ret mutation
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2021 ◽  
Vol 37 (2) ◽  
pp. 1-9
Author(s):  
Seonyoung Min ◽  
Hyunseok Kang

Thyroid cancer refers to various cancers arising from thyroid gland. Differentiated thyroid cancers (DTCs) include papillary, follicular, and Hurthle cell carcinomas and represent cancers retain normal thyroid functions such as iodine uptake. Radioactive iodine (RAI) is generally used for upfront treatment of metastatic DTCs, but RAI refractory DTCs remain to be clinical challenges. Sorafenib and lenvatinib were approved for the treatment of RAI refractory DTCs and more recently, genomics-based targeted therapies have been developed for NTRK and RET gene fusion-positive DTCs. Poorly differentiated and anaplastic thyroid cancers (ATCs) are extremely challenging diseases with aggressive courses. BRAF/MEK inhibition has been proven to be highly effective in BRAF V600E mutation-positive ATCs and immune checkpoint inhibitors have shown promising activities. Medullary thyroid cancers, which arise from parafollicular cells of thyroid, represent a unique subset of thyroid cancer and mainly driven by RET mutation. In addition to vandetanib and cabozantinib, highly specific RET inhibitors such as selpercatinib and pralsetinib have demonstrated impressive activity and are in clinical use.


Author(s):  
Shihong Ma ◽  
Hui Wang ◽  
Wanling Li ◽  
Zhe Yan ◽  
Xuanming Luo ◽  
...  

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.


Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5554
Author(s):  
Alessandro Prete ◽  
Antonio Matrone ◽  
Carla Gambale ◽  
Valeria Bottici ◽  
Virginia Cappagli ◽  
...  

Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.


2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Elia Damavandi ◽  
Fatemeh Vand-Rajabpour ◽  
Maliheh Javadi-Arjmand ◽  
Mohammad-Reza Mohajeri Tehrani ◽  
Bagher Larijani ◽  
...  

Background. The aim of this study was to identify germline mutation of the RET (rearranged during transfection) gene in patients with medullary thyroid carcinoma (MTC) and their first-degree relatives to find presymptomatic carriers for possible prophylactic thyroidectomy. Methods/Patients. We examined all six hot spot exons (exons 10, 11, 13, and 14–16) of the RET gene by PCR and bidirectional Sanger sequencing in 45 Iranian patients with MTC (either sporadic or familial form) from 7 unrelated kindred and 38 apparently sporadic cases. First-degree relatives of RET positive cases were also genotyped for index mutation. Moreover, presymptomatic carriers were referred to the endocrinologist for further clinical management and prophylactic thyroidectomy if needed. Results. Overall, the genetic status of all of the participants was determined by RET mutation screening, including 61 affected individuals, 22 presymptomatic carriers, and 29 genetically healthy subjects. In 37.5% (17 of 45) of the MTC referral index patients, 8 distinct RET germline mutations were found, including p.C634R (35.3%), p.M918T (17.6%), p.C634Y (11.8%), p.C634F (5.9%), p.C611Y (5.9%), p.C618R (5.9%), p.C630R (5.9%), p.L790F (5.9%), and one uncertain variant p.V648I (5.9%). Also, we found a novel variant p.H648R in one of our apparently sporadic patients. Conclusion. RET mutation detection is a promising/golden screening test and provides an accurate presymptomatic diagnostic test for at-risk carriers (the siblings and offspring of the patients) to consider prophylactic thyroidectomy. Thus, according to the ATA recommendations, the screening of the RET proto-oncogene is indicated for patients with MTC.


2021 ◽  
Vol 146 (23) ◽  
pp. 1527-1532
Author(s):  
Matthias Kroiss ◽  
Viktoria Florentine Köhler ◽  
Christine Spitzweg

Was ist neu? Diagnose und Prognose Calcitonin ist ein sensitiver und spezifischer Tumormarker zur Früherkennung und Verlaufskontrolle des MTC. Daneben kommt dem Ultraschall der Schilddrüse eine entscheidende Rolle zu. Rolle des RET-Proto-Onkogens Das medulläre Schilddrüsenkarzinom (MTC) nimmt seinen Ursprung aus den parafollikulären Calcitonin-produzierenden C-Zellen. Es macht nur ca. 3–8 % aller Schilddrüsenkarzinome aus. Aktivierende Mutationen im RET (rearranged during transfection)-Gen liegen bei etwa 25 % der Patienten in der Keimbahn vor, werden aber auch beim sporadischen MTC als somatische Mutationen in ca. 60 % der Fälle beobachtet. Bei metastasierter Erkrankung findet sich in 90 % eine RET-Mutation. RET-Mutationen gelten als Treibermutationen und schließen weitere Treibermutationen weitestgehend aus. Seltener sind somatische Mutationen der RAS-Gene. Chirurgische Therapie Die chirurgische Resektion ist bis heute der einzige kurative Therapieansatz. Entscheidend für eine frühzeitige Diagnosestellung ist die Bestimmung des Serum-Calcitonins bei Nachweis von Schilddrüsenknoten. Die chirurgische Therapie steht auch bei der Behandlung lokoregionärer Rezidive oder lokal angehbarer Metastasen im Zentrum. Systemtherapie Bei irresektabel fortgeschrittener und progredienter Erkrankung mit signifikanter Tumorlast kann eine systemische Therapie erforderlich werden. Neuerdings ist die Kenntnis einer RET-Mutation im Tumorgewebe therapeutisch relevant, da mit den selektiven RET-Inhibitoren Selpercatinib und zukünftig Pralsetinib neue, effektive und gut verträgliche Systemtherapien zur Verfügung stehen. Ihr Einsatz ist nach Vortherapie mit einem der Multityrosinkinase-Inhibitoren Vandetanib oder Cabozantinib zugelassen und wird derzeit in der Erstlinientherapie in klinischen Studien untersucht.


Medicine ◽  
2021 ◽  
Vol 100 (22) ◽  
pp. e26230
Author(s):  
Yan Li ◽  
Ya-qin Tan ◽  
Zhi-xiang Tang ◽  
Qing-hui Liao ◽  
Zhong-qiu Guo ◽  
...  

2021 ◽  
Vol 24 (5) ◽  
pp. 54-54
Author(s):  
Silke Wedekind
Keyword(s):  

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A994-A994
Author(s):  
Bhavana Konda ◽  
Erminia Massarelli ◽  
Jennifer Wright ◽  
Victoria Soldatenkova ◽  
Roderick Clifton-Bligh

Abstract Activating RET gene alterations have been reported in solid tumors including the rare cancer, pheochromocytoma (PHEO) found sporadically and in familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a highly selective and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-altered solid tumors. Described are the initial 3 PHEO patients treated with selpercatinib (LIBRETTO-001/NCT03157128). Case 1: 70-year-old white male with MEN2A and a history of medullary thyroid cancer (MTC) and PHEO s/p thyroidectomy and adrenalectomy, received MIBG in 1991 and 2016 due to symptom reoccurrence. Progressive metastatic disease associated with severe hypertension was treated with Lutate in 2017 and germline RET mutation p.Cys634Phe was confirmed. After developing severe back pain due to a T6 vertebral metastasis, he began selpercatinib treatment. As of Mar 2020, he has a partial response (PR) as assessed by investigator; his back pain resolved, normetanephrine and metanephrine levels decreased, and has ceased alpha and beta blockers. He remains on treatment with only grade 1-2 adverse events, none requiring interruption or dose modification. Case 2: 51-year-old white female with MEN2A and history of MTC and PHEO s/p thyroidectomy and adrenalectomy in 2010. She developed metastatic PHEO in 2013, with multiple bone, omentum, lung, liver, and spleen metastases. Between 2013 and 2018 she was treated with multiple courses of radiation and, additional surgical resections; a PR with sunitinib lasted 13 months followed by temozolomide/capecitabine treatment. A bone lesion biopsy in 2018 confirmed RET C618S mutation and with her disease progression and uncontrolled bone pain, she began selpercatinib treatment, experiencing a PR. After 5.5 months in the study, she discontinued treatment due to disease progression. Case 3: 45-year-old African American female diagnosed with sporadic PHEO in 1996, s/p multiple surgical resections. She received 2 cycles of cyclophosphamide/vincristine/dacarbazine without clinical benefit. I-131-MIBG therapy with autologous stem cell rescue in 2017 improved blood pressure, palpitations, and flushing but without tumor shrinkage while abdominal pain persisted. Somatic M918T RET-mutation was confirmed, and she began selpercatinib treatment in 2018 with symptom resolution and improved plasma metanephrine levels. She required dose reduction for grade 3 palmar-plantar erthrodysesthesia and had stable disease for 22 months until a new bone metastasis was identified. Due to ongoing clinical benefit, she remains on treatment despite disease progression. Conclusion: These are the initial reports of RET-mutant PHEO patients treated with selpercatinib adding to the diversity of RET-altered tumor types that may benefit from a selective RET inhibitor.


2021 ◽  
Vol 62 (2) ◽  
pp. 110-119
Author(s):  
Sara Milićević ◽  
Damijan Bergant ◽  
Tina Žagar ◽  
Barbara Perić

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