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RET fusion

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
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
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
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
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
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
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...
September 9, 2016: Journal of Thoracic Oncology
Shumeng Zhang, Bing Yan, Jing Zheng, Jing Zhao, Jianying Zhou
Lung cancer with mediastinal lymph node metastasis is more likely to develop recurrence and metastasis after complete resection and targeted therapy is a promising treatment strategy. We performed amplification refractory mutation system (ARMS) fluorescence quantitative PCR to detect the gene status of EGFR, ALK, ROS1 and RET in resected samples from 280 patients who were confirmed to have primary lung adenocarcinomas with N1-N2 lymph node metastasis. Of the 280 patients enrolled, the frequency of EGFR mutations, ALK fusions, ROS1 fusions, RET fusions and no mutations was 42...
August 22, 2016: Oncotarget
Qingling Huang, Valentina E Schneeberger, Noreen Luetteke, Chengliu Jin, Roha Afzal, Mikalai M Budzevich, Rikesh J Makanji, Gary V Martinez, Tao Shen, Lichao Zhao, Kar-Ming Fung, Eric B Haura, Domenico Coppola, Jie Wu
RET fusions have been found in lung adenocarcinoma, of which KIF5B-RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B-RET-dependent cell lines for preclinical modeling of KIF5B-RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B-RET expression. By culturing KIF5B-RET-dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RET(V804L) mutation and vandetanib-resistant-RET(G810A) mutation...
October 2016: Molecular Cancer Therapeutics
Chen Lin, Shanshan Wang, Weiwei Xie, Rongliang Zheng, Yu Gan, Jianhua Chang
The Rearranged during transfection (RET) fusion gene is a newly identified oncogenic mutation in non-small cell lung cancer (NSCLC). The aim of this study is to explore the biological functions of the gene in tumorigenesis and metastasis in RET gene fusion-driven preclinical models. We also investigate the anti-tumor activity of Apatinib, a potent inhibitor of VEGFR-2, PDGFR-β, c-Src and RET, in RET-rearranged lung adenocarcinoma, together with the mechanisms underlying. Our results suggested that KIF5B-RET fusion gene promoted cell invasion and migration, which were probably mediated through Src signaling pathway...
August 1, 2016: Oncotarget
Amanda J Watson, Gemma V Hopkins, Samantha Hitchin, Habiba Begum, Stuart Jones, Allan Jordan, Sarah Holt, H Nikki March, Rebecca Newton, Helen Small, Alex Stowell, Ian D Waddell, Bohdan Waszkowycz, Donald J Ogilvie
RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases...
2016: F1000Research
Christina Y Lee, Lauren M Sholl, Bin Zhang, Emily A Merkel, Sapna M Amin, Joan Guitart, Pedram Gerami
The natural history of atypical Spitz neoplasms remains poorly understood, resulting in significant patient and clinician anxiety. We sought to better characterize outcomes that correlated with molecular features by performing a prospective cohort study of pediatric atypical spitzoid neoplasms in which fluorescence in situ hybridization studies were obtained for diagnosis. Cases with sufficient tissue underwent additional retrospective assessment for translocations in ALK, NTRK1, BRAF, RET, and ROS1. Among 246 total patients assessed, 13% had a positive fluorescence in situ hybridization result...
July 7, 2016: American Journal of Dermatopathology
Jin Sung Jang, Xiaoke Wang, Peter T Vedell, Ji Wen, Jinghui Zhang, David W Ellison, Jared M Evans, Sarah H Johnson, Ping Yang, William R Sukov, Andre Oliveira, George Vasmatzis, Zhifu Sun, Jin Jen, Eunhee S Yi
BACKGROUND: We performed a genomic study in lung adenocarcinoma cases with discordant anaplastic lymphoma kinase (ALK) status by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). METHODS: DNA from formalin-fixed paraffin embedded (FFPE) tissues of 16 discordant (4 FISH+/IHC- and 12 FISH-/IHC+) cases by Vysis ALK Break Apart FISH and ALK1 IHC testing were subjected to whole gene capture and next generation sequencing (NGS) of nine genes including ALK, EML4, KIF5B, SND1, BRAF, RET, EZR, ROS1, and TERT...
June 22, 2016: Journal of Thoracic Oncology
Zhengbo Song, Xinmin Yu, Guoping Cheng, Yiping Zhang
BACKGROUND: Several clinical trials have shown that immune treatment focus on programmed death-1 and programmed death-ligand 1 (PD-L1) yields a good clinical efficacy in advanced non-small cell lung cancer (NSCLC). We investigated whether the PD-L1 expression was related to clinicopathologic and molecular characteristics in patients with surgically resected NSCLC. METHODS: Between December 2008 and 2013, formalin-fixed, paraffin-embedded samples were obtained from patients with lung adenocarcinoma at Zhejiang Cancer Hospital...
2016: Journal of Translational Medicine
Kai Wang, Jeffrey S Russell, Jessica D McDermott, Julia A Elvin, Depinder Khaira, Adrienne Johnson, Timothy A Jennings, Siraj M Ali, Molly Murray, Carrie Marshall, Dwight Oldham, Donna Washburn, Stuart Wong, Juliann Chmiekecki, Roman Yelensky, Doron Lipson, Vincent Miller, Hilary S Serracino, Philip J Stephens, Jeffrey S Ross, Daniel W Bowles
PURPOSE: We sought to identify genomic alterations (GAs) in salivary gland adenocarcinomas, not otherwise specified (NOS), salivary duct carcinomas (SDC), carcinoma ex pleomorphic adenoma (ca ex PA), and salivary carcinoma, NOS. EXPERIMENTAL DESIGN: DNA was extracted from 149 tumors. Comprehensive genomic profiling (CGP) was performed on hybridization-captured adaptor ligation-based libraries of 182 or 315 cancer-related genes plus introns from 14 or 28 genes frequently rearranged for cancer and evaluated for all classes of GAs...
June 22, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ming Zhang, Yi Pan, Xueling Qi, Yan Liu, Rongfang Dong, Danfeng Zheng, Qing Chang, Jing Zhang, Weigang Fang, Yanfeng Zhong
BACKGROUND: Isocitrate dehydrogenase (IDH) mutations have been reported as biomarkers associated with tumorigenesis and prognosis in gliomas. However, genes affected by these mutations are still under investigation. The purpose of this study is to identify new molecular biomarkers associated with IDH mutation and prognosis in astrocytic tumors, which account for the largest proportion of gliomas. MATERIALS AND METHODS: NanoString analysis was conducted on 40 astrocytic tumors...
June 2, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Arnaud Uguen, Marc De Braekeleer
The ROS1 gene belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. A literature review identified a ROS1 fusion in 2.54% of the patients with lung adenocarcinoma and even higher frequencies in spitzoid neoplasms and inflammatory myofibroblastic tumors. At present, 26 genes were found to fuse with ROS1, some of them already known to fuse with RET and ALK. All the fusion proteins retain the ROS1 kinase domain, but rarely its transmembrane domain. Most of the partners have dimerization domains that are retained in the fusion, presumably leading to constitutive ROS1 tyrosine kinase activation...
August 2016: Future Oncology
L Heukamp, R Menon, J Müller, S Lakis, M Netchaeva, F Griesinger, W Eberhardt, J M Heuckmann
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
Mi-Sook Lee, Ryong Nam Kim, Hoseok I, Doo-Yi Oh, Ji-Young Song, Ka-Won Noh, Yu-Jin Kim, Jung Wook Yang, Maruja E Lira, Chang Hun Lee, Min Ki Lee, Yeoung Dae Kim, Mao Mao, Joungho Han, Jhingook Kim, Yoon-La Choi
REarranged during Transfection (RET) fusion genes are detected in approximately 1% of lung adenocarcinomas and known primarily as oncogenic driver factors. Here, we found a novel RET fusion gene, KIAA1217-RET, and examined the functional differences of RET51 and RET9 protein, fused with KIAA1217 in cancer progression and drug response. KIAA1217-RET, resulting from the rearrangement of chromosome 10, was generated by the fusion of KIAA1217 exon 11 and RET exon 11 from a non-small cell lung cancer patient. Expression of this gene led to increased cell growth and invasive properties through activations of the PI3K/AKT and ERK signaling pathways and subsequently enabled oncogenic transformation of lung cells...
May 2, 2016: Oncotarget
Katayoon Kasaian, Sam M Wiseman, Blair A Walker, Jacqueline E Schein, Martin Hirst, Richard A Moore, Andrew J Mungall, Marco A Marra, Steven J M Jones
Medullary thyroid cancer (MTC) is a malignancy of the calcitonin-producing parafollicular cells of the thyroid gland. Surgery is the only curative treatment for this cancer. External beam radiation therapy is reserved for adjuvant treatment of MTC with aggressive features. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large subpopulation of MTCs...
March 2016: Cold Spring Harbor Molecular Case Studies
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