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1
Chatterjee, Sumantra, Kameko M. Karasaki, Lauren E. Fries, Ashish Kapoor, and Aravinda Chakravarti. "A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease." Genome Research 31, no. 12 (November 15, 2021): 2199–208. http://dx.doi.org/10.1101/gr.275667.121.
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The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis-regulatory elements (CREs) of the receptor tyrosine kinase gene RET, which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce RET gene expression, and dysregulate other ENS and HSCR genes in the RET–EDNRB gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate RET CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect RET gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on RET gene expression. These, coupled with our prior results, show that common sequence variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting RET gene expression, extending the known RET–EDNRB GRN to reveal an extensive regulatory code modulating disease risk at a single gene.
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&NA;. "Germline mutation of RET gene." Advances in Anatomic Pathology 2, no. 3 (May 1995): 187. http://dx.doi.org/10.1097/00125480-199505000-00030.
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Gou, Qitao, Xiaochuan Gan, Longhao Li, Qiheng Gou, and Tao Zhang. "Precious Gene: The Application of RET-Altered Inhibitors." Molecules 27, no. 24 (December 13, 2022): 8839. http://dx.doi.org/10.3390/molecules27248839.
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The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy.
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Schoffski, Patrick, Philippe Georges Aftimos, Christophe Massard, Antoine Italiano, Christiane Jungels, Karen Andreas, Mitchell Keegan, and Peter T. C. Ho. "A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS3162. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps3162.
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TPS3162 Background: RET gene alterations (mutations and fusions) leading to constitutive kinase activity have been identified in various tumor types including non-small cell lung cancer (NSCLC), medullary thyroid (MTC), colon, breast and ovarian cancer. The current generation of multi-kinase inhibitors approved for treatment of such tumors, do not selectively target RET and exhibit significant off-target activity especially against vascular endothelial growth factor receptor 2 (VEGFR2), resulting in dose-limiting toxicities that prevent the full inhibition of RET in those tumors. Recently, early clinical data from a class of more selective RET inhibitors have shown promising results with a more favorable safety profile in patients with RET alterations. BOS172738 is a novel RET inhibitor with nanomolar potency against RET and approximately 300-fold selectivity against VEGFR2. This phase 1 study is assessing the safety and tolerability of BOS172738 in patients with advanced solid tumors with RET alterations. Methods: NCT03780517 is a phase 1, open label, multicenter, dose escalation trial to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BOS172738, an orally dosed RET kinase inhibitor, in patients with advanced solid tumors with RET gene alterations. RET gene alteration status will be assessed locally but confirmed centrally. The study is comprised of 2 parts: in Part A (dose escalation), patients with advanced solid tumors with RET gene alterations will receive BOS172738 orally once daily in each 28-day cycle. Select patients in Part A are eligible for intrapatient dose escalation. On establishing the recommended phase 2 dose (RP2D), Part B (expansion) will enroll up to an additional 60 patients to 1 of 3 tumor type-specific cohorts. The 3 expansion cohorts will each consist of up to 20 advanced cancer patients with: 1) RET gene-fusion NSCLC; 2) RET gene-mutant MTC; and 3) other RET gene-altered advanced tumors or NSCLC/MTC with prior specific RET gene-targeted therapy. Patients in expansion cohorts will receive BOS172738 daily at the RP2D until disease progression or other discontinuation criteria have been met. The study is currently open to enrollment globally with the first patient entered in 01/2019. Clinical trial information: NCT03780517.
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Sijmons, R. H., R. M. W. Hofstra, F. A. Wijburg, T. P. Links, R. P. Zwierstra, A. Vermey, D. C. Aronson, et al. "Oncological implications of RET gene mutations in Hirschsprung’s disease." Gut 43, no. 4 (October 1, 1998): 542–47. http://dx.doi.org/10.1136/gut.43.4.542.
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Background—Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5–5% of sporadic and familial cases of Hirschsprung’s disease. Some patients with Hirschsprung’s disease may therefore be exposed to a highly increased risk of tumours.Aims—To define clinical use of RET gene testing in Hirschsprung’s disease and related patient management from an oncological point of view.Methods—Sixty patients with Hirschsprung’s disease were screened for RET mutations. In three, MEN2A type RET mutations were detected. Case reports for these three patients are presented.Results and conclusions—Only 22 families or sporadic patients with Hirschsprung’s disease and MEN2A type RET mutations have been reported. Therefore, it is difficult to predict tumour risk for patients with familial or sporadic Hirschsprung’s disease, and their relatives, who carry these mutations. For these mutation carriers, periodic screening for tumours as in MEN2A is advised, but prophylactic thyroidectomy is offered hesitantly. RET gene testing in familial or sporadic Hirschsprung’s disease is not recommended at present outside a complete clinical research setting. In combined MEN2A/Hirschsprung’s disease families RET gene testing, tumour screening, and prophylactic thyroidectomy are indicated as in MEN2A.
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Ramone, Teresa, Chiara Mulè, Raffaele Ciampi, Valeria Bottici, Virginia Cappagli, Alessandro Prete, Antonio Matrone, et al. "RET Copy Number Alteration in Medullary Thyroid Cancer Is a Rare Event Correlated with RET Somatic Mutations and High Allelic Frequency." Genes 12, no. 1 (December 29, 2020): 35. http://dx.doi.org/10.3390/genes12010035.
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Copy number variations (CNV) of the RET gene have been described in 30% of Medullary Thyroid Cancer (MTC), but no information is available about their role in this tumor. This study was designed to clarify RET gene CNV prevalence and their potential role in MTC development. RET gene CNV were analyzed in 158 sporadic MTC cases using the ION Reporter Software (i.e., in silico analysis) while the multiplex ligation-dependent probe amplification assay (i.e., in vitro analysis) technique was performed in 78 MTC cases. We identified three categories of RET ploidy: 137 in 158 (86.7%) cases were diploid and 21 in 158 (13.3%) were aneuploid. Among the aneuploid cases, five out of 21 (23.8%) showed an allelic deletion while 16 out of 21 (76.2%) had an allelic amplification. The prevalence of amplified or deleted RET gene cases (aneuploid) was higher in RET positive tumors. Aneuploid cases also showed a higher allelic frequency of the RET driver mutation. The prevalence of patients with metastatic disease was higher in the group of aneuploid cases while the higher prevalence of disease-free patients was observed in diploid tumors. A statistically significant difference was found when comparing the ploidy status and mortality. RET gene CNVs are rare events in sporadic MTC and are associated with RET somatic mutation, suggesting that they could not be a driver mechanism of tumoral transformation per se. Finally, we found a positive correlation between RET gene CNV and a worse clinical outcome.
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Kim, Jeong-Oh, Jung-Young Shin, Min Young Kim, Kyoung Hwa Son, Chan-Kwon Jung, Tae-Jung Kim, Su Young Kim, et al. "Coexistence of rearranged during transfection (RET) variants and activating EGFR mutations with their molecular implications in lung adenocarcinomas." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20610-e20610. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20610.
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e20610 Background: RET rearrangements have been identified in 1-2% of lung adenocarcinomas. The most common fusion is the KIF5B-RET, the function and roles of the RET fusion oncogene, and its downstream signaling molecules remain unclear. Methods: We constructed a tissue microarray (TMA) comprising 581 resected tumor tissues from lung adenocarcinoma patients and investigated them using FISH with RET break-apart and KIF5B-RET SY translocation probes. NanoString’s nCounter technology was used to assay RETtranscripts. We evaluated the protein expressions of RET and RET-related signaling molecules, including p-AKT and p-ERK, using TMA-based IHC staining. Results: Using FISH, we identified 51 cases (8.8%) of RET variants and 10 cases (1.7%) of KIF5B-RET fusion genes among the 581 cases. RET protein expression was lower in the group harboring KIF5B-RET fusion gene than that in the group harboring a wild type RET gene. We found the activating EGFR mutations in 11 (21.6%) cases of 51 RET variants. For the group with KIF5B-RET fusion gene, the expression of p-ERK was significantly lower in EGFR mutation subgroup with presence of RET protein compared to EGFR mutation subgroup with absence of RET protein. For the group with RET rearrangement, there were significant differences in the expression level of p-AKT (P = 0.028) and, p-ERK protein expression was remarkably increased, especially in cases with no RET protein expression. Conclusions: Taken together, the expression of p-ERK protein was meaningfully increased in the RET variants group regardless of RET protein expression. This result suggests that RET inhibitors combined with ERK inhibitors may be an effective treatment strategy for lung adenocarcinoma patients harboring the RET variants.
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Ciampi, Raffaele, Thomas J. Giordano, Kathryn Wikenheiser-Brokamp, Ronald J. Koenig, and Yuri E. Nikiforov. "HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma." Endocrine-Related Cancer 14, no. 2 (June 2007): 445–52. http://dx.doi.org/10.1677/erc-07-0039.
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Chromosomal rearrangements of the RET proto-oncogene (RET/PTC) are the common feature of papillary thyroid carcinoma (PTC). In this study, we report the identification, cloning, and functional characterization of a novel type of RET/PTC rearrangement that results from the fusion of the 3′-portion of RET coding for the tyrosine kinase (TK) domain of the receptor to the 5′-portion of the Homo sapiens hook homolog 3 (HOOK3) gene. The novel fusion was identified in a case of PTC that revealed a gene expression signature characteristic of RET/PTC on DNA microarray analysis, but was negative for the most common types of RET rearrangement. A fusion product between exon 11 of HOOK3 and exon 12 of RET gene was identified by 5′RACE, and the presence of chimeric HOOK3-RET protein of 88 kDa was detected by western blot analysis with an anti-RET antibody. The protein is predicted to contain a portion of the coiled-coil domains of HOOK3 and the intact TK domain of RET. Expression of the HOOK3-RET cDNA in NIH3T3 cells resulted in the formation of transformed foci and in tumor formation after injection into nude mice, confirming the oncogenic nature of HOOK3-RET.
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Takahashi, M., and G. M. Cooper. "ret transforming gene encodes a fusion protein homologous to tyrosine kinases." Molecular and Cellular Biology 7, no. 4 (April 1987): 1378–85. http://dx.doi.org/10.1128/mcb.7.4.1378-1385.1987.
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The ret transforming gene was activated by recombination between two unlinked segments of human DNA, most likely during transfection of NIH 3T3 cells. To further define this transforming gene, we isolated and sequenced ret cDNA clones. The nucleotide sequence indicates that the active ret transforming gene encodes a fusion protein with a carboxy-terminal domain which is 40 to 50% homologous to members of the tyrosine kinase gene family. This tyrosine kinase domain is preceded by a hydrophobic sequence characteristic of a transmembrane domain. Transcription of the ret tyrosine kinase sequence was detected in the SK-N-SH neuroblastoma, HL-60 promyelocytic leukemia, and THP-1 monocytic leukemia cell lines, but not in 25 other human tumor cell lines surveyed. The ret tyrosine kinase may thus represent a cell surface receptor which is expressed in a restricted range of human cells.
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Takahashi, M., and G. M. Cooper. "ret transforming gene encodes a fusion protein homologous to tyrosine kinases." Molecular and Cellular Biology 7, no. 4 (April 1987): 1378–85. http://dx.doi.org/10.1128/mcb.7.4.1378.
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The ret transforming gene was activated by recombination between two unlinked segments of human DNA, most likely during transfection of NIH 3T3 cells. To further define this transforming gene, we isolated and sequenced ret cDNA clones. The nucleotide sequence indicates that the active ret transforming gene encodes a fusion protein with a carboxy-terminal domain which is 40 to 50% homologous to members of the tyrosine kinase gene family. This tyrosine kinase domain is preceded by a hydrophobic sequence characteristic of a transmembrane domain. Transcription of the ret tyrosine kinase sequence was detected in the SK-N-SH neuroblastoma, HL-60 promyelocytic leukemia, and THP-1 monocytic leukemia cell lines, but not in 25 other human tumor cell lines surveyed. The ret tyrosine kinase may thus represent a cell surface receptor which is expressed in a restricted range of human cells.
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Kucharczyk, Tomasz, Paweł Krawczyk, Dariusz M. Kowalski, Adam Płużański, Tomasz Kubiatowski, and Ewa Kalinka. "RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy." Cancers 14, no. 21 (October 27, 2022): 5298. http://dx.doi.org/10.3390/cancers14215298.
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Mutations and fusions of RET (rearranged during transfection) gene are detected in a few common types of tumors including thyroid or non-small cells lung cancers. Multiple kinase inhibitors (MKIs) do not show spectacular effectiveness in patients with RET-altered tumors. Hence, recently, two novel RET-specific inhibitors were registered in the US and in Europe. Selpercatinib and pralsetinib showed high efficacy in clinical trials, with fewer adverse effects, in comparison to previously used MKIs. However, the effectiveness of these new drugs may be reduced by the emergence of resistance mutations in RET gene and activation of different activating signaling pathways. This review presents the function of the normal RET receptor, types of molecular disturbances of the RET gene in patients with various cancers, methods of detecting these abnormalities, and the effectiveness of modern anticancer therapies (ranging from immunotherapies, through MKIs, to RET-specific inhibitors).
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Subbiah, Vivek, Dong Yang, Vamsidhar Velcheti, Alexander Drilon, and Funda Meric-Bernstam. "State-of-the-Art Strategies for Targeting RET-Dependent Cancers." Journal of Clinical Oncology 38, no. 11 (April 10, 2020): 1209–21. http://dx.doi.org/10.1200/jco.19.02551.
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Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non–small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.
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Wang, Rui, Haichuan Hu, Yunjian Pan, Yuan Li, Ting Ye, Chenguang Li, Xiaoyang Luo, et al. "RET Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 30, no. 35 (December 10, 2012): 4352–59. http://dx.doi.org/10.1200/jco.2012.44.1477.
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Purpose The RET fusion gene has been recently described in a subset of non–small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene. Patients and Methods We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected. Results Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months. Conclusion RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.
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Chatterjee, Sumantra, and Aravinda Chakravarti. "A gene regulatory network explains RET–EDNRB epistasis in Hirschsprung disease." Human Molecular Genetics 28, no. 18 (July 17, 2019): 3137–47. http://dx.doi.org/10.1093/hmg/ddz149.
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Abstract Disruptions in gene regulatory networks (GRNs), driven by multiple deleterious variants, potentially underlie complex traits and diseases. Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We previously demonstrated that RET transcription in the ENS is controlled by an extensive GRN involving the transcription factors (TFs) RARB, GATA2 and SOX10 and other HSCR genes. We now demonstrate, using human and mouse cellular and animal models, that EDNRB is transcriptionally regulated in the ENS by GATA2, SOX10 and NKX2.5 TFs. Significantly, RET and EDNRB expression is regulated by their shared use of GATA2 and SOX10, and in turn, these TFs are controlled by EDNRB and RET in a dose-dependent manner. This study expands the ENS development GRN to include both RET and EDNRB, uncovers the mechanistic basis for RET–EDNRB epistasis and emphasizes how functionally different genes associated with a complex disorder can be united through a common GRN.
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Mulè, Chiara, Raffaele Ciampi, Teresa Ramone, Alessandro Prete, Antonio Matrone, Virginia Cappagli, Liborio Torregrossa, Fulvio Basolo, Rossella Elisei, and Cristina Romei. "Higher RET Gene Expression Levels Do Not Represent anAlternative RET Activation Mechanism in Medullary Thyroid Carcinoma." Biomolecules 11, no. 10 (October 19, 2021): 1542. http://dx.doi.org/10.3390/biom11101542.
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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.
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Gao, Yuan, Bizhi Huang, Fuxia Bai, Fei Wu, Zihui Zhou, Zhenyu Lai, Shipeng Li, et al. "Two Novel SNPs in RET Gene Are Associated with Cattle Body Measurement Traits." Animals 9, no. 10 (October 21, 2019): 836. http://dx.doi.org/10.3390/ani9100836.
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The rearrangement of the transfection (RET) gene, which mediates the functions of the ganglion in the gastrointestinal tract, plays an important role in the development of the gastrointestinal nervous system. Therefore, the RET gene is a potential factor influencing animal body measurement. The aim of this study was to reveal the significant genetic variations in the bovine RET gene and investigate the relationship between genotypes and body measurement in two Chinese cattle breeds (Qinchuan and Nanyang cattle). In this study, two SNPs (c.1407A>G and c.1425C>G) were detected in the exon 7 of RET gene by sequencing. For the SNP1 and SNP2, the GG genotype was significantly associated with body height, hip height, and chest circumference in Qinchuan cattle (p < 0.05). Individuals with an AG-CC genotype showed the lowest value of all body measurement in both breeds. Our results demonstrate that the polymorphisms in the bovine RET gene were significantly associated with body measurement, which could be used as DNA marker on the marker-assisted selection (MAS) and improve the performance of beef cattle.
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Siaw, Joachim T., Jonatan L. Gabre, Ezgi Uçkun, Marc Vigny, Wancun Zhang, Jimmy Van den Eynden, Bengt Hallberg, Ruth H. Palmer, and Jikui Guan. "Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells." Cancers 13, no. 8 (April 15, 2021): 1909. http://dx.doi.org/10.3390/cancers13081909.
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Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.
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Cheung, Carol C., Bessie Carydis, Shereen Ezzat, Yvan C. Bedard, and Sylvia L. Asa. "Analysis of ret/PTC Gene Rearrangements Refines the Fine Needle Aspiration Diagnosis of Thyroid Cancer." Journal of Clinical Endocrinology & Metabolism 86, no. 5 (May 1, 2001): 2187–90. http://dx.doi.org/10.1210/jcem.86.5.7504.
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Papillary carcinoma (PC) represents the most common malignancy of the thyroid gland. Therefore, the assessment of fine needle aspiration biopsies of thyroid nodules rests heavily on the identification of nuclear features of PC. The ret/PTC oncogene, formed by several gene rearrangements, is specific for PC among thyroid tumors. In this study we examined thyroid aspirates for the presence of ret/PTC gene rearrangements by RT-PCR and Southern hybridization. We prospectively collected thyroid aspirates in Cytolyt solution and prepared slides for cytological examination using the ThinPrep method. All remaining material was then used for nucleic acid extraction with subsequent RT-PCR for the housekeeping gene PGK-1 to ensure ribonucleic acid integrity, for thyroglobulin to ensure the presence of follicular epithelial cells, and for the three most common ret/PTC gene rearrangements (ret/PTC-1, -2, and -3). The results of the first 73 cases with surgical follow-up were correlated with the cytological diagnosis and final histopathology. ret/PTC gene rearrangements were detected in 17 of 33 samples (52%) that were PC on histopathology; the presence of gene rearrangements was confirmed by molecular analysis of corresponding surgically resected frozen tissue. There were no false positives. The identification of ret/PTC gene rearrangements refined the diagnosis of PC in 9 of 15 specimens (60%) that would otherwise have been considered indeterminate and in 2 of 6 that were considered insufficient for cytological diagnosis. The results indicate that RT-PCR for ret/PTC is a specific marker that can be applied to fine needle aspiration biopsies and improves the diagnosis of malignancy when used as an adjunct to traditional cytology.
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Staubitz, Julia Isabelle, Thomas Johannes Musholt, Arno Schad, Erik Springer, Hauke Lang, Krishnaraj Rajalingam, Wilfried Roth, and Nils Hartmann. "ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma." Cancer Genetics 238 (October 2019): 10–17. http://dx.doi.org/10.1016/j.cancergen.2019.07.002.
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Santoro, Massimo, Rosa Marina Melillo, and Alfredo Fusco. "RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture." European Journal of Endocrinology 155, no. 5 (November 2006): 645–53. http://dx.doi.org/10.1530/eje.1.02289.
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Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms of thyroid cell transformation, activation of downstream signal transduction pathways and modulation of gene expression induced by RET/PTC. These findings have advanced our understanding of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to this disease.
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Platt, Adam, Paul Elvin, John Morten, Qunsheng Ji, Emma Donald, Chris Womack, Xinying Su, et al. "Retrospective evaluation of RET biomarker status and outcome to vandetanib in four phase III randomized NSCLC trials." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8045. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8045.
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8045 Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been estimated at 0.2–6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from 4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling, to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel ± V 100mg), ZEAL (NCT00418886; pemetrexed ± V 100mg), ZEPHYR (NCT00404924; V 300mg vs placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234 had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944 and 1102. RET fusions (in >10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n=3; comparator, n=4), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanib-treated RET fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor shrinkage in 2. Overall, 2.8% (n=26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in >10% tumor cells), 8.1% (n=76) had lower RET gene copy number gain (4–6 copies in ≥40% tumor cells) and 8.3% (n=92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). There was no difference in ORR between vandetanib and comparator for the RET amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1% [3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44], respectively). Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886; NCT00404924.
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Sherman, Steven I., Ezra E. W. Cohen, Patrick Schoffski, Rossella Elisei, Martin Schlumberger, Lori J. Wirth, Milan Mangeshkar, Dana T. Aftab, Douglas O. Clary, and Marcia S. Brose. "Efficacy of cabozantinib (Cabo) in medullary thyroid cancer (MTC) patients with RAS or RET mutations: Results from a phase III study." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 6000. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.6000.
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6000 Background: Cabo extends progression-free survival (PFS) in patients (pts) with progressive, metastatic MTC (Schöffski, J Clin Oncol 30, 2012). Mutations in the RET oncogene are associated with most hereditary cases and ~half of sporadic cases of MTC. RAS gene mutations have recently been identified in subsets of RET wild type (wt) cases. Therefore, we investigated the association of RET (a prospectively defined endpoint) and RAS mutations (a post hoc analysis) with efficacy outcomes in the phase 3 study of cabo in MTC. Methods: Pts enrolled into the double-blind, placebo-controlled phase III trial were evaluated for the presence of somatic and germline RET mutations using Sanger and next generation methods. A subset of pts determined to be RET wt (44 pts) or RET unknown (41 pts) were then evaluated for tumor-associated mutations in KRAS, NRAS, and HRAS in codons 12, 13, and 61 by next generation sequencing. Impact of RET and RAS gene mutation status was evaluated with respect to PFS and tumor response rate (RR) according to RECIST. Results: RET status was determined in 65% of the study pts (215/330), of which 79% harbored an activating mutation, and 21% were RET wt. All RET mutational subgroups (RET mutated, RET wt, and RET unknown) showed hazard ratios indicating PFS benefit from cabo treatment, and demonstrated RRs between 22% and 32%. However pts harboring a RET mutation had longer median PFS on cabo (60 wks) than pts with wt RET (25 wks, PFS difference p=0.0001). Also, pts with the poor prognosis mutation RET M918T showed a longer median PFS on cabo treatment (61 wks) than pts with any other RET mutation (36 wks, PFS difference p=0.009). Patients with hereditary MTC had similar PFS to those with sporadic disease, and the presence of the common RET polymorphism G691S had no effect on either PFS or RR. Sixteen of 85 tested pts (5% of total study pts) with wt or unknown RET status were found to harbor a RAS gene mutation. The RAS-mutated pts showed a similar RR (31%) and PFS (47 wks) as RET mutated pts (32% and 60 wks). Conclusions: While hazard ratios indicate PFS improvement for all RET subgroups on cabo, the extent of benefit may depend in part on RET genotype. Cabo treatment benefit is also seen in pts harboring a RAS mutation. Clinical trial information: NCT00704730.
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Santos, Marcelo A. C. G. dos, Elisangela Pereira de S. Quedas, Rodrigo de Almeida Toledo, Delmar M. Lourenço-Júnior, and Sergio Pereira de A. Toledo. "Screening of RET gene mutations in multiple endocrine neoplasia type-2 using Conformation Sensitive Gel Electrophoresis (CSGE)." Arquivos Brasileiros de Endocrinologia & Metabologia 51, no. 9 (December 2007): 1468–76. http://dx.doi.org/10.1590/s0004-27302007000900009.
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Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited tumor syndrome caused by RET proto-oncogene germline mutations (RET). Here we tested the Conformation Sensitive Gel Electrophoresis (CSGE) as a screening method for RET hot-spot mutations. Seven MEN2 families were studied by direct sequencing analysis, CSGE and Single Strand Conformational Polymorphism (SSCP). Using CSGE/SSCP, we were able to detect four out of five types of RET mutations verified by sequencing analysis: Cys620Arg, Cys634Arg, Cys634Tyr, and Met918Thr, furthermore a missense substitution at codon 648 (Val648Ile). RET polymorphisms 691 and 769 were also verified. Data obtained using CSGE/SSCP were fully concordant. We conclude that CSGE showed to be a sensitive, fast, low-cost, and simple procedure to detect RET mutations in codons which are reported as the most prevalent RET variants (~ 95%) in large MEN2 series. As to the Val804Met mutation, this method still needs to be optimized.
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Goodfellow, P. J., and S. A. Wells. "RET Gene and Its Implications for Cancer." JNCI Journal of the National Cancer Institute 87, no. 20 (October 18, 1995): 1515–23. http://dx.doi.org/10.1093/jnci/87.20.1515.
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Cetta, Francesco, Gennaro Chiappetta, Rosa Marina Melillo, Margherita Petracci, Giulia Montalto, Massimo Santoro, and Alfredo Fusco. "The ret/ptc1 Oncogene Is Activated in Familial Adenomatous Polyposis-Associated Thyroid Papillary Carcinomas1." Journal of Clinical Endocrinology & Metabolism 83, no. 3 (March 1, 1998): 1003–6. http://dx.doi.org/10.1210/jcem.83.3.4614.
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Familial adenomatous polyposis (FAP) is caused by germ-line mutations of the apc gene, and it is associated with an increased risk of developing papillary thyroid carcinomas. We have previously reported that a significant fraction of sporadic human papillary thyroid carcinomas is characterized by gene rearrangements affecting the ret protooncogene. These rearrangements generate chimeric transforming oncogenes designated ret/ptc. By a combined immunohistochemical and RT-PCR approach, we analyzed, for ret/ptc oncogene activation, papillary thyroid carcinomas occurred in two FAP kindreds, both showing typical apc gene mutations. Kindred 1 had seven members affected by FAP, and among these, three patients showed papillary thyroid carcinomas. Kindred 2 had two patients, mother and daughter, affected by colonic polyposis; the 20-yr-old daughter showed also a papillary carcinoma. Here we report that ret/ptc1 oncogene was activated in two of the three papillary carcinomas of FAP kindred 1 and in the papillary carcinoma of FAP kindred 2. These findings document that loss of function of apc coexists with gain of function of ret in some papillary thyroid carcinomas, suggesting that ret/ptc1 oncogene activation could be a progression step in the development of FAP-associated thyroid tumors.
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Bongarzone, I., N. Monzini, M. G. Borrello, C. Carcano, G. Ferraresi, E. Arighi, P. Mondellini, G. Della Porta, and M. A. Pierotti. "Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A." Molecular and Cellular Biology 13, no. 1 (January 1993): 358–66. http://dx.doi.org/10.1128/mcb.13.1.358-366.1993.
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The ret oncogene frequently has been found activated in papillary thyroid carcinomas. A previous characterization of ret activation revealed recombination of its tyrosine kinase domain and sequences derived from an uncharacterized locus (D10S170). The mechanism leading to this recombination was identified as a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with the breakpoints occurring where ret and D10S170 were mapped. To further characterize the activation of ret in papillary thyroid carcinomas, we have now isolated and sequenced a second type of ret oncogenic rearrangement not involving the D10S170 locus. The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA). This is the first example of an oncogenic activity involving a PKA gene. PKA is the main intracellular cyclic AMP receptor, and its RI alpha subunit gene is located on chromosome 17q. RI alpha-ret transcripts encode two isoforms of the chimeric protein (p76 and p81), which display constitutive tyrosine phosphorylation as well as a tyrosine kinase enzymatic activity. Under nonreducing conditions, both isoforms are found in a dimeric configuration because of both homo- and heterodimer formation. Thus, the in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement.
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Bongarzone, I., N. Monzini, M. G. Borrello, C. Carcano, G. Ferraresi, E. Arighi, P. Mondellini, G. Della Porta, and M. A. Pierotti. "Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A." Molecular and Cellular Biology 13, no. 1 (January 1993): 358–66. http://dx.doi.org/10.1128/mcb.13.1.358.
Full textAbstract:
The ret oncogene frequently has been found activated in papillary thyroid carcinomas. A previous characterization of ret activation revealed recombination of its tyrosine kinase domain and sequences derived from an uncharacterized locus (D10S170). The mechanism leading to this recombination was identified as a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with the breakpoints occurring where ret and D10S170 were mapped. To further characterize the activation of ret in papillary thyroid carcinomas, we have now isolated and sequenced a second type of ret oncogenic rearrangement not involving the D10S170 locus. The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA). This is the first example of an oncogenic activity involving a PKA gene. PKA is the main intracellular cyclic AMP receptor, and its RI alpha subunit gene is located on chromosome 17q. RI alpha-ret transcripts encode two isoforms of the chimeric protein (p76 and p81), which display constitutive tyrosine phosphorylation as well as a tyrosine kinase enzymatic activity. Under nonreducing conditions, both isoforms are found in a dimeric configuration because of both homo- and heterodimer formation. Thus, the in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement.
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Stinchcombe, Thomas E. "Current management of RET rearranged non-small cell lung cancer." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592092863. http://dx.doi.org/10.1177/1758835920928634.
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The identification of oncogenic drivers, and the subsequent development of targeted therapies established biomarker-based care for metastatic non-small cell lung cancer (NSCLC). Biomarker testing is standard of care in NSCLC patients with adenocarcinoma because multiple targeted therapies are available. Rearranged during transfection ( RET) rearrangements were identified as oncogenic drivers in NSCLC, and are more common among younger patients, adenocarcinoma histology, and patients with a history of never smoking. The prevalence is estimated to be 1–2% among patients with adenocarcinoma histology. The most common rearrangement is between intron 11 of the RET gene and intron 15 of the KIF5B gene, and the next most frequent rearrangement is with the CCDC6 gene. RET rearrangements lead to constitutive activation of the RET tyrosine kinase and increased cell proliferation, migration, and survival. Phase II studies investigated the activity of multi-targeted tyrosine kinase inhibitors in patients with NSCLC with a confirmed RET rearrangement. These agents have limited potency against RET, and activity against the epidermal growth factor receptor and vascular endothelial growth factor pathways. These agents revealed modest activity, and were poorly tolerated due to the off-target toxicities. These struggles contributed to the development of more potent and specific RET tyrosine kinase inhibitors. Preliminary results from early phase trials of selpercatinib (LOXO-292) and pralsetinib (BLU-667) revealed promising efficacy and improved tolerability. The availability of these agents will make routine testing for RET rearrangements a priority.
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Puppo, Francesca, Marco Musso, Doroti Pirulli, Paola Griseri, Tiziana Bachetti, Sergio Crovella, Giovanna Patrone, Isabella Ceccherini, and Roberto Ravazzolo. "Comparative genomic sequence analysis coupled to chromatin immunoprecipitation: a screening procedure applied to search for regulatory elements at the RET locus." Physiological Genomics 23, no. 3 (November 17, 2005): 269–74. http://dx.doi.org/10.1152/physiolgenomics.00036.2005.
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RET gene expression is characterized by high tissue and stage specificity during the development of neural crest derivatives and in the pathogenesis of inherited cancer syndromes and Hirschsprung disease. Identifying all elements contributing to its transcriptional regulation might provide new clues to clarify both developmental and pathogenic mechanisms. We previously demonstrated that chromatin acetylation affects RET transcription; therefore, we have set up a strategy based on analysis of sequences conserved among species at the RET locus, combined with the characterization of their chromatin structure, to identify new potential regulatory elements. The histone acetylation level was evaluated by the chromatin immunoprecipitation method applied to cells displaying different degrees of endogenous RET expression. Real-time quantitative PCR of immunoprecipitated DNA-protein complexes and transfection experiments, with constructs expressing a reporter gene in which the putative regulatory regions are inserted, indicate a correlation between histone acetylation and endogenous RET expression and highlight conserved sequences with potential regulatory roles. This paper presents a reliable screening procedure to unearth elements able to affect gene regulation at the transcriptional level in a large genomic region.
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Santoro, Massimo, Rosa Marina Melillo, Francesca Carlomagno, Giancarlo Vecchio, and Alfredo Fusco. "Minireview: RET: Normal and Abnormal Functions." Endocrinology 145, no. 12 (December 1, 2004): 5448–51. http://dx.doi.org/10.1210/en.2004-0922.
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Abstract The RET gene encodes a single-pass transmembrane receptor tyrosine kinase. RET is the oncogene that causes papillary thyroid carcinoma and medullary thyroid carcinoma. The latter may arise as a component of multiple endocrine neoplasia type 2 syndromes; germline mutations in RET are responsible for multiple endocrine neoplasia type 2 inheritance. In this report we review data on the mechanisms leading to RET oncogenic conversion and on RET targeting as a strategy in thyroid cancer treatment.
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Santoro, Massimo, Marialuisa Moccia, Giorgia Federico, and Francesca Carlomagno. "RET Gene Fusions in Malignancies of the Thyroid and Other Tissues." Genes 11, no. 4 (April 15, 2020): 424. http://dx.doi.org/10.3390/genes11040424.
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Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer.
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Kim, Sung Won, Bong Ju Lee, Joo Yeun Kim, Kang Dae Lee, Byung Joo Lee, and In Ju Kim. "Analysis of RET Gene Point Mutation with Multiple Endocrine Neoplasia Type 2B." Journal of Clinical Otolaryngology Head and Neck Surgery 18, no. 1 (May 2007): 79–85. http://dx.doi.org/10.35420/jcohns.2007.18.1.79.
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de Groot, Jan Willem B., Thera P. Links, John T. M. Plukker, Cornelis J. M. Lips, and Robert M. W. Hofstra. "RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors." Endocrine Reviews 27, no. 5 (July 18, 2006): 535–60. http://dx.doi.org/10.1210/er.2006-0017.
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The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.
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Korpershoek, Esther, Bart-Jeroen Petri, Francien H. van Nederveen, Winand N. M. Dinjens, Albert A. Verhofstad, Wouter W. de Herder, Sonja Schmid, Aurel Perren, Paul Komminoth, and Ronald R. de Krijger. "Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma." Endocrine-Related Cancer 14, no. 2 (June 2007): 453–62. http://dx.doi.org/10.1677/erc-06-0044.
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Pheochromocytomas (PCCs) are rare tumors that arise from chromaffin tissue in the adrenal medulla, but can also occur in the abdomen outside the adrenals and are then called sympathetic paragangliomas (sPGLs). According to the literature, between 15 and 25% of apparently sporadic adrenal PCC and sPGL are caused by germline mutations in RET, von Hippel–Lindau disease (VHL), succinate dehydrogenase subunit B (SDHB), or subunit D SDHD. However, few studies have addressed the mutationfrequency of these candidate genes in selected subgroups of PCC andsPGL, such as bilateral adrenal PCC or extra-adrenal sPGL, and none have looked at somatic mutations by analyzing tumor tissue. Therefore, we have investigated the occurrence of germline and somatic mutations in RET, VHL, SDHB, and SDHD in comparatively large series of bilateral adrenal PCC (n = 33 patients) and sPGL (n = 26 patients), with the aim of determining the mutation frequency of each of these genes and to establish a genetic testing algorithm. Twenty-one RET, two VHL germline, and one SDHD mutations were found in the patients with bilateral adrenal PCC. In sPGL, one novel SDHB germline and one novel SDHB somatic mutation were observed. In addition, two SDHD germline mutations were found. We conclude that germline RET mutations are predominantly found in bilateral PCC, and that somatic and germline SDHB and SDHD mutations usually occur in sPGL, which has practical consequences for genetic testing algorithms. We suggest that sequential mutation analysis should be directed first at RET, followed by VHL and SDHD for patients with bilateral adrenal PCC at diagnosis, and at SDHB and SDHD for patients with sPGL.
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Ball, Douglas, Peter Illei, and Reza Pishdad. "RF11 | PSAT273 RET Gene Fusion In a Putative Case of Medullary Thyroid Cancer." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A853—A854. http://dx.doi.org/10.1210/jendso/bvac150.1765.
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Abstract Background Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non-medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic medullary thyroid cancer (MTC). The presence of a RET gene fusion provides a target for selective RET inhibitor drugs. We describe an unusual patient with suspected MTC and a positive RET gene fusion, with excellent response to targeted therapy. Clinical Case A 50-year-old male presented to our institution with cough, fatigue, heat intolerance, and flushing. His only remarkable history was stage IIIBS Hodgkin lymphoma treated with chemotherapy, in remission for approximately 6 years. CT chest revealed new bulky mediastinal and hilar adenopathy with bulky cervical nodes. VATS biopsy of a mediastinal node showed metastatic neuroendocrine neoplasm with plasmacytoid features that was immunoreactive for calcitonin, CEA and cytokeratin, but negative for TTF1 and PAX-8. The differential diagnosis included MTC or metastatic atypical carcinoid tumor. Next Generation Sequencing was negative, including RET and RAS point mutations. Subsequent testing for re-arrangements showed a KIF5B-RET gene fusion, an oncogene identified in lung adenocarcinoma. Biochemical findings showed a calcitonin level of 16,033 (normal < 10 pg/mL) and CEA 6.9 (normal < 4.7 ng/mL). Chromogranin A was 146.6 (normal < 101.16 ng/mL). ACTH and cortisol were normal. Neck US revealed a calcified 5 mm right upper pole thyroid nodule and extensive bilateral cervical nodes. A provisional diagnosis was made of MTC. Vandetanib was started. Two months later, he reported worsening orthopnea, diarrhea, and weight loss. CT chest showed marked worsening with enlarging mediastinal hilar and supraclavicular adenopathy with new moderate sized pericardial and pleural effusion. Vandetanib was discontinued and Selpercatinib started, following FDA approval. He reported prompt resolution of dyspnea and diarrhea and improved weight and energy. Calcitonin declined to <2 pg/mL, and CEA to1.6 ng/mL four months into treatment. CT neck showed marked shrinkage of lymph nodes with a persistent calcified thyroid nodule. CT chest showed marked shrinkage of mediastinal and hilar masses, with resolution of bronchial narrowing and right pleural effusion. Nine months after presentation, there were no chest symptoms and biochemical markers and imaging remained stable. Conclusion Approximately 25% of MTC tumors lack activating point mutations in RET or RAS genes. Analysis of actionable fusion mutations should be considered if there is metastatic disease. High serum calcitonin levels are not pathognomonic for MTC and tumor histology may overlap with neuroendocrine lung cancers, creating a diagnostic challenge. Depending on whether this patient's tumor originated in the thyroid gland, it may represent an unusual case of RET gene fusion in MTC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m.
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Dawson, D. M., E. G. Lawrence, G. MacLennan, and T. G. Pretlow. "C-Ret Proto-Oncogene Expression in Human Prostate: An Immunohistochemical Evaluation." Microscopy and Microanalysis 3, S2 (August 1997): 21–22. http://dx.doi.org/10.1017/s1431927600006991.
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C-ret proto-oncogene encodes a protein in the tyrosine kinase (TK) family of transmembrane receptors for growth factors. C-ret expression has been identified in normal tissues and tumors of neural crest origin such as inherited MEN (multiple endocrine neoplasia) syndromes, particularly medullary thyroid cancers where there are confirmed germ-line mutations. Gene rearrangement has been observed in papillary thyroid carcinomas (PTC) and has been shown to have cytoplasmic localization of the altered gene product. C-ret proto-oncogene product is also necessary for the normal development of the peripheral nervous system, enteric nervous system and the kidney. A recent profile of the TK receptors in prostate cancer (PCA) identified c-ret protein in prostate cancer tissue and xenograft derived from human PCA. This study is the first to report the immunohistochemical (IH) evaluation of c-ret in human prostatic tissue.Thirty radical prostatectomy specimens for PCA were formalin-fixed, sectioned at 5mm and paraffin-embedded.
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Santoro, Massimo, Francesca Carlomagno, and Rosa Marina Melillo. "RET: A Multi-Faceted Gene in Human Cancer." Endocrinology and Metabolism 27, no. 3 (2012): 173. http://dx.doi.org/10.3803/enm.2012.27.3.173.
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Kusafuka, Takeshi, and Prem Puri. "Altered RET gene mRNA expression in Hirschsprung's disease." Journal of Pediatric Surgery 32, no. 4 (April 1997): 600–604. http://dx.doi.org/10.1016/s0022-3468(97)90716-8.
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DAUGER, STÉPHANE, FABIEN GUIMIOT, SYLVAIN RENOLLEAU, BÉATRICE LEVACHER, BERNADETTE BODA, CHRISTOPHE MAS, VIRGINIE NÉPOTE, MICHEL SIMONNEAU, CLAUDE GAULTIER, and JORGE GALLEGO. "MASH-1/RET pathway involvement in development of brain stem control of respiratory frequency in newborn mice." Physiological Genomics 7, no. 2 (December 21, 2001): 149–57. http://dx.doi.org/10.1152/physiolgenomics.00056.2001.
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Respiratory abnormalities have been described in MASH-1 (mammalian achaete-scute homologous gene) and c-RET (“rearranged during transfection”) mutant newborn mice. However, the neural mechanisms underlying these abnormalities have not been studied. We tested the hypothesis that the MASH-1 mutation may impair c-RET expression in brain stem neurons involved in the control of breathing. To do this, we analyzed brain stem c-RET expression and respiratory phenotype in MASH-1 +/+ wild-type, MASH-1 +/− heterozygous, and MASH-1 −/− knock-out newborn mice during the first 2 h of life. In MASH-1 −/− newborns, c-RET gene expression was absent in the noradrenergic nuclei (A2, A5, A6, A7) that contribute to modulate respiratory frequency and in scattered cells of the rostral ventrolateral medulla. The c-RET transcript levels measured by quantitative RT-PCR were lower in MASH-1 −/− and MASH-1 +/− than in MASH-1 +/+ brain stems ( P = 0.001 and P = 0.003, respectively). Breath durations were shorter in MASH-1 −/− and MASH-1 +/− than in MASH-1 +/+ mice ( P = 0.022) and were weakly correlated with c-RET transcript levels ( P = 0.032). Taken together, these results provide evidence that MASH-1 is upstream of c-RET in noradrenergic brain stem neurons important for respiratory rhythm modulation.
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Jung, Hye Sook, Dong Wook Kim, Young Suk Jo, Hyo Kyun Chung, Jung Hun Song, Jong Sun Park, Ki Cheol Park, et al. "Regulation of Protein Kinase B Tyrosine Phosphorylation by Thyroid-Specific Oncogenic RET/PTC Kinases." Molecular Endocrinology 19, no. 11 (November 1, 2005): 2748–59. http://dx.doi.org/10.1210/me.2005-0122.
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Abstract Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.
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Bhattarai, Chacchu, Phanindra Prasad Poudel, Arnab Ghosh, and Sneha Guruprasad Kalthur. "The <i>RET</i> gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and <i>RET</i> mutation results in Hirschsprung's disease." AIMS Neuroscience 9, no. 1 (2022): 128–49. http://dx.doi.org/10.3934/neuroscience.2022008.
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<abstract> <p>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 (<italic>RET</italic>) gene and its protein RET plays a crucial role in the formation of enteric neurons. This review describes the molecular mechanism by which the <italic>RET</italic> 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 <italic>RET</italic> gene result in Hirschsprung's disease.</p> </abstract>
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Japón, Miguel A., Angel G. Urbano, Carmen Sáez, Dolores I. Segura, Alfonso Leal Cerro, Carlos Diéguez, and Clara V. Alvarez. "Glial-Derived Neurotropic Factor and RET Gene Expression in Normal Human Anterior Pituitary Cell Types and in Pituitary Tumors." Journal of Clinical Endocrinology & Metabolism 87, no. 4 (April 1, 2002): 1879–84. http://dx.doi.org/10.1210/jcem.87.4.8383.
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Abstract Glial-derived neurotropic factor (GDNF) signaling is mediated through a 2-component system consisting of the so-called GDNF receptor-α (GFRα1), which binds to GDNF. This complex activates the tyrosine kinase receptor RET. In this paper we demonstrate GDNF, GFRα1, and RET mRNA and protein expression in the human anterior pituitary gland. Double immunohistochemistry of anterior pituitary sections showed GDNF immunoreactivity in more than 95% of somatotrophs and to a lesser extent in corticotrophs (20%); it was almost absent in the remaining cell types. Also, although more than 95% of somatotrophs were stained for RET, no positive immunostaining could be detected in other cell types. Furthermore, we have looked for GDNF and RET in human pituitary adenomas of various hormonal phenotypes. Strong positive immunostaining was found for c-RET in all of the GH-secreting adenomas screened as well as in 50% of ACTH-producing adenomas. Positive immunostaining for GDNF was found in all of the GH-secreting adenomas and in 10% of the corticotropinomas. Lastly, we found strong positive immunostaining for GFRα1 in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas. All of the remaining pituitary tumors screened were negative for RET, GDNF, and GFRα1. This study indicates that GDNF may well be acting in the regulation of somatotroph cell growth and/or cell function in the normal human anterior pituitary gland. The expression of RET in all of the somatotropinomas and in 50% of the ACTH-producing tumors implies that GDNF and RET could be involved in the pathogenesis of pituitary tumors.
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Diaz-Rodriguez, Esther, Angela R. Garcia-Rendueles, Alejandro Ibáñez-Costa, Ester Gutierrez-Pascual, Montserrat Garcia-Lavandeira, Alfonso Leal, Miguel A. Japon, et al. "Somatotropinomas, But Not Nonfunctioning Pituitary Adenomas, Maintain a Functional Apoptotic RET/Pit1/ARF/p53 Pathway That Is Blocked by Excess GDNF." Endocrinology 155, no. 11 (November 1, 2014): 4329–40. http://dx.doi.org/10.1210/en.2014-1034.
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Abstract Acromegaly is caused by somatotroph cell adenomas (somatotropinomas [ACROs]), which secrete GH. Human and rodent somatotroph cells express the RET receptor. In rodents, when normal somatotrophs are deprived of the RET ligand, GDNF (Glial Cell Derived Neurotrophic Factor), RET is processed intracellularly to induce overexpression of Pit1 [Transcription factor (gene : POUF1) essential for transcription of Pituitary hormones GH, PRL and TSHb], which in turn leads to p19Arf/p53-dependent apoptosis. Our purpose was to ascertain whether human ACROs maintain the RET/Pit1/p14ARF/p53/apoptosis pathway, relative to nonfunctioning pituitary adenomas (NFPAs). Apoptosis in the absence and presence of GDNF was studied in primary cultures of 8 ACROs and 3 NFPAs. Parallel protein extracts were analyzed for expression of RET, Pit1, p19Arf, p53, and phospho-Akt. When GDNF deprived, ACRO cells, but not NFPAs, presented marked level of apoptosis that was prevented in the presence of GDNF. Apoptosis was accompanied by RET processing, Pit1 accumulation, and p14ARF and p53 induction. GDNF prevented all these effects via activation of phospho-AKT. Overexpression of human Pit1 (hPit1) directly induced p19Arf/p53 and apoptosis in a pituitary cell line. Using in silico studies, 2 CCAAT/enhancer binding protein alpha (cEBPα) consensus-binding sites were found to be 100% conserved in mouse, rat, and hPit1 promoters. Deletion of 1 cEBPα site prevented the RET-induced increase in hPit1 promoter expression. TaqMan qRT-PCR (real time RT-PCR) for RET, Pit1, Arf, TP53, GDNF, steroidogenic factor 1, and GH was performed in RNA from whole ACRO and NFPA tumors. ACRO but not NFPA adenomas express RET and Pit1. GDNF expression in the tumors was positively correlated with RET and negatively correlated with p53. In conclusion, ACROs maintain an active RET/Pit1/p14Arf/p53/apoptosis pathway that is inhibited by GDNF. Disruption of GDNF's survival function might constitute a new therapeutic route in acromegaly.
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Minna, Emanuela, Paola Romeo, Matteo Dugo, Loris De Cecco, Antonella Aiello, Federico Pistore, Andrea Carenzo, Angela Greco, and Maria Grazia Borrello. "Medullary Thyroid Carcinoma Mutational Spectrum Update and Signaling-Type Inference by Transcriptional Profiles: Literature Meta-Analysis and Study of Tumor Samples." Cancers 14, no. 8 (April 13, 2022): 1951. http://dx.doi.org/10.3390/cancers14081951.
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Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. Although RET and RAS genes are recognized drivers in MTC, associated downstream signaling pathways are largely unknown. In this study, we report 17 sporadic MTCs, collected at our institution, comprising patient-matched primary and lymph node metastatic tumors investigated for mutational and transcriptional profiles. As we identified two uncommon RET deletions (D898_E901del and E632_L633del), we also performed a literature review and meta-analysis to assess the occurrence of unconventional alterations in MTC, focusing on next-generation sequencing studies. We found that new gene alterations are emerging, along with the known RET/RAS drivers, involving not only RET by multiple concurrent mutations or deletions but also other previously underestimated cancer-related genes, especially in sporadic MTCs. In our MTC gene profiles, we found transcriptome similarity between patient-matched tissues and expression of immune genes only by a few samples. Furthermore, we defined a gene signature able to stratify samples into two distinct signaling types, termed MEN2B-like and MEN2A-like. We provide an updated overview of the MTC mutational spectrum and describe how transcriptional profiles can be used to define distinct MTC signaling subtypes that appear to be shared by various gene drivers, including the unconventional ones.
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Marcello, Krista, Marcia S. Brose, Taofeek K. Owonikoko, Karen L. Reckamp, Laura J. Tafe, Rachael Andrie, and Kevin Obholz. "Clinical application of precision medicine among oncologists: A case study in RET-targeted therapy." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e18705-e18705. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e18705.
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e18705 Background: Precision medicine has revolutionized cancer care across multiple tumor types and new actionable biomarkers and targeted therapies are emerging at an unprecedented pace, creating myriad opportunities to optimize care and mitigate the often-dire sequelae of traditional cancer therapy. Many oncology healthcare professionals (HCPs) in practice are not employing optimal testing methodologies to detect biomarkers in patients who could benefit from novel targeted therapies. In this study, we analyze HCP awareness and application of RET alteration testing and integration of recently approved, new-generation selective RET inhibitors into practice for appropriate patients with NSCLC and thyroid cancer. Methods: In August 2020 HCPs were surveyed on RET alteration testing and use of RET-targeted therapeutics in their current practice. Study eligibility criteria included active HCPs in an oncology, pulmonology, or pathology practice. A curriculum of live and online educational activities was then developed for any interested oncologists and pathologists on RET alteration testing and/or targeted therapy for RET-altered lung and thyroid cancers. These activities included case studies, polling, and evaluations that provided additional insight on self-identified practice trends. In June 2021, at the completion of the educational program, eligible HCPs were surveyed again on RET alteration testing and selection of RET inhibitor therapy for appropriate patients. Results: In August 2020, 123 practicing HCPs completed the initial survey and 33% were testing patients for RET gene alterations and 18% were aware of the most sensitive testing assay for detection of RET fusions. 25% and 7%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Self-identified practice trends identified among the unselected cohort of 12,537 individual HPCs participating in the educational activities also demonstrated similar lack of appropriate testing for RET alterations and use of RET inhibitors. In June 2021, 60 practicing HCPs completed the follow-up survey and 40% were testing patients for RET gene alterations and 25% were aware of the most sensitive testing assay for detection of RET fusions. 52% and 22%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Conclusions: The rate of broad testing for RET alterations across patients with NSCLC and thyroid cancer remains low and many HCPs lack understanding of when to consider treating with a RET inhibitor. These results underscore the lag in adoption of optimal precision medicine approaches in oncology and the need for expert guidance and educational activities to optimize individualized, biomarker-driven treatment approaches for patients with cancer.
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Marcello, Krista, Marcia S. Brose, Taofeek K. Owonikoko, Karen L. Reckamp, Laura J. Tafe, Rachael Andrie, and Kevin Obholz. "Clinical application of precision medicine among oncologists: A case study in RET-targeted therapy." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e18705-e18705. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e18705.
Full textAbstract:
e18705 Background: Precision medicine has revolutionized cancer care across multiple tumor types and new actionable biomarkers and targeted therapies are emerging at an unprecedented pace, creating myriad opportunities to optimize care and mitigate the often-dire sequelae of traditional cancer therapy. Many oncology healthcare professionals (HCPs) in practice are not employing optimal testing methodologies to detect biomarkers in patients who could benefit from novel targeted therapies. In this study, we analyze HCP awareness and application of RET alteration testing and integration of recently approved, new-generation selective RET inhibitors into practice for appropriate patients with NSCLC and thyroid cancer. Methods: In August 2020 HCPs were surveyed on RET alteration testing and use of RET-targeted therapeutics in their current practice. Study eligibility criteria included active HCPs in an oncology, pulmonology, or pathology practice. A curriculum of live and online educational activities was then developed for any interested oncologists and pathologists on RET alteration testing and/or targeted therapy for RET-altered lung and thyroid cancers. These activities included case studies, polling, and evaluations that provided additional insight on self-identified practice trends. In June 2021, at the completion of the educational program, eligible HCPs were surveyed again on RET alteration testing and selection of RET inhibitor therapy for appropriate patients. Results: In August 2020, 123 practicing HCPs completed the initial survey and 33% were testing patients for RET gene alterations and 18% were aware of the most sensitive testing assay for detection of RET fusions. 25% and 7%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Self-identified practice trends identified among the unselected cohort of 12,537 individual HPCs participating in the educational activities also demonstrated similar lack of appropriate testing for RET alterations and use of RET inhibitors. In June 2021, 60 practicing HCPs completed the follow-up survey and 40% were testing patients for RET gene alterations and 25% were aware of the most sensitive testing assay for detection of RET fusions. 52% and 22%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Conclusions: The rate of broad testing for RET alterations across patients with NSCLC and thyroid cancer remains low and many HCPs lack understanding of when to consider treating with a RET inhibitor. These results underscore the lag in adoption of optimal precision medicine approaches in oncology and the need for expert guidance and educational activities to optimize individualized, biomarker-driven treatment approaches for patients with cancer.
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Jia, Cong-Cong, Wang Chen, Zi-Li Feng, and Zhao-Peng Liu. "Recent developments of RET protein kinase inhibitors with diverse scaffolds as hinge binders." Future Medicinal Chemistry 13, no. 1 (January 2021): 45–62. http://dx.doi.org/10.4155/fmc-2020-0170.
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RET is a proto-oncogene encoding a receptor tyrosine kinase. RET regulates key aspects of cellular proliferation, differentiation and survival. The activation of RET via gene fusions or point mutations is closely related to lung, thyroid and other cancers. This review summarizes the developments of a diversity of small molecule RET protein kinase inhibitors in the past 10 years. These RET inhibitors are classified according to their hinge binder chemotypes as: pyrimidines, including the pyrazolopyrimidines, pyrimidine oxazines, quinazolines, 4-aminopyrimidines and 4-aminopyridines; indolinones; 5-aminopyrazole-4-carboxamides; 3-trifluoromethylanilines; imidazopyridines, imidazopyridazines and pyrazopyridines; nicotinonitriles; pyridones and 1,2,4-triazoles. In each section, the biological activities of the inhibitors, their structure–activity relationships and possible binding modes with the RET kinase are introduced.
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Puxeddu, E., J. A. Knauf, M. A. Sartor, N. Mitsutake, E. P. Smith, M. Medvedovic, C. R. Tomlinson, S. Moretti, and J. A. Fagin. "RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response." Endocrine-Related Cancer 12, no. 2 (June 2005): 319–34. http://dx.doi.org/10.1677/erc.1.00947.
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RET/PTC rearrangements represent key genetic events involved in papillary thyroid carcinoma (PTC) initiation. The aim of the present study was to identify the early changes in gene expression induced by RET/PTC in thyroid cells. For this purpose, microarray analysis was conducted on PCCL3 cells conditionally expressing the RET/PTC3 oncogene. Gene expression profiling 48 h after activation of RET/PTC3 identified a statistically significant modification of expression of 270 genes. Quantitative PCR confirmation of 20 of these demonstrated 90% accuracy of the microarray. Functional clustering of genes with greater than or less than 1.75-fold expression change (86 genes) revealed RET/PTC3-induced regulation of genes with key functions in apoptosis (Ripk3, Tdga), cell–cell signaling (Cdh6, Fn1), cell cycle (Il24), immune and inflammation response (Cxcl10, Scya2, Il6, Gbp2, Oas1, Tap1, RT1Aw2, C2ta, Irf1, Lmp2, Psme2, Prkr), metabolism (Aldob, Ptges, Nd2, Gss, Gstt1), signal transduction (Socs3, Nf1, Jak2, Cpg21, Dusp6, Socs1, Stat1, Stat3, Cish) and transcription (Nr4a1, Junb, Hfh1, Runx1, Foxe1). Genes coding for proteins involved in the immune response and in intracellular signal transduction pathways activated by cytokines and chemokines were strongly represented, indicating a critical role of RET/PTC3 in the early modulation of the immune response.
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Kovac, Michal, Connor Woolley, Sebastian Ribi, Claudia Blattmann, Eva Roth, Marco Morini, Monika Kovacova, et al. "Germline RET variants underlie a subset of paediatric osteosarcoma." Journal of Medical Genetics 58, no. 1 (March 16, 2020): 20–24. http://dx.doi.org/10.1136/jmedgenet-2019-106734.
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BackgroundAlthough considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone.Methods and resultsWe followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma.ConclusionsAfter Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.
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Calvo, Javier, Gabriel Torrealba, Adriana Sáenz, Carlos Santamaría, Estela Morera, Silvia Alvarado, Yolanda Roa, and Michelle González. "Genetic and Clinical Features of Medullary Thyroid Carcinoma: The Experience of a Single Center in Costa Rica." Journal of Cancer Epidemiology 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/9637173.
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Background. Activating mutations in the RET gene leads to medullary thyroid carcinoma (MTC). Guidelines encourage performing RET analysis in subjects with hereditary and sporadic disease. Materials and Methods. Design. Observational, case series report study. Patients. Subjects diagnosed with MTC, with a thyroidectomy performed in a single center in Costa Rica between the years 2006 and 2015. Diagnosis and Follow-Up. Pre- and postoperative calcitonin, RET mutation, and neck ultrasound and tomography were obtained. Results. 21 subjects with histological diagnosis of MTC were followed up. The average age at diagnosis was 52.0 ± 15.7 years. The preoperative mean value of calcitonin was 1340 ± 665 pg/mL. Evidence of RET mutation was found in 26.3% of the patients, with only 2 of them grouped in the same kindred. We found statistically significant differences in mean ages between mutated (38.4 ± 20.2 y) versus nonmutated RET gene (54.6 ± 11.8 y, p=0.04). There were no significant differences regarding tumor size, metastases, and surgical reintervention. Conclusions. We report the results of RET mutation analysis in subjects with MTC in a single center of Costa Rica. The availability of this tool increases the probability of identifying familial MTC, with the benefit of detecting affected subjects and their relatives at an earlier age.