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Michaël Duruisseaux, Anne McLeer-Florin, Martine Antoine, Sanaz Alavizadeh, Virginie Poulot, Roger Lacave, Nathalie Rabbe, Jacques Cadranel, Marie Wislez
Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28-87% of the cases. NRG1 fusions were recently discovered in KRAS-negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed...
October 21, 2016: Cancer Medicine
A S Mansfield, S J Murphy, F R Harris, S I Robinson, R S Marks, S H Johnson, J B Smadbeck, G C Halling, E S Yi, D Wigle, G Vasmatzis, J Jen
BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy...
October 14, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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
Limin Zhang, Tao Jiang, Chao Zhao, Wei Li, Xuefei Li, Sha Zhao, Xiaozhen Liu, Yijun Jia, Hui Yang, Shengxiang Ren, Caicun Zhou
BACKGROUND: ROS1 rearrangement is a novel molecular subgroup of non-small-cell lung cancer (NSCLC). This study aimed to investigate the efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement. RESULTS: A total of 2309 patients received ROS1 fusion detection and 51(2.2%) patients had ROS1 rearrangement. There was no significant difference between ROS1 fusion-positive and fusion-negative cohorts in demographic data...
October 12, 2016: Oncotarget
Wensheng Ge, Chaodong Han, Jing Wang, Yunping Zhang
Laryngeal squamous cell carcinoma (LSCC) is a common aggressive head and neck cancer with high mortality and incidence. MicroRNAs (miRNAs) are short, non-coding and endogenous RNAs that posttranscriptionally inhibit gene expression. In this study, we showed that miR-300 expression was downregulated in LSCC tissues compared with adjacent no-tumor tissues. MiR-300 overexpression inhibited Hep-2 cell proliferation, as well as the expression of ki-67 and PCNA. Moreover, overexpression of miR-300 repressed the cell invasion in Hep-2 cells...
2016: American Journal of Translational Research
Jing Zhao, Jing Zheng, Mei Kong, Jianya Zhou, Wei Ding, Jianying Zhou
Defining distinctive histologic characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) may help identify cases that merit molecular testing. However, the majority of previous reports have focused on surgical specimens but only limited studies assessed histomorphology of advanced NSCLCs. In order to identify the clinical and histological characteristics of ROS1-rearranged advanced NSCLCs, we examined five hundred sixteen Chinese patients with advanced NSCLCs using ROS1 fluorescence in situ hybridization and real-time polymerase chain reaction and then analyzed for clinical and pathological features...
September 30, 2016: Oncotarget
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
Adam J de Smith, Juhi Ojha, Stephen S Francis, Erica Sanders, Alyson A Endicott, Helen M Hansen, Ivan Smirnov, Amanda M Termuhlen, Kyle M Walsh, Catherine Metayer, Joseph L Wiemels
High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4)...
September 24, 2016: Oncotarget
M Caccese, R Ferrara, S Pilotto, L Carbognin, G Grizzi, A Caliò, M Brunelli, F Cuppone, S Petraglia, A Scarpa, G Tortora, E Bria
The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies...
October 8, 2016: Expert Opinion on Pharmacotherapy
Yu Yang, Honggui La, Kai Tang, Daisuke Miki, Lan Yang, Bangshing Wang, Cheng-Guo Duan, Wenfeng Nie, Xingang Wang, Siwen Wang, Yufeng Pan, Elizabeth J Tran, Lizhe An, Huiming Zhang, Jian-Kang Zhu
Epigenetic regulation is important for organismal development and response to the environment. Alteration in epigenetic status has been known mostly from the perspective of enzymatic actions of DNA methylation and/or histone modifications. In a genetic screen for cellular factors involved in preventing epigenetic silencing, we isolated an Arabidopsis mutant defective in SAC3B, a component of the conserved TREX-2 complex that couples mRNA transcription with nuleo-cytoplasmic export. Arabidopsis SAC3B dysfunction causes gene silencing at transgenic and endogenous loci, accompanied by elevation in the repressive histone mark H3K9me2 and by reduction in RNA polymerase Pol II occupancy...
September 26, 2016: Nucleic Acids Research
Jianya Zhou, Jing Zhao, Jing Zheng, Mei Kong, Ke Sun, Bo Wang, Xi Chen, Wei Ding, Jianying Zhou
AIMS: To identify the clinical and histological characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) and build a prediction model to prescreen suitable patients for molecular testing. METHODS AND RESULTS: We identified 27 cases of ROS1-rearranged lung adenocarcinomas in 1165 patients with NSCLCs confirmed by real-time PCR and FISH and performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement and finally developed prediction model...
2016: PloS One
Sergey Lekomtsev, Sofia Aligianni, Ana Lapao, Tilmann Bürckstümmer
BACKGROUND: Chromosomal translocations are a hallmark of cancer cells and give rise to fusion oncogenes. To gain insight into the mechanisms governing tumorigenesis, adequate model cell lines are required. RESULTS: We employ the versatile CRISPR/Cas system to engineer cell lines in which chromosomal translocations are either generated de novo (CD74-ROS1) or existing translocations are reverted back to the original configuration (BCR-ABL1). To this end, we co-apply two guide RNAs to artificially generate two breakpoints and screen for spontaneous fusion events by PCR...
2016: BMC Genomics
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
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
Tindara Franchina, Alessandro Russo, Giuseppina Rosaria Ricciardi, Giuseppina Liguori, Astrid Herberg, Nicola Normanno, Vincenzo Adamo
During the last decade the therapeutic landscape of Non Small Cell Lung Cancer (NSCLC) has profoundly changed with the identification of actionable genetic alterations that defined molecularly selected subgroups of patients with specific clinic-pathological characteristics and increased sensitivity to specific targeted agents. The presence of ROS1 rearrangements defines a small subgroup of lung adenocarcinomas (∼1-2%) with peculiar clinic-pathological characteristics and increased sensitivity to Crizotinib...
August 12, 2016: Cancer Biology & Therapy
Christina I Selinger, Bob T Li, Nick Pavlakis, Matthew Links, Anthony J Gill, Adrian Lee, Stephen Clarke, Thang N Tran, Trina Lum, Po Yee Yip, Lisa Horvath, Bing Yu, Maija R J Kohonen-Corish, Sandra A O'Toole, Wendy A Cooper
AIMS: To assess the prevalence of ROS1 rearrangements in a retrospective and prospective diagnostic Australian cohort and evaluate the effectiveness of immunohistochemical screening. METHODS: A retrospective cohort of 278 early stage lung adenocarcinomas and an additional 104 prospective NSCLC cases referred for routine molecular testing were evaluated. ROS1 immunohistochemistry (IHC) was performed (D4D6 clone, Cell Signaling Technology) on all cases as well as fluorescence in situ hybridisation (FISH) using the ZytoVision and Abbott Molecular ROS1 FISH probes, with >15% of cells with split signals considered positive for rearrangement...
September 6, 2016: Histopathology
Fang Zhou, Andre L Moreira
Context .- In the burgeoning era of molecular genomics, immunoperoxidase (IPOX) testing grows increasingly relevant as an efficient and effective molecular screening tool. Patients with lung carcinoma may especially benefit from the use of IPOX because most lung carcinomas are inoperable at diagnosis and only diagnosed by small tissue biopsy or fine-needle sampling. When such small specimens are at times inadequate for molecular testing, positive IPOX results still provide actionable information. Objective ...
September 2, 2016: Archives of Pathology & Laboratory Medicine
D F Heigener, M Horn, M Reck
Between 10 and 15 % of non-small cell lung cancers (NSCLC) proliferate due to the presence of a so-called driver mutation. This molecular alteration allows the cancer to continue to proliferate and can be deliberately inhibited. In addition to mutations in the epidermal growth factor receptor gene (EGFR) and translocations between the echinoderm microtubule-associated protein-like 4 gene (EML 4) and the anaplastic lymphoma kinase gene (ALK), this applies to ROS1 gene translocations. For the former two alterations, many inhibitors are already available, whereas for ROS1 and other driving mutations the evidence is sparse due to the rare occurrence of these mutations in NSCLC...
September 1, 2016: Der Internist
Marcel Wiesweg, Wilfried E E Eberhardt, Henning Reis, Saskia Ting, Nikoleta Savvidou, Charlotte Skiba, Thomas Herold, Daniel C Christoph, Johannes Meiler, Karl Worm, Stefan Kasper, Dirk Theegarten, Jörg Hense, Thomas Hager, Kaid Darwiche, Filiz Oezkan, Clemens Aigner, Stefan Welter, Hilmar Kühl, Martin Stuschke, Kurt W Schmid, Martin Schuler
PURPOSE: Chromosomal rearrangements involving ROS1 define a rare entity of lung adenocarcinomas with exquisite sensitivity to molecularly targeted therapy. We report clinical outcomes and genomic findings of patients with ROS1-positive lung cancer that were prospectively identified within a multiplex biomarker profiling program at the West German Cancer Center. PATIENTS AND METHODS: Standardized immunohistochemistry, fluorescence in situ-hybridization (FISH) and hotspot mutation analyses were performed in 1,345 advanced cancer patients, including 805 patients with metastatic lung adenocarcinoma...
August 26, 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
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