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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 and 44% both). Common physician-cited barriers to RET mutation testing included high cost, difficulty accessing the 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 a substantial disease/treatment burden. Conclusion: Patients with aMTC report a substantial disease/treatment burden. Outcomes could be improved by identifying patients eligible for treatment with selective RET inhibitors through more optimal RET mutation testing.

RET somatic mutation analysis in sporadic MTC should be guided by postoperative evaluation results.

ObjectiveTo determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study.MethodsRetrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups.ResultsGenetic 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).ConclusionThis 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.

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. Key words: medullary thyroid carcinoma, ATF4, PCT, RET mutation, recurrence, survival. Cette etude portait sur le lien entre l'expression d'ATF4 et de PCT combinees a la mutation de RET avec la stadification pathologique et le pronostic clinique du cancer medullaire de la thyroide sporadique (CMTS). Nous avons recueilli 50 cas (tissu tumoral) de CMTS diagnostique de maniere clinicopathologique et selectionne des patients atteints de goitre nodulaire en tant que temoins normaux. Nous avons etudie le site de mutation de RET a l'aide d'un kit de detection et l'expression de PCT et d'ATF4 dans le CMTS a l'aide de l'immunobuvardage de Western et de l'immunohistochimie. A l'aide de regressions lineaires multiples, nous avons etudie le lien entre des facteurs de risque (expression de PCT ou d'ATF4, mutation de RET, differentiation tumorale, stade du CMTS, metastases lymphatiques) et la recidive et la survie a 5 ans pour les CMTS. L'expression d'ATF4 et de PCT presentaient respectivement une diminution et une augmentation notables avec la hausse du stade du CMTS. La mutation du gene RET la plus frequente dans le tissu tumoral etait M 22458A dans l'exon 16. L'expression d'ATF4 et de PCT de meme que les mutations de RET etaient associees de facon notable avec la recidive a 5 ans, tandis que l'expression d'ATF4 etait liee de facon marquee a une meilleure survie a 5 ans. En conclusion, l'expression d'ATF4 et de PCT associees a une mutation de RET sont liees au pronostic clinique du CMTS et peuvent permettre de prevoir le stade du CMTS. [Traduit par la Redaction] Mots-des: cancer medullaire de la thyroide, ATF4, PCT, mutation de RET, recidive, survie., Introduction Medullary thyroid carcinoma (MTC) is a common clinical malignant tumor in the endocrine system, which originates from parafollicular cells of the thyroid (also known as C cell) (Daniels 2018). [...]

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.

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.

Objective To explore clinical and genetic manifestation of pheochromocytoma patients with RET gene mutation. Methods Clinical data, laboratory examination results and RET gene mutations of 23 pheochromocytoma patients with RET mutation treated in Peking Union Medical College Hospital from 2013 to 2019 were retrospectively analyzed. Results The diagnosis age of pheochromocytoma in 23 patients was 32±10 years. In 22 patients with multiple endocrine neoplasia (MEN) 2A, mutations were clustered in exon 16 (18 cases), especially in codon 634 (16 cases), followed by exon 10 and 14, and one patient with MEN2B had M918T in exon 16. Among the 23 patients, 9 had paroxysmal hypertension, 5 had sustained hypertension, 3 were normotensive, and 6 had episodic palpitations but their blood pressures were not measured during the attacks. 24 h urinary catecholamine excretion was as following: norepinephrine (NE): 65.8 (36.9,235.9) μg/24 h, Epinephrine (E): 5.4 (2.8, 37.2) μg/24 h and Dopamine (DA): 277 (198, 297) μg/24 h. 15 patients had abnormally increased NE, E or DA, while 8 patients had normal catecholamine excretion. The median diameter of the tumors was 4 (3, 6) cm. Fifteen patients had bilateral pheochromocytoma and 17 had medullary thyroid carcinoma. Conclusions Pheochromocytoma patients with RET mutation are consistent with those reported in western countries in terms of age at diagnosis, tumor size and mutation profile. Most patients have paroxysmal hypertension or normal pressure, and some of them have normal urinary catecholamine excretion, which are potential risk factors of missed diagnosis.

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.)

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.

Mechanisms of acquired resistance to RET tyrosine kinase inhibitors in lung cancers are largely unknown. Here, the authors report in a lung adenocarcinoma patient harboring a CCDC6-RET mutation in the RET kinase (S904F) that results in resistance to the kinase inhibitor vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase.

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 RETM918T mutation and expressed pluripotency hallmarks. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice.

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.

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. RETC634Y-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.

Byline: Roopa. Vijayan, Vasantha. Nair, Usha. Menon, Harish. Kumar Familial medullary thyroid carcinoma (FMTC) is a variant of multiple endocrine neoplasia type 2 (MEN2) associated with the RET gene mutation. [...]

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.)