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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.


Medullary thyroid cancer or MTC is present in sporadic form (75% of cases) and in familial form (25% of cases), in this latter situation, the MTC is a part of Multiple Endocrine Neoplasia type 2 (MEN 2). The MEN2 is divided into MEN2A, MEN2B and FMTC or isolated familial MTC. The MEN2 are rare hereditary disease, transmitted as an autosomal dominant mode, linked to mutations of the RET gene. The discovery of a mutation in the RET proto-oncogene by molecular biology techniques in a index case of MTC confirms the diagnosis of familial and allows the genetic testing of healthy clinically related index case: those who carry the genetic mutation, will be offered prophylactic thyroidectomy before any biological or clinical manifestation. The genetic analysis of the RET gene was performed by PCR / sequencing. The E768D mutation was found in the exon 13 of the RET gene in 2 differences sequences forms (GAG/GAC et GAG/GAT). This mutation, already described, found in the FMTC.


Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1542
Author(s):  
Chiara Mulè ◽  
Raffaele Ciampi ◽  
Teresa Ramone ◽  
Alessandro Prete ◽  
Antonio Matrone ◽  
...  

This study was designed to investigate whether RET (rearranged during transfection) mRNA over-expression could be considered an alternative driver event for the development of medullary thyroid carcinoma (MTC), and if different RET isoforms could play a role in MTC tumorigenesis. Eighty-three MTC patients, whose mutational profile was previously identified by next-generation sequencing (NGS) IONS5, were included in this study. Expression analysis was performed by the quantitative reverse transcription-polymerase chain reaction technique. RET expression levels were found to be significantly higher in cases with RET somatic mutations than in cases that were negative for RET somatic mutations (p = 0.003) as well as in cases with a somatic mutation, either in RET or RAS than in cases negative for both these mutations (p = 0.01). All cases were positive for the RET51 isoform expression while only 72/83 (86.7%) were positive for RET9 isoform expression. A statistically significant higher expression of the RET51 isoform was found in cases positive for RET somatic mutation than in cases either positive for RAS mutation (p = 0.0006) or negative for both mutations (p = 0.001). According to our data, RET gene over-expression does not play a role in MTC tumorigenesis, neither as an entire gene or as an isoform. At variance, the RET gene, and in particular the RET51 isoform, is expressed higher in RET mutated cases. On the basis of these results we can hypothesize that the overexpression of RET, and in particular of RET51, could potentiate the transforming activity of mutated RET, making these cases more aggressive.


Author(s):  
Sudheer Menon

Hirschsprung is a birth defect of Enteric Nervous System (ENS) which is characterized by the absence of enteric neurons along the length of intestine. Hirschsprung is one of the complex diseases which has become a important topic of human genetics. In this article we have focused on RET gene mutation that is most common cause of HSCR disease. Out of seven mutations in RET gene, one mutation S339L is found to be tolerated and have no effect on protein function.


2021 ◽  
Author(s):  
Paola Silvestri ◽  
Antonio Pizzuti ◽  
Paolo Rinaldi ◽  
Veronica Giansanti ◽  
Giusy Russo ◽  
...  

Abstract Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder characterized by a failure in physiologic autonomic control of breathing resulting in apnoea, hypoxemia, and hypoventilation episodes, associated to a large spectrum of autonomic nervous system dysfunctions. Despite this condition is most likely caused by mutations in the PHOX2B gene, other genes have been found responsible for CCHS in rare cases. Case report: We report a 15-month-old toddler presenting episodes of central and obstructive apnoea with cyanosis, hypertonia, hypercapnia, and cyanotic breath-holding spells. The CCHS diagnosis was supported by central desaturating apnoea/hypopneas episodes during rapid eye movement sleep and obstructive apnoea in polysomnography, as well as by the presence of hypoxia and hypercapnia in arterial blood gas during critical episodes. Autonomic dysregulation with sporadic profuse sweating and gastrointestinal dysmotility resulting in gastro-oesophageal reflux and chronic constipation were also associated. Next Generation Sequencing revealed the missense variant p.Met918Thr in the RET gene.Conclusion: This case, identifying a de novo pathogenic variant in the RET gene, highlights the importance of using clinical exome sequencing or a panel of genes associated with the specific disease, rather than looking for mutations in the single most frequently correlated gene.


2021 ◽  
pp. clincanres.0967.2021
Author(s):  
Janice Kim ◽  
Diana Bradford ◽  
Erin Larkins ◽  
Lee H. Pai-Scherf ◽  
Somak Chatterjee ◽  
...  

2021 ◽  
pp. 102359
Author(s):  
Zhifei Xu ◽  
Dandi Ma ◽  
Yunxiao Wu ◽  
Liang Wang ◽  
Yuanjie Zhang ◽  
...  
Keyword(s):  

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Leylah M. Drusbosky ◽  
Estelamari Rodriguez ◽  
Richa Dawar ◽  
Chukwuemeka V. Ikpeazu

AbstractThe recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1–2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.


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