation. At first assessment, four family members had evidence of large pheochromocytomas. One patient was found to have micromedullary thyroid cancer at 79 years of age. None of the patients had primary hyperparathyroidism. Patients with MEN2A caused by a D631Y RET mutation most commonly present with pheochromocytomas. Medullary thyroid cancer is a less common part of the syndrome when compared with other RET mutations.
- Published
- 2017
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27. Plasma Calcitonin Levels and miRNA323 Expression in Medullary Thyroid Carcinoma Patients with or without RET Mutation
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Ehyaei S, Hedayati M, Zarif-Yeganeh M, Sheikholeslami S, Ahadi M, and Amini SA
- Abstract
Background: Medullary thyroid cancer (MTC) is an endocrine tumor featuring parafollicular or C-cell differentiation, with calcitonin as a specific biomarker in MTC diagnosis. Germline mutations in the RET proto-oncogene are considered responsible for its familial occurrence and somatic mutations can cause sporadic lesions. MicroRNAs can act as oncogenes or tumor suppressors by inhibiting the expression of target genes.. The aim of this study was to investigate relationships between plasma levels of calcitonin and miRNA323 expression in MTC patients with or without RET mutation. Methods: In this cross-sectional study, MTC lesions (based on pathological confirmation) were investigated. Genomic DNA was extracted and Exons 10 and 11 of RET were genotyped using PCR-sequencing. Division was into two groups of 43 cases each with or without mutation. Plasma levels of calcitonin were determined in both. Results: miRNA323 was measured using real-time-PCR. After performing normality tests, independent T-tests and Mann Whitney tests were used for the statistical comparison of parametric and nonparametric data, respectively. Plasma levels of calcitonin were significantly higher in MTC cases without a RET mutation compared to those with a mutation. Conclusion: There was no significant difference between the two groups regarding the expression of miRNA323 so that this parameter could not be used as a bio-index germ line mutations in MTCs. However, determination of calcitonin levels in plasma might be helpful in this regard., (Creative Commons Attribution License)
- Published
- 2017
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28. Novel Somatic RET Mutation Questioning the Causality of the RET I852M Germline Sequence Variant in Multiple Endocrine Neoplasia 2A.
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Mathiesen JS, van Overeem Hansen T, Rasmussen ÅK, Hjortshøj TD, Kiss K, Larsen SR, Krogh LN, Frederiksen AL, Hermann AP, and Godballe C
- Subjects
- Aged, Female, Humans, Germ-Line Mutation, Multiple Endocrine Neoplasia Type 2a genetics, Proto-Oncogene Proteins c-ret genetics
- Published
- 2017
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29. Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2B (MEN2B) syndrome with "highest risk" RET mutation.
- Author
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Bennaceur-Griscelli A, Hadoux J, Féraud O, Opolon P, Divers D, Gobbo E, Schlumberger M, Griscelli F, and Turhan AG
- Subjects
- Cell Line, Humans, Risk Factors, Young Adult, Cell Culture Techniques methods, Induced Pluripotent Stem Cells pathology, Multiple Endocrine Neoplasia Type 2b genetics, Multiple Endocrine Neoplasia Type 2b pathology, Mutation genetics, Proto-Oncogene Proteins c-ret genetics
- Abstract
Multiple Endocrine Neoplasia Type 2B (MEN2B) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC) and pheochromocytoma. Currently, there is no satisfactory model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 918 who developed pheochromocytoma and MTC. These iPSC had normal karyotype, harboured the RET
M918T mutation and expressed pluripotency hallmarks. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2017
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30. Long-Term Control of Hypercortisolism by Vandetanib in a Case of Medullary Thyroid Carcinoma with a Somatic RET Mutation.
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Paepegaey AC, Cochand-Priollet B, Louiset E, Sarfati PO, Alifano M, Burnichon N, Bienvenu-Perrard M, Lahlou N, Bricaire L, and Groussin L
- Subjects
- Calcitonin blood, Carcinoma, Neuroendocrine complications, Carcinoma, Neuroendocrine surgery, Cushing Syndrome blood, Cushing Syndrome etiology, Cytoreduction Surgical Procedures, Humans, Hydrocortisone blood, Male, Middle Aged, Neck Dissection, Thyroid Neoplasms complications, Thyroid Neoplasms surgery, Thyroidectomy, Carcinoma, Neuroendocrine genetics, Cushing Syndrome drug therapy, Piperidines therapeutic use, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-ret genetics, Quinazolines therapeutic use, Thyroid Neoplasms genetics
- Abstract
Background: Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies., Patient Findings: The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753T>C) somatic mutation was identified in a lymph node metastasis., Conclusion: Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.
- Published
- 2017
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31. A cohort study on 10-year survival of sporadic medullary thyroid carcinoma with somatic RET mutation.
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Chuang LL, Hwang DY, Tsai KB, Chan HM, Chiang FY, and Hsiao PJ
- Subjects
- Adult, Aged, Base Sequence, Cohort Studies, Female, Humans, Male, Middle Aged, Proto-Oncogene Mas, Survival Analysis, Young Adult, Carcinoma, Neuroendocrine genetics, Mutation genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Somatic rearranged during transfection (RET) mutations are reported in 40-50% of sporadic medullary thyroid carcinoma (sMTC) patients with prognostic significance. As there is a lack of somatic RET mutations reported previously for the Taiwanese population, we tried to assess the presence of somatic RET mutations and evaluate the potential outcome predictors for our sMTC patients. We collected data from seven sMTC patients from the years 1997 to 2005 and analyzed their clinic-pathological features up to 2015. All patients were still alive to follow up for 11∼18 years. Tumor DNAs were extracted to assess exons 10-11 and 13-16, and the intron-exon boundaries of the RET gene. Six cases (86%) were screened positive of somatic RET gene mutations in hotspot regions, one at M918T, one at C620R, and three at C634S, with another two rare mutations at L629Q and V642I. Comparing the current tumor, node, metastases staging system, the 10-year survival outcomes for our sMTC patients was not predicted by serum calcitonin and/or carcinoembryonic antigen, surgical extent, and presence of the somatic RET gene mutations. The small cohort demonstrated a relatively good outcome of sMTC patients to survive >10 years. In addition, intensive treatment with total thyroidectomy with extensive neck lymph node dissection seemed to be the critical determinant of better survival outcome for sMTC patients., (Copyright © 2016 Kaohsiung Medical University. Published by Elsevier Taiwan.. All rights reserved.)
- Published
- 2016
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32. Germline RET mutation carriers in Japanese patients with apparently sporadic medullary thyroid carcinoma: A single institution experience.
- Author
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Kihara M, Miyauchi A, Yoshioka K, Oda H, Nakayama A, Sasai H, Yabuta T, Masuoka H, Higashiyama T, Fukushima M, Ito Y, Kobayashi K, and Miya A
- Subjects
- Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Asian People, Carcinoma, Medullary genetics, Carcinoma, Medullary surgery, Carcinoma, Neuroendocrine surgery, Child, DNA Mutational Analysis, Female, Germ-Line Mutation, Humans, Japan, Male, Middle Aged, Multiple Endocrine Neoplasia Type 2a surgery, Neoplasms, Multiple Primary surgery, Proto-Oncogene Mas, Thyroid Neoplasms surgery, Thyroidectomy, Young Adult, Carcinoma, Medullary congenital, Carcinoma, Neuroendocrine genetics, Multiple Endocrine Neoplasia Type 2a genetics, Neoplasms, Multiple Primary genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Objective: Genetic testing for RET germline mutation can be useful to distinguish whether a patient with medullary thyroid carcinoma (MTC) is genuinely sporadic or hereditary. Conducting a routine preoperative germline RET genetic screening for all patients with MTC has the clinical benefit, i.e., avoidance of unnecessary total thyroidectomy in the selected patients. We sought to clarify the incidence of germline RET mutation carriers in Japanese patients with apparently sporadic MTC and to address the differences in clinicopathological characteristics between true sporadic MTC and hereditary MTC in these patients, all of whom were treated at Kuma Hospital., Methods: A total of 134 patients with apparently sporadic MTC who underwent surgery between 1996 and 2014 were enrolled. All patients underwent a germline RET gene mutation analysis preoperatively., Results: Germline mutations in RET proto-oncogene were identified in 20 of the 134 (14.9%) apparently sporadic MTC patients. No significant difference in clinicopathological characteristics was observed between the patients with sporadic MTC (n=114) and those with hereditary MTC (n=20) except for the RET gene carriers' younger age at diagnosis and presence of multifocal and bilateral lesions., Conclusion: Germline RET mutations were identified in 14.9% of Japanese patients with apparently sporadic MTC. No clearly decisive clinicopathological characteristics was observed to distinguish whether an apparently sporadic MTC case was genuinely sporadic or unconsciously hereditary. For the treatment strategy decision, it is advantageous to conduct a routine preoperative germline RET genetic screening for all patients with MTC, even if their MTC is apparently sporadic., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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33. RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR variant p.G513D.
- Author
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Qi XP, Zhao JQ, Chen ZG, Cao JL, Du J, Liu NF, Li F, Sheng M, Fu E, Guo J, Jia H, Zhang YM, and Ma JM
- Subjects
- Adolescent, Adult, Aged, Amyloidosis, Familial complications, Amyloidosis, Familial metabolism, Calcitonin metabolism, Carcinoma, Medullary genetics, Carcinoma, Medullary metabolism, Cell Proliferation, Child, China, DNA Mutational Analysis, Family Health, Female, Fluorescent Antibody Technique, Indirect, Genetic Association Studies, Genetic Variation, Genetic Vectors, Germ-Line Mutation, HEK293 Cells, Heterozygote, Humans, Male, Multiple Endocrine Neoplasia Type 2a metabolism, Phenotype, Skin Diseases, Genetic complications, Skin Diseases, Genetic metabolism, Thyroid Neoplasms metabolism, Amyloidosis, Familial genetics, Carcinoma, Medullary congenital, Multiple Endocrine Neoplasia Type 2a genetics, Mutation, Oncostatin M Receptor beta Subunit genetics, Proto-Oncogene Proteins c-ret genetics, Skin Diseases, Genetic genetics, Thyroid Neoplasms genetics
- Abstract
There are no reports on the relationship between familial medullary thyroid carcinoma (FMTC) associated with cutaneous amyloidosis (CA) and RET or OSMR/IL31RA gene mutations. In this study, we investigated a Chinese family with FMTC/CA and found a recurrent RET c.2671T>G (p.S891A) mutation in six of 17 family members. Three of the six p.S891A mutation carriers presented with medullary thyroid carcinoma (MTC). Of them, three (two with and one without MTC) were diagnosed as having combined lichen/macular biphasic CA. We also identified a novel RET variant, c.1573C>T (p.R525W) in five members. Of them, three carriers had no evidence of thyroid/skin or basal serum/stimulated calcitonin abnormalities. In vitro cell proliferation assay indicated that oncogenic activity of RET p.S891A was slightly enhanced by p.R525W, whereas p.R525W alone had no effect on cell proliferation. Meanwhile, we identified a novel OSMR variant, c.1538G>A (p.G513D) in seven members. We noticed that three OSMR p.G513D carriers presenting with CA also had the RET p.S891A mutation. Our investigation indicated that the RET p.S891A mutation combined with OSMR p.G513D may underlie a novel phenotype manifesting as FMTC and CA.
- Published
- 2015
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34. C-Cell Neoplasia in Asymptomatic Carriers of RET Mutation in Extracellular Cysteine-Rich and Intracellular Tyrosine Kinase Domain.
- Author
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Abi-Raad R, Virk RK, Dinauer CA, Prasad A, Morotti RA, Breuer CK, Sosa JA, Udelsman R, Rivkees SA, and Prasad ML
- Subjects
- Adolescent, Adult, Carcinoma, Neuroendocrine, Child, Child, Preschool, Female, Genetic Predisposition to Disease genetics, Germ-Line Mutation, Heterozygote, Humans, Infant, Male, Middle Aged, Multiple Endocrine Neoplasia complications, Protein Structure, Tertiary, Proto-Oncogene Mas, Young Adult, Multiple Endocrine Neoplasia genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Germline mutations in RET proto-oncogene associated with multiple endocrine neoplasia type 2 (MEN2) may affect codons for the extracellular cysteine-rich (ECR) or the intracellular tyrosine kinase (ITK) domain of the transmembrane receptor tyrosine kinase protein. We compared C-cell pathology in asymptomatic carriers of RET mutation affecting the 2 domains. Twenty-two asymptomatic carriers (median age, 9.5 years), 10 with mutations in the ECR (codons 634, 611, 618, and 620) and 12 with mutations in the ITK domain (codons 804, 790, 891, and 918), underwent total thyroidectomy. C-cell hyperplasia was identified in 16 (73%), was multifocal and/or bilateral in 11, and was associated with medullary thyroid carcinoma (MTC) in 10 thyroids. When comparing the ECR and ITK groups in 21 carriers from MEN2A/familial MTC families, C-cell hyperplasia was more frequent in the former (90% versus 55%), as was multifocality (70% versus 27%) and MTC (60% versus 27%), despite the significantly younger median age in the former group (5 versus 23 years, P = .04). One asymptomatic carrier had de novo codon 918 mutation (MEN2B) and showed bilateral microcarcinoma with lymph node metastasis at presentation and progressive disease on follow-up. In conclusion, asymptomatic carriers of high-risk RET mutations affecting the ECR were significantly younger and frequently showed C-cell neoplasia, multifocality, and MTC when compared with mutations affecting the ITK domain in the MEN2A/familial MTC families. The presence of C-cell disease, its severity, and aggressiveness correlated with the mutated codon and with increasing age., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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35. Chronic intestinal pseudo-obstruction in a child harboring a founder Hirschsprung RET mutation.
- Author
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Rossi V, Mosconi M, Nozza P, Murgia D, Mattioli G, Ceccherini I, and Pini Prato A
- Subjects
- Biopsy, Female, Hirschsprung Disease diagnosis, Humans, Infant, Newborn, Phenotype, Proto-Oncogene Mas, Founder Effect, Genetic Association Studies, Hirschsprung Disease genetics, Intestinal Pseudo-Obstruction diagnosis, Intestinal Pseudo-Obstruction genetics, Mutation, Proto-Oncogene Proteins c-ret genetics
- Abstract
Chronic intestinal pseudo obstruction (CIPO) is a rare clinical entity characterized by symptoms and signs of intestinal obstruction without either recognizable anatomical abnormalities or intestinal aganglionosis. A Chinese female infant presented to our institution with a clinical diagnosis of CIPO. Aganglionosis was ruled out by full thickness colonic and ileal biopsies and by rectal suction biopsies. Unexpectedly, direct sequencing and PCR amplification of RET proto-oncogene from peripheral blood extracted DNA identified a RET R114H mutation. This mutation has already been reported as strongly associated with Asian patients affected by Hirschsprung's disease (HSCR) and is considered a founder mutation in Asia. The same mutation has never been reported in patients with CIPO, so far. These findings support the role of RET in the development of the enteric nervous system but underline the importance of other genetic or environmental factors contributing to the gastrointestinal phenotype of the disease. Somehow, this RET R114H mutation proved to have a role in the etiology of both CIPO and HSCR and could contribute to a more diffuse imbalance of gut dysmotility. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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36. RET mutation and increased angiogenesis in medullary thyroid carcinomas.
- Author
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Verrienti A, Tallini G, Colato C, Boichard A, Checquolo S, Pecce V, Sponziello M, Rosignolo F, de Biase D, Rhoden K, Casadei GP, Russo D, Visani M, Acquaviva G, Ferdeghini M, Filetti S, and Durante C
- Subjects
- Carcinoma, Neuroendocrine metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Microvessels, Mutation, Neovascularization, Pathologic metabolism, Proto-Oncogene Proteins c-ret metabolism, Receptor, Notch3 genetics, Receptor, Notch3 metabolism, Receptor, Platelet-Derived Growth Factor alpha genetics, Receptor, Platelet-Derived Growth Factor alpha metabolism, Signal Transduction, Thyroid Neoplasms metabolism, Vascular Endothelial Growth Factor Receptor-1 genetics, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Vascular Endothelial Growth Factor Receptor-3 genetics, Vascular Endothelial Growth Factor Receptor-3 metabolism, Carcinoma, Neuroendocrine genetics, Neovascularization, Pathologic genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors., (© 2016 Society for Endocrinology.)
- Published
- 2016
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37. Clinical significance of RET mutation screening in a pedigree of multiple endocrine neoplasia type 2A.
- Author
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Ying R and Feng J
- Subjects
- Adult, Biomarkers, DNA Mutational Analysis, Female, Follow-Up Studies, Genetic Testing, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia Type 2a blood, Multiple Endocrine Neoplasia Type 2a surgery, Phenotype, Proto-Oncogene Mas, Treatment Outcome, Young Adult, Multiple Endocrine Neoplasia Type 2a diagnosis, Multiple Endocrine Neoplasia Type 2a genetics, Mutation, Pedigree, Proto-Oncogene Proteins c-ret genetics
- Abstract
The clinical characteristics and RET proto-oncogene (RET‑PO) mutation status of a patient with multiple endocrine neoplasia type 2A pedigree (MEN2A) was analyzed with the aim of preliminarily exploring the molecular mechanisms and clinical significance of the disease. Clinical characteristics of a single MEN2A patient were analyzed. Genomic DNA was extracted from the peripheral blood of the proband and 10 family members. The 21 exons of RET‑PO were PCR amplified and the amplified products were sequenced. Of the family members, 5 exhibited a C634Y (TGC→TAC) missense mutation in exon 11 of RET‑PO, among which 2 family members were screened as mutation carriers, while the others did not exhibit clinical symptoms of the mutation. The screening and analysis of RET‑PO mutations for the MEN2A proband and the family members suggests potential clinical phenotypes and enables assessment of the risk of disease development, thus providing useful information for determining the surgical timing of preventive thyroid gland removal.
- Published
- 2016
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38. Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status.
- Author
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Steiner F, Hauser-Kronberger C, Rendl G, Rodrigues M, and Pirich C
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Calcitonin blood, Carcinoma, Neuroendocrine genetics, Carcinoma, Neuroendocrine metabolism, Child, Child, Preschool, ErbB Receptors genetics, Female, Humans, Male, Middle Aged, Mutation, Thyroid Neoplasms genetics, Thyroid Neoplasms metabolism, Thyroid Nuclear Factor 1, Young Adult, Cadherins metabolism, Carcinoma, Neuroendocrine pathology, ErbB Receptors metabolism, Nuclear Proteins metabolism, Proto-Oncogene Proteins c-ret genetics, Tenascin metabolism, Thyroid Neoplasms pathology, Transcription Factors metabolism
- Abstract
Tenascin C expression correlates with tumor grade and indicates worse prognosis in several tumors. Epidermal growth factor receptor (EGFR) plays an important role in driving proliferation in many tumors. Loss of E-cadherin function is associated with tumor invasion and metastasis. Thyroid transcription factor-1 (TTF-1) is involved in rearranged during transfection (RET) transcription in Hirschsprung's disease. Tenascin C, EGFR, E-cadherin, TTF-1-expression, and their correlations with RET mutation status were investigated in 30 patients with medullary thyroid carcinoma (MTC) (n = 26) or C-cell hyperplasia (n = 4). Tenascin C was found in all, EGFR in 4/26, E-cadherin in 23/26, and TTF-1 in 25/26 MTC. Tenascin C correlated significantly with tumor proliferation (overall, r = 0.61, p < 0.005; RET-mutated, r = 0.81, p < 0.01). E-cadherin showed weak correlation, whereas EGFR and TTF-1 showed no significant correlation with tumor proliferation. EGFR, E-cadherin, and TTF-1 showed weak correlation with proliferation of RET-mutated tumors. Correlation between TTF-1 and tenascin C, E-cadherin, and EGFR was r = -0.10, 0.37, and 0.21, respectively. In conclusion, MTC express tenascin C, E-cadherin, and TTF-1. Tenascin C correlates significantly with tumor proliferation, especially in RET-mutated tumors. EGFR is low, and tumors expressing EGFR do not exhibit higher proliferation. TTF-1 does not correlate with RET mutation status and has a weak correlation with tenascin C, E-cadherin, and EGFR expression.
- Published
- 2016
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39. Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2A (MEN2A) syndrome with RET mutation.
- Author
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Hadoux J, Féraud O, Griscelli F, Opolon P, Divers D, Gobbo E, Schlumberger M, Bennaceur-Griscelli A, and Turhan AG
- Abstract
Multiple Endocrine Neoplasia Type 2A (MEN2A) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC), pheochromocytoma, hyperparathyroidism and cutaneous lichen amyloidosis (CLA) and/or Hirschsprung disease in some variants. Currently, there is no satisfactory animal model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 634 who developed pheochromocytoma and MTC. RET
C634Y -mutated cells were reprogrammed by non-integrative viral transduction. These iPSCs had normal karyotype, harboured the RETC634Y mutation and expressed pluripotency hallmarks as well as RET. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2016
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40. Somatic RET mutation in a patient with pigmented adrenal pheochromocytoma.
- Author
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Maison N, Korpershoek E, Eisenhofer G, Robledo M, de Krijger R, and Beuschlein F
- Abstract
Unlabelled: Pheochromocytomas (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest. Mutations in the RET-proto-oncogene are associated with sporadic pheochromocytoma, familial or sporadic medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2. In the past, only few cases of pigmented PCCs, PGLs, and one case of pigmented MTC have been reported in the literature. Herein, we present the case of a 77-year old woman with a history of Tako-tsubo-cardiomyopathy and laboratory, as well as radiological, high suspicion of pheochromocytoma, who underwent left-sided adrenalectomy. The 3 cm tumor, which was located on the upper pole of the left adrenal, appeared highly pigmented with dark red to black color. Histologic examinations revealed highly pleomorphic cells with bizarre, huge hyperchromatic nuclei, that immunohistochemically were positive for chromogranin A and synaptophysin, focally positive for HMB45 and negative for melan A. These clinical and pathological features led to the diagnosis of the rare variant of a melanotic 'black' pheochromocytoma. In our case a somatic RET mutation in exon 16 (RET c.2753T>C, p.Met918Thy) was detected by targeted next generation sequencing. In summary, this case represents a rare variant of catecholamine-producing tumor with distinct histological features. A potential relationship between the phenotype, the cellular origin and the genetic alterations is discussed., Learning Points: Pheochromocytoma is a rare neuroendocrine tumor.Pigmentation is seen in several types of tumors arising from the neural crest. The macroscopic black aspect can mislead to the diagnosis of a metastasis deriving from a malignant melanoma.RET mutation are seen in catecholamine and non-catecholamine producing tumors of the same cellular origin.
- Published
- 2016
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- View/download PDF
41. Occurrence of phaeochromocytoma tumours in RET mutation carriers - a single-centre study.
- Author
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Kotecka-Blicharz A, Hasse-Lazar K, Jurecka-Lubieniecka B, Pawlaczek A, Oczko-Wojciechowska M, Bugajska B, Ledwon A, Król A, Michalik B, and Jarząb B
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Middle Aged, Multiple Endocrine Neoplasia Type 2a genetics, Pheochromocytoma genetics, Pheochromocytoma metabolism, Proto-Oncogene Mas, Risk, Young Adult, Genetic Predisposition to Disease, Multiple Endocrine Neoplasia Type 2a complications, Mutation, Pheochromocytoma epidemiology, Proto-Oncogene Proteins c-ret genetics
- Abstract
Introduction: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant genetic syndrome caused by germline mutation in RET proto-oncogene. The most common mutations are in a cysteine rich domain. Phaeochromocytoma will develop in approximately 50% of RET proto-oncogene carriers., Material and Methods: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy)., Results: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma., Conclusions: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma.
- Published
- 2016
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- View/download PDF
42. Case of Concurrent MTC and PTC in a Patient with a Germline RET Mutation.
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Shah K, Zena M, Adickes ED, and Anderson RJ
- Subjects
- Base Sequence, Carcinoma genetics, Carcinoma, Neuroendocrine genetics, Carcinoma, Papillary, Humans, Male, Middle Aged, Molecular Sequence Data, Neoplasms, Multiple Primary genetics, Thyroid Cancer, Papillary, Thyroid Neoplasms genetics, Carcinoma pathology, Carcinoma, Neuroendocrine pathology, Germ-Line Mutation, Neoplasms, Multiple Primary pathology, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms pathology
- Published
- 2015
- Full Text
- View/download PDF
43. Overexpression of genes involved in miRNA biogenesis in medullary thyroid carcinomas with RET mutation.
- Author
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Puppin C, Durante C, Sponziello M, Verrienti A, Pecce V, Lavarone E, Baldan F, Campese AF, Boichard A, Lacroix L, Russo D, Filetti S, and Damante G
- Subjects
- Adolescent, Adult, Aged, Carcinoma, Medullary pathology, Child, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mutation, Thyroid Neoplasms pathology, Young Adult, Carcinoma, Medullary genetics, MicroRNAs genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile.
- Published
- 2014
- Full Text
- View/download PDF
44. Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case.
- Author
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Hibi Y, Ohye T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, Mizuno Y, Uchino S, Kosugi S, Kurahashi H, and Iwase K
- Subjects
- Adrenal Gland Neoplasms diagnosis, Adrenal Gland Neoplasms pathology, Adrenal Gland Neoplasms surgery, Adrenalectomy, Calcitonin, Diagnostic Imaging, Female, Humans, Middle Aged, Multiple Endocrine Neoplasia, Multiple Endocrine Neoplasia Type 2a diagnosis, Multiple Endocrine Neoplasia Type 2a pathology, Multiple Endocrine Neoplasia Type 2a surgery, Pedigree, Pheochromocytoma diagnosis, Pheochromocytoma pathology, Pheochromocytoma surgery, Protein Structure, Tertiary genetics, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases genetics, Thyroid Function Tests methods, Thyroid Neoplasms diagnosis, Thyroid Neoplasms pathology, Thyroid Neoplasms surgery, Thyroidectomy, Adrenal Gland Neoplasms genetics, Multiple Endocrine Neoplasia Type 2a genetics, Mutation, Pheochromocytoma genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.
- Published
- 2014
- Full Text
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45. RET mutation and expression in small-cell lung cancer.
- Author
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Dabir S, Babakoohi S, Kluge A, Morrow JJ, Kresak A, Yang M, MacPherson D, Wildey G, and Dowlati A
- Subjects
- Aged, Cell Line, Tumor, Cell Proliferation, DNA Mutational Analysis, Follow-Up Studies, Humans, Immunoblotting, Immunohistochemistry, Lung Neoplasms metabolism, Lung Neoplasms pathology, Proto-Oncogene Proteins c-ret metabolism, Real-Time Polymerase Chain Reaction, Retrospective Studies, Signal Transduction, Small Cell Lung Carcinoma metabolism, Small Cell Lung Carcinoma pathology, Gene Expression Regulation, Neoplastic, Lung Neoplasms genetics, Mutation, Proto-Oncogene Proteins c-ret genetics, RNA, Neoplasm genetics, Small Cell Lung Carcinoma genetics
- Abstract
Background: There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis., Methods: DNA was extracted from six tumors, three primary and three metastatic, and analyzed by SEQUENOM platform technology., Results: Primary-resected tumor tissue represents less than 3% of all diagnostic specimens in this disease, highlighting the limited access to tissue sufficient for comprehensive genomic analyses. We identified an activating M918T RET somatic mutation in a metastatic SCLC tumor specimen. Bioinformatic search identified RET mutations in other SCLC studies. Stable overexpression of both mutant M918T and wild-type RET in two SCLC cell lines, H1048 and SW1271, activated ERK signaling, MYC expression, and increased cell proliferation, particularly by mutant RET. Stable cells became sensitized to the RET tyrosine kinase inhibitors, vandetanib and ponatinib. Further analysis of RET mRNA expression in SCLC revealed wide variability in both cells and tumors, and SCLC cells demonstrated significantly higher RET expression compared with adenocarcinoma lung cells., Conclusions: Our data suggest that a subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. Coupled with the presence of RET fusion proteins in non-small-cell lung cancer, our data indicate an emerging role for RET in SCLC.
- Published
- 2014
- Full Text
- View/download PDF
46. Genome-wide copy number analysis in a family with p.G533C RET mutation and medullary thyroid carcinoma identified regions potentially associated with a higher predisposition to lymph node metastasis.
- Author
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Araujo AN, Moraes L, França MI, Hakonarson H, Li J, Pellegrino R, Maciel RM, and Cerutti JM
- Subjects
- Adult, Aged, Carcinoma, Neuroendocrine, Comparative Genomic Hybridization, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Lymphatic Metastasis, Male, Middle Aged, Young Adult, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology
- Abstract
Context: Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers., Objective: The aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis., Design: Fifteen p.G533C carriers with MTC were chosen for the initial screening. The subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. The results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). The identified CNVs were validated by quantitative PCR in an extended cohort (n = 32)., Results: Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. The validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057)., Conclusion: Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness.
- Published
- 2014
- Full Text
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47. The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma.
- Author
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Qi XP, Zhang RX, Cao JL, Chen ZG, Jin HY, and Yang RR
- Subjects
- Adult, Carcinoma, Medullary genetics, China, Female, Humans, Male, Middle Aged, Pedigree, Proto-Oncogene Mas, Carcinoma genetics, Carcinoma, Medullary congenital, Multiple Endocrine Neoplasia Type 2a genetics, Mutation, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T greater than G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A greater than G (p.A45A), IVS4 + 48A greater than G, c. 1296A greater than G (p.A432A), c. 2071G greater than A (p.G691S), c. 2307T greater than G (p.L769L) and a variant c. 833C greater than A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.
- Published
- 2014
- Full Text
- View/download PDF
48. Clinical spectrum of MEN2A in a large family caused by the infrequent RET mutation Cys609Phe.
- Author
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Oriola J, Biarnes J, Hernandez C, and Simó R
- Subjects
- Adolescent, Adrenal Gland Neoplasms genetics, Adrenal Gland Neoplasms pathology, Adult, Carcinoma genetics, Carcinoma pathology, Carcinoma, Papillary, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia genetics, Multiple Endocrine Neoplasia pathology, Phenotype, Proto-Oncogene Mas, Thyroid Cancer, Papillary, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Young Adult, Multiple Endocrine Neoplasia Type 2a genetics, Mutation, Proto-Oncogene Proteins c-ret genetics
- Abstract
Mutations in RET proto-oncogene cause multiple endocrine neoplasia 2A (MEN2A). Mutations in codons 609 and 611 are not frequent. We identified two MEN2A families with the Cys609Phe RET mutation, which turned out to be the same family. This mutation has been described a couple of times with no clinical details. We have characterized the clinical phenotype of this large kindred. A 54-year-old woman, with a medullary thyroid carcinoma (MTC), and a 33-year-old woman, who was operated on for an adrenal pheochromocytoma, were the index cases. 35 relatives were studied. Sixteen turned out to be carriers and 12 of them have been operated on. This family showed eight patients with C-cell hyperplasia, six patients affected by MTC and two showing pheochromocytoma. A papillary thyroid carcinoma was also found, together with the MTC, in one of the carriers. The phenotype in this large kindred is clearly of MEN2A. In carriers presenting the Cys609Phe mutation, the timing of the presentation of the syndrome is highly unpredictable. Therefore, a strict follow up of MTC must be carried out because of risk, and pheochromocytoma should not be ignored. These results reinforce the scarce data observed on this particular mutation., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
49. The rare intracellular RET mutation p.Ser891Ala in an apparently sporadic medullary thyroid carcinoma: a case report and review of the literature.
- Author
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Blom CB, Ceolin L, Romitti M, Siqueira D, and Maia AL
- Subjects
- Carcinoma, Neuroendocrine, Humans, Male, Middle Aged, Pedigree, Proto-Oncogene Mas, Rare Diseases genetics, Mutation genetics, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms genetics
- Abstract
Medullary thyroid carcinoma (MTC) is a malignant tumor originating from parafollicular C-cells and accounts for 4-10% of all thyroid carcinomas. MTC develops in either sporadic (75%) or hereditary form (25%). Mutations in the RET proto-oncogene are responsible for hereditary MTC and the rate of heritable disease among apparently sporadic MTC (sMTC) cases varies from 6 to 15%. RET genetic testing is now considered fundamental in MTC management but the extent of the molecular analysis required to exclude inherited disease is still controversial. While the screening of all known mutation loci is recommended by some authors, the high costs associated with a full analysis should be also taken into consideration. Here, we illustrate and discuss this controversial issue by reporting a patient who present all characteristic features of sMTC, and in whom a standard genetic analysis by restriction enzyme restriction excluded hereditary disease. Nevertheless, an extensive molecular analysis that included all codons was prompted by the diagnosis of thyroid neoplasm in a patient's sister, and identified the rare intracellular RET p.Ser891Ala mutation.
- Published
- 2012
- Full Text
- View/download PDF
50. Low prevalence of the somatic M918T RET mutation in micro-medullary thyroid cancer.
- Author
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Romei C, Ugolini C, Cosci B, Torregrossa L, Vivaldi A, Ciampi R, Tacito A, Basolo F, Materazzi G, Miccoli P, Vitti P, Pinchera A, and Elisei R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Neuroendocrine, Cell Line, Tumor, DNA Mutational Analysis, Disease Progression, Female, HeLa Cells, Humans, Male, Middle Aged, Prevalence, Thyroid Neoplasms epidemiology, Treatment Outcome, Point Mutation, Proto-Oncogene Proteins c-ret genetics, Thyroid Neoplasms diagnosis, Thyroid Neoplasms genetics
- Abstract
Background: The prevalence of RET somatic mutations in sporadic medullary thyroid cancer (MTCs) is ∼40%-50%, and the most frequent somatic mutation is M918T. RET-positive MTCs have been demonstrated to have a more advanced stage at diagnosis and a worse outcome., Aims: The aim of the present work was to compare the prevalence of RET somatic mutations in sporadic microMTCs (<1 cm) and in larger MTCs., Patients: We analyzed the M918T RET point mutation in 160 sporadic MTC cases. Tumors were classified according to their size: group A, <1 cm; group B, >1 and <2 cm; group C, >2 and <3 cm; and group D, >3 cm., Results: The overall prevalence of the somatic M918T RET mutation was 19.4% (31/160). RET mutations were distributed differently among the four groups. The prevalence was 11.3% (6/53) in group A, 11.8% (8/68) in group B, 31.8% (7/22) in group C, and 58.8% (10/17) in group D, exhibiting an increase with increasing size of the tumor. When comparing the prevalence of mutations in the four groups, we found a lower prevalence in microMTCs (p<0.0001)., Conclusions: The overall prevalence of RET somatic mutations was lower than expected, and the prevalence of the somatic M918T RET mutation was significantly lower in microMTCs than in larger tumors. To explain this finding, we can hypothesize either that other oncogene(s) might be responsible for the majority of microMTC, thus identifying a tumor subset, or that the RET mutation might, or might not, occur later during tumor progression.
- Published
- 2012
- Full Text
- View/download PDF
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