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https://www.readbyqxmd.com/read/29045518/negative-hyper-selection-of-metastatic-colorectal-cancer-patients-for-anti-egfr-monoclonal-antibodies-the-pressing-case-control-study
#1
C Cremolini, F Morano, R Moretto, R Berenato, E Tamborini, F Perrone, D Rossini, A Gloghini, A Busico, G Zucchelli, C Baratelli, E Tamburini, M Tampellini, E Sensi, G Fucà, C Volpi, M Milione, M Di Maio, G Fontanini, F De Braud, A Falcone, F Pietrantonio
Background: Refining the selection of metastatic colorectal cancer (mCRC) patients candidates for anti-EGFR monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signaling pathways, have been suggested by preclinical and retrospective studies. Patients and methods: We conducted this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations (PRESSING panel), including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions, and HER2/PI3K/PTEN/AKT1 mutations...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29044514/ccdc6-the-identity-of-a-protein-known-to-be-partner-in-fusion
#2
REVIEW
Aniello Cerrato, Francesco Merolla, Francesco Morra, Angela Celetti
Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types...
October 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28975018/comprehensive-genomic-profiling-of-a-rare-thyroid-follicular-dendritic-cell-sarcoma
#3
Jaime I Davila, Jason S Starr, Steven Attia, Chen Wang, Ryan A Knudson, Brian M Necela, Vivekananda Sarangi, Zhifu Sun, Yingxue Ren, John D Casler, David M Menke, Gavin R Oliver, Richard W Joseph, John A Copland, Alexander S Parker, Jean-Pierre A Kocher, E Aubrey Thompson, Robert C Smallridge, Yan W Asmann
We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53...
July 3, 2017: Rare Tumors
https://www.readbyqxmd.com/read/28955006/phase-i-ii-study-of-alectinib-in-lung-cancer-with-ret-fusion-gene-study-protocol
#4
Shinji Takeuchi, Toshinori Murayama, Kenichi Yoshimura, Takahiro Kawakami, Shizuko Takahara, Yasuhito Imai, Yoshikazu Kuribayashi, Katsuhiko Nagase, Koichi Goto, Makoto Nishio, Yoshinori Hasegawa, Miyako Satouchi, Katsuyuki Kiura, Takashi Seto, Seiji Yano
BACKGROUND: The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. METHODS/DESIGN: RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design...
2017: Journal of Medical Investigation: JMI
https://www.readbyqxmd.com/read/28911147/kif5b-ret-rearrangement-in-a-carcinoma-of-the-thyroid-gland-a-case-report-of-a-fatal-disease
#5
David Viola, Carlotta Giani, Salvatore Mazzeo, Clara Ugolini, Raffaele Ciampi, Eleonora Molinaro, Laura Agate, Nicla Borrelli, Antonio Chella, Gabriella Fontanini, Fulvio Basolo, Rossella Elisei
Background: The diffuse sclerosing variant of papillary thyroid cancer (DSV-PTC) is a rare variant of papillary thyroid cancer (PTC) with different clinicopathological features compared with conventional PTC. Case: An advanced DSV-PTC was diagnosed in a 39-year-old man. The radioiodine posttherapeutic whole-body-scan showed only an uptake in the central neck, whereas the computerized tomography showed multiple latero-cervical and mediastinum lymph node metastases, a single and spiculated lung lesion and multiple bilateral cerebellum metastases...
September 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28877471/kif5b-ret-oncoprotein-signals-through-a-multi-kinase-signaling-hub
#6
Tirtha Kamal Das, Ross Leigh Cagan
Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation, including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. The KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation, including invadopodia-like processes...
September 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28860428/-current-status-and-future-perspectives-of-scrum-japan
#7
Atsushi Ohtsu, Koichi Goto, Takayuki Yoshino, Wataru Okamoto, Katsuya Tsuchihara
SCRUM-Japan was launched as a nation-wide genome screening consortium for recruiting patients to 35 sponsor-/investigator- initiated registration trials in collaboration with 15 pharmaceutical companies and 240 hospitals. During the first period between February 2015 and March 2017, a total of 4,805 patients have been enrolled. Genomic profiling of each cancer were analyzed and newdrug applications of label expansion are in preparation based on the results of several registration studies including investigator-initiated trial of vandetanib for RET fusion gene positive non-small cell lung cancer...
August 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28857077/fusions-in-solid-tumours-diagnostic-strategies-targeted-therapy-and-acquired-resistance
#8
REVIEW
Alison M Schram, Matthew T Chang, Philip Jonsson, Alexander Drilon
Structural gene rearrangements resulting in gene fusions are frequent events in solid tumours. The identification of certain activating fusions can aid in the diagnosis and effective treatment of patients with tumours harbouring these alterations. Advances in the techniques used to identify fusions have enabled physicians to detect these alterations in the clinic. Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions...
August 31, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28838400/emergence-of-fgfr3-tacc3-fusions-as-a-potential-by-pass-resistance-mechanism-to-egfr-tyrosine-kinase-inhibitors-in-egfr-mutated-nsclc-patients
#9
Sai-Hong Ignatius Ou, Leora Horn, Marcelo Cruz, Davood Vafai, Christine M Lovly, Allison Spradlin, Michael J Williamson, Ibiayi Dagogo-Jack, Adrienne Johnson, Vincent A Miller, Shirish Gadgeel, Siraj M Ali, Alexa B Schrock
Resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) with activating EGFR mutations generally involve development of acquired secondary or tertiary EGFR mutations, such as T790M or C797S. However, case reports have demonstrated that actionable receptor tyrosine kinase fusions such as EML4-ALK, CCDC6-RET, and FGFR3-TACC3 can potentially confer resistance to EGFR TKIs. We seeked to identify the prevalence of FGFR3-TACC3 fusion transcripts as resistance mechanism to EGFR TKIs...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28838384/cell-free-circulating-tumor-dna-supplementing-tissue-biopsies-for-identification-of-targetable-mutations-implications-for-precision-medicine-and-considerations-for-reconciling-results
#10
J Kevin Hicks, James Saller, Emilie Wang, Theresa Boyle, Jhanelle E Gray
Cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is emerging as a noninvasive technique for detecting targetable mutations. We describe two lung adenocarcinoma cases that show the clinical utility of supplementing tumor biopsy molecular interrogation with ctDNA NGS. For both cases, ctDNA NGS identified actionable mutations that were previously not reported by molecular interrogation of tissue. Explanations are provided for the observed differences between ctDNA and tumor biopsy genomic results along with considerations for reconciling findings...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28802831/validation-of-a-targeted-rna-sequencing-assay-for-kinase-fusion-detection-in-solid-tumors
#11
Julie W Reeser, Dorrelyn Martin, Jharna Miya, Esko A Kautto, Ezra Lyon, Eliot Zhu, Michele R Wing, Amy Smith, Matthew Reeder, Eric Samorodnitsky, Hannah Parks, Karan R Naik, Joseph Gozgit, Nicholas Nowacki, Kurtis D Davies, Marileila Varella-Garcia, Lianbo Yu, Aharon G Freud, Joshua Coleman, Dara L Aisner, Sameek Roychowdhury
Kinase gene fusions are important drivers of oncogenic transformation and can be inhibited with targeted therapies. Clinical grade diagnostics using RNA sequencing to detect gene rearrangements in solid tumors are limited, and the few that are available require prior knowledge of fusion break points. To address this, we have analytically validated a targeted RNA sequencing assay (OSU-SpARKFuse) for fusion detection that interrogates complete transcripts from 93 kinase and transcription factor genes. From a total of 74 positive and 36 negative control samples, OSU-SpARKFuse had 93...
August 8, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28795691/evaluation-of-in-vitro-and-in-vivo-activity-of-a-multityrosine-kinase-inhibitor-al3810-against-human-thyroid-cancer
#12
Qin Xie, Hui Chen, Jing Ai, Ying-Lei Gao, Mei-Yu Geng, Jian Ding, Yi Chen
Thyroid cancer is the most common type of endocrine neoplasia. Despite recent breakthroughs in treatment of the disease, the treatment of advanced, progressive thyroid cancers remains challenging with limited therapeutic options available. In this study, we evaluated a novel and orally bioavailable small-molecule multiple tyrosine kinases inhibitor, AL3810, in preclinical models of thyroid cancer in vitro and in vivo. AL3810 (2-5 μmol/L) dose-dependently inhibited the proliferation of human thyroid cancer cell lines TT, SW579 and TPC-1 in vitro with IC50 values ranging from 0...
August 10, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28751246/concordance-between-comprehensive-cancer-genome-profiling-in-plasma-and-tumor-specimens
#13
Judith N Müller, Markus Falk, Jatin Talwar, Nicole Neemann, Erika Mariotti, Miriam Bertrand, Tobias Zacherle, Sotirios Lakis, Roopika Menon, Christian Gloeckner, Markus Tiemann, Lukas C Heukamp, Roman K Thomas, Frank Griesinger, Johannes M Heuckmann
INTRODUCTION: Detection of somatic genomic alterations in the plasma of patients with cancer ("liquid biopsy") are increasingly being used in the clinic. However, the concordance of alterations identified in liquid biopsies with those detected in cancer specimens is not routinely being determined. METHODS: We sought to systematically compare alterations found by a massively parallel sequencing liquid biopsy assay covering 39 genes (NEOliquid [NEO New Oncology GmbH, Köln, Germany]) with those identified through routine diagnostic testing in a certified central pathology laboratory in a cohort of patients with nonsquamous NSCLC...
July 24, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28676214/dna-mismatch-repair-deficiency-in-surgically-resected-lung-adenocarcinoma-microsatellite-instability-analysis-using-the-promega-panel
#14
Kazuya Takamochi, Fumiyuki Takahashi, Yoshiyuki Suehara, Eiichi Sato, Shinji Kohsaka, Takuo Hayashi, Shigehisa Kitano, Toshihide Uneno, Shinya Kojima, Kengo Takeuchi, Hiroyuki Mano, Kenji Suzuki
OBJECTIVES: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas. MATERIALS AND METHODS: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28634282/genomic-alterations-in-fatal-forms-of-non-anaplastic-thyroid-cancer-identification-of-med12-and-rbm10-as-novel-thyroid-cancer-genes-associated-with-tumor-virulence
#15
Tihana Ibrahimpasic, Bin Xu, Iñigo Landa, Snjezana Dogan, Sumit Middha, Venkatraman Seshan, Shyam Deraje, Diane L Carlson, Jocelyn Migliacci, Jeffrey A Knauf, Brian Untch, Michael F Berger, Luc Morris, R Michael Tuttle, Timothy Chan, James A Fagin, Ronald Ghossein, Ian Ganly
Purpose: Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT cancers have not been reported.Experimental Design: We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC.Results: There was a very high prevalence of TERT promoter mutations, comparable with that of ATC, and these co-occurred with BRAF and RAS mutations...
October 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28615362/drugging-the-catalytically-inactive-state-of-ret-kinase-in-ret-rearranged-tumors
#16
Dennis Plenker, Maximilian Riedel, Johannes Brägelmann, Marcel A Dammert, Rakhee Chauhan, Phillip P Knowles, Carina Lorenz, Marina Keul, Mike Bührmann, Oliver Pagel, Verena Tischler, Andreas H Scheel, Daniel Schütte, Yanrui Song, Justina Stark, Florian Mrugalla, Yannic Alber, André Richters, Julian Engel, Frauke Leenders, Johannes M Heuckmann, Jürgen Wolf, Joachim Diebold, Georg Pall, Martin Peifer, Maarten Aerts, Kris Gevaert, René P Zahedi, Reinhard Buettner, Kevan M Shokat, Neil Q McDonald, Stefan M Kast, Oliver Gautschi, Roman K Thomas, Martin L Sos
Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors...
June 14, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28577945/systematic-identification-of-cancer-related-long-noncoding-rnas-and-aberrant-alternative-splicing-of-quintuple-negative-lung-adenocarcinoma-through-rna-seq
#17
Lu Zhang, Shiyong Li, Yoon-La Choi, Jinseon Lee, Zhuolin Gong, Xiaoqiao Liu, Yunfei Pei, Awei Jiang, Mingzhi Ye, Mao Mao, Xuegong Zhang, Jhingook Kim, Ronghua Chen
OBJECTIVES: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer prevalent in Asia. There is a dearth of understanding regarding the transcriptome landscape of LUAD without primary known driver mutations. In this study, LUAD samples without well-known driver mutations occurring in EGFR, KRAS, ALK, ROS1 or RET (quintuple-negative) were used for transcriptome study with a focus on long noncoding RNAs (lncRNAs), alternative splicing and gene fusions. MATERIALS AND METHODS: 24 pairs of LUAD and adjacent normal samples and 13 tumor-only samples derived from 37 quintuple-negative patients were used...
July 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28575860/in-vitro-and-in-vivo-anti-tumor-activity-of-alectinib-in-tumor-cells-with-ncoa4-ret
#18
Sachiko Arai, Kenji Kita, Azusa Tanimoto, Shinji Takeuchi, Koji Fukuda, Hiroshi Sato, Seiji Yano
Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1-2% of all NSCLCs. To date, RET fusions that involve at least six fusion partners in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1, have been identified. Recent clinical trials for RET fusion-positive NSCLC using vandetanib or cabozantinib demonstrated positive clinical response and considerable differential activities for RET inhibitors among fusion partners. Alectinib, an approved ALK inhibitor, is reported to inhibit KIF5B-RET and CCDC6-RET...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28569245/genetic-diagnosis-of-a-chinese-multiple-endocrine-neoplasia-type-2a-family-through-whole-genome-sequencing
#19
Zhen-Fang DU, Peng-Fei Li, Jian-Qiang Zhao, Zhi-Lie Cao, Feng Li, Ju-Ming Ma, Xiao-Ping Qi
Approximately 98% of patients with multiple endocrine neoplasia type 2A (MEN 2A) have an identifiable RET mutation. Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management. The general strategy for RET screening on family members at risk is to sequence the most commonly affected exons and, if negative, to extend sequencing to additional exons. However, different families with MEN 2A due to the same RET mutation often have significant variability in the clinical exhibition of disease and aggressiveness of the MTC, which implies additional genetic loci exsit beyond RET coding region...
June 2017: Journal of Biosciences
https://www.readbyqxmd.com/read/28515244/what-when-and-how-of-biomarker-testing-in-non-small-cell-lung-cancer
#20
Gregory L Riely
Biomarker testing is recommended for all patients diagnosed with non-small cell lung cancer. At a minimum, testing should include the mutations/fusions EGFR, ALK, ROS1, and the protein programmed death ligand-1 (PD-L1), because FDA-approved therapies are available for these alterations. Other actionable molecular findings include RET rearrangements, BRAF(V600E) mutations, and MET exon 14 alterations. If adequate testing was not performed at treatment initiation, molecular testing should be performed before administration of subsequent lines of therapy...
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
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