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https://www.readbyqxmd.com/read/27912827/new-targets-in-non-small-cell-lung-cancer
#1
REVIEW
Soo J Park, Soham More, Ayesha Murtuza, Brian D Woodward, Hatim Husain
With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27873490/egf-induced-ret-inhibitor-resistance-in-ccdc6-ret-lung-cancer-cells
#2
Hyun Chang, Ji Hea Sung, Sung Ung Moon, Han Soo Kim, Jin Won Kim, Jong Seok Lee
PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes...
January 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/27864876/kinase-gene-fusions-in-defined-subsets-of-melanoma
#3
Jacqueline Turner, Kasey Couts, Jamie Sheren, Siriwimon Saichaemchan, Witthawat Ariyawutyakorn, Izabela Avolio, Ethan Cabral, Magdelena Glogowska, Carol Amato, Steven Robinson, Jennifer Hintzsche, Allison Applegate, Eric Seelenfreund, Rita Gonzalez, Keith Wells, Stacey Bagby, John Tentler, Aik-Choon Tan, Joshua Wisell, Marileila Varella-Garcia, William Robinson
Genomic rearrangements resulting in activating kinase fusions have been increasingly described in a number of cancers including malignant melanoma, but their frequency in specific melanoma subtypes has not been reported. We used break-apart fluorescence in-situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1...
November 19, 2016: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/27849443/fusion-oncogenes-are-the-main-genetic-events-found-in-sporadic-papillary-thyroid-carcinomas-from-children
#4
Maria Isabel Cunha Vieira Cordioli, Lais Moraes, André Uchimura Bastos, Paloma Besson, Maria Teresa de Seixas Alves, Rosana Delcelo, Osmar Monte, Carlos A Longui, Adriano Namo Cury, Janete Cerutti
BACKGROUND: Previous studies reported significant differences in the clinical presentation and outcomes of papillary thyroid carcinoma (PTC) in pediatric patients compared to adults. Previous studies have suggested that the clinicopathological differences observed between pediatric and adult PTC may be due the existence of distinct genetic alterations. However, the knowledge of genetic events in pediatric PTC is based primarily on studies in radiation-exposed PTC or in few studies that enrolled predominantly adolescent patients...
November 16, 2016: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/27836695/clinical-validation-of-a-next-generation-sequencing-genomic-oncology-panel-via-cross-platform-benchmarking-against-established-amplicon-sequencing-assays
#5
Sabah Kadri, Bradley C Long, Ibro Mujacic, Chao J Zhen, Michelle N Wurst, Shruti Sharma, Nadia McDonald, Nifang Niu, Sonia Benhamed, Jigyasa Tuteja, Tanguy Seiwert, Kevin White, Megan E McNerney, Carrie Fitzpatrick, Y Lynn Wang, Larissa V Furtado, Jeremy P Segal
Next-generation sequencing (NGS) genomic oncology profiling assays have emerged as key drivers of personalized cancer care and translational research. However, validation of these assays to meet strict clinical standards has been historically problematic because of both significant assay complexity and a scarcity of optimal validation samples. Herein, we present the clinical validation of 76 genes from a novel 1212-gene large-scale hybrid capture cancer sequencing assay (University of Chicago Medicine OncoPlus) using full-data comparisons against multiple clinical NGS amplicon-based assays to yield dramatic increases in per-sample data comparison efficiency compared with previously published validations...
November 8, 2016: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27826534/fusion-gene-and-splice-variant-analyses-in-liquid-biopsies-of-lung-cancer-patients
#6
REVIEW
Cristina Aguado, Ana Giménez-Capitán, Niki Karachaliou, Ana Pérez-Rosado, Santiago Viteri, Daniela Morales-Espinosa, Rafael Rosell
Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance. In contrast, a blood extraction is safe, can be performed at many time points during the course disease and encourages appropriate therapy modifications, potentially improving the patient's clinical outcome and quality of life. Fusion of the tyrosine kinase genes anaplastic lymphoma kinase (ALK), C-ROS oncogen 1 (ROS 1), rearranged during transfection (RET) and neurotrophic tyrosine kinase 1 (NTRK1) occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors...
October 2016: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/27825637/ret-inhibitors-for-patients-with-ret-fusion-positive-and-ret-wild-type-non-small-cell-lung-cancer
#7
Rafael Rosell, Niki Karachaliou
No abstract text is available yet for this article.
November 4, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27825636/cabozantinib-in-patients-with-advanced-ret-rearranged-non-small-cell-lung-cancer-an-open-label-single-centre-phase-2-single-arm-trial
#8
Alexander Drilon, Natasha Rekhtman, Maria Arcila, Lu Wang, Andy Ni, Melanie Albano, Martine Van Voorthuysen, Romel Somwar, Roger S Smith, Joseph Montecalvo, Andrew Plodkowski, Michelle S Ginsberg, Gregory J Riely, Charles M Rudin, Marc Ladanyi, Mark G Kris
BACKGROUND: RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. METHODS: We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease...
November 4, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27821319/a-phase-ii-study-of-sorafenib-in-recurrent-and-or-metastatic-salivary-gland-carcinomas-translational-analyses-and-clinical-impact
#9
L D Locati, F Perrone, B Cortelazzi, C Bergamini, P Bossi, E Civelli, C Morosi, S Lo Vullo, M Imbimbo, P Quattrone, G P Dagrada, R Granata, C Resteghini, A Mirabile, S Alfieri, E Orlandi, L Mariani, G Saibene, S Pilotti, L Licitra
BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and β, RET, KIT)...
November 4, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27821131/frequency-of-egfr-t790m-mutation-and-multimutational-profiles-of-rebiopsy-samples-from-non-small-cell-lung-cancer-developing-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-japanese-patients
#10
Ryo Ko, Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Mitsuhiro Isaka, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto, Kazuhisa Takahashi, Toshiaki Takahashi
BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs...
November 8, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27794403/clinicopathologic-characteristics-genetic-variability-and-therapeutic-options-of-ret-rearrangements-patients-in-lung-adenocarcinoma
#11
Zhengbo Song, Xinmin Yu, Yiping Zhang
BACKGROUND: RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. PATIENTS AND METHODS: For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases...
November 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27780967/modeling-human-mll-af9-translocated-acute-myeloid-leukemia-from-single-donors-reveals-ret-as-a-potential-therapeutic-target
#12
F Barabé, L Gil, M Celton, A Bergeron, V Lamontagne, É Roques, K Lagacé, A Forest, R Johnson, L Pécheux, J Simard, J Pelloux, A Bellemare-Pelletier, E Gagnon, J Hebert, S Cellot, B T Wilhelm
Acute myeloid leukemias (AML) result from a series of genetic events occurring in a stem or progenitor hematopoietic cell which gives rise to their clonal expansion and an impaired capacity to differentiate. To circumvent the genetic heterogeneity of AML patient cohorts, we have developed a model system, driven by the MLL-AF9 (MA9) oncogene, to generate multiple human leukemias using progenitor cells from a single healthy donor. Through stepwise RNA-sequencing data generated using this model and AML patients, we have identified consistent changes associated with MA9-driven leukemogenesis and demonstrate that no recurrent secondary mutations are required...
October 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27776007/a-comparison-of-morphologic-and-molecular-features-of-braf-alk-and-ntrk1-fusion-spitzoid-neoplasms
#13
Sapna M Amin, Alexandra M Haugh, Christina Y Lee, Bin Zhang, Jeffrey A Bubley, Emily A Merkel, Anna Elisa Verzì, Pedram Gerami
Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET...
October 21, 2016: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/27738759/comprehensive-study-of-mutational-and-clinicopathologic-characteristics-of-adenocarcinoma-with-lepidic-pattern-in-surgical-resected-lung-adenocarcinoma
#14
Ye Xu, Chen Zhu, Wenliang Qian, Min Zheng
PURPOSE: Although many studies have explored clinicopathologic characteristics and prognosis of lung adenocarcinoma, a few literatures reported the mutational status of lung adenocarcinomas with lepidic pattern and whether there is difference between adenocarcinomas with pure lepidic component and lepidic predominant adenocarcinomas remain unknown. METHODS: One hundred and thirty-three patients including 92 adenocarcinomas with pure lepidic component and 41 lepidic predominant adenocarcinomas were subjected to the study...
October 13, 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27686809/developments-for-personalized-medicine-of-lung-cancer-subtypes-mass-spectrometry-based-clinical-proteogenomic-analysis-of-oncogenic-mutations
#15
Toshihide Nishimura, Haruhiko Nakamura
Molecular therapies targeting lung cancers with mutated epidermal growth factor receptor (EGFR) by EGFR-tyrosin kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, changed the treatment system of lung cancer. It was revealed that drug efficacy differs by race (e.g., Caucasians vs. Asians) due to oncogenic driver mutations specific to each race, exemplified by gefitinib / erlotinib. The molecular target drugs for lung cancer with anaplastic lymphoma kinase (ALK) gene translocation (the fusion gene, EML4-ALK) was approved, and those targeting lung cancers addicted ROS1, RET, and HER2 have been under development...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27683183/ret-aberrations-in-diverse-cancers-next-generation-sequencing-of-4-871-patients
#16
Shumei Kato, Vivek Subbiah, Erica Marchlik, Sheryl K Elkin, Jennifer L Carter, Razelle Kurzrock
PURPOSE: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multi-kinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RET. EXPERIMENTAL DESIGN: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments (CLIA) certified targeted next-generation sequencing (NGS) of 182 or 236 gene panels...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27646564/ret-kinase-inhibitors-a-review-of-recent-patents-2012-2015
#17
Luca Mologni, Carlo Gambacorti-Passerini, Peter Goekjian, Leonardo Scapozza
INTRODUCTION: Tyrosine kinases are involved in the control of several biological processes and have been recognized as hot spots of oncogenic transformation, thus representing a major therapeutic target. Dysregulated activation of RET kinase, either through point mutations or gene fusions, is accountable for a significant fraction of thyroid carcinomas, as well as a minor population of lung cancers. Two drugs are currently available for the treatment of medullary thyroid carcinoma and two additional compounds have been approved for differentiated thyroid carcinoma...
September 26, 2016: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27635639/clinicopathological-characteristics-and-survival-of-alk-ros1-and-ret-rearrangements-in-non-adenocarcinoma-non-small-cell-lung-cancer-patients
#18
Zhengbo Song, Xinmin Yu, Yiping Zhang
BACKGROUND: ALK, ROS1 and RET rearrangements represent three most frequent fusion genes in non-small cell lung cancer (NSCLC). Rearrangements of these three genes exist predominantly in lung adenocarcinoma while rarely in non-adenocarcinoma. Our objective was to explore the frequency, clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma NSCLC patients. METHODS: ALK, ROS1 and RET rearrangements were screened by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with completely resected non-adenocarcinoma NSCLC...
September 16, 2016: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/27626672/drosophila-cancer-models-identify-functional-differences-between-ret-fusions
#19
Sarah Levinson, Ross L Cagan
We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities...
September 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27615396/comprehensive-characterization-of-oncogenic-drivers-in-asian-lung-adenocarcinoma
#20
Shiyong Li, Yoon-La Choi, Zhuolin Gong, Xiao Liu, Maruja Lira, Zhengyan Kan, Ensel Oh, Jian Wang, Jason C Ting, Xiangsheng Ye, Christoph Reinhart, Xiaoqiao Liu, Yunfei Pei, Wei Zhou, Ronghua Chen, Shijun Fu, Gang Jin, Awei Jiang, Julio Fernandez, James Hardwick, Min Woong Kang, Hoseok I, Hancheng Zheng, Jhingook Kim, Mao Mao
INTRODUCTION: The incidence rate of lung adenocarcinoma (LUAD), the predominant histological subtype of lung cancer, is elevated in Asians, particularly in female nonsmokers. The mutation patterns in LUAD in Asians might be distinct from those in LUAD in whites. METHODS: We profiled 271 resected LUAD tumors (mainly stage I) to characterize the genomic landscape of LUAD in Asians with a focus on female nonsmokers. RESULTS: Mutations in EGFR, KRAS, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), and BRAF; gene fusions involving anaplastic lymphoma receptor tyrosine kinase gene (ALK), ROS1, and ret proto-oncogene (RET); and Met Proto-Oncogene Tyrosine Kinase (MET) exon 14 skipping were the major drivers in LUAD in Asians, exhibiting mutually exclusive and differing prevalence from those reported in studies of LUAD in non-Asians...
December 2016: Journal of Thoracic Oncology
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