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https://www.readbyqxmd.com/read/28433570/association-between-environmental-tobacco-smoke-exposure-and-the-occurrence-of-egfr-mutations-and-alk-rearrangements-in-never-smokers-with-non-small-cell-lung-cancer-analyses-from-a-prospective-multinational-ets-registry
#1
Ross A Soo, Akihito Kubo, Masahiko Ando, Tomoya Kawaguchi, Myung-Ju Ahn, Sai-Hong Ignatius Ou
BACKGROUND: Molecular studies have demonstrated actionable driver oncogene alterations are more frequent in never-smokers with non-small-cell lung cancer (NSCLC). The etiology of these driver oncogenes in patients with NSCLC remains unknown, and environmental tobacco smoke (ETS) is a potential cause in these cases. MATERIALS AND METHODS: We assembled clinical and genetic information for never-smoker patients with NSCLC accrued in Japan, Korea, Singapore, and the United States...
January 19, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28433077/development-and-clinical-utility-of-a-blood-based-test-service-for-the-rapid-identification-of-actionable-mutations-in-non-small-cell-lung-carcinoma
#2
Hestia Mellert, Trudi Foreman, Leisa Jackson, Dianna Maar, Scott Thurston, Kristina Koch, Amanda Weaver, Samantha Cooper, Nicholas Dupuis, Ubaradka G Sathyanarayana, Jakkie Greer, Westen Hahn, Dawne Shelton, Paula Stonemetz, Gary A Pestano
Nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder the ability to pursue optimal treatment strategies. This study validates a blood-based genome-testing service that provides accurate results within 72 hours. We focused on targetable variants in advanced non-small cell lung carcinoma-epidermal growth factor receptor gene (EGFR) variant L858R, exon 19 deletion (ΔE746-A750), and T790M; GTPase Kirsten ras gene (KRAS) variants G12C/D/V; and echinoderm microtubule associated protein like and 4 anaplastic lymphoma receptor tyrosine kinase fusion (EML4-ALK) transcripts 1/2/3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28433076/identification-of-ntrk3-fusions-in-childhood-melanocytic-neoplasms
#3
Lu Wang, Klaus J Busam, Ryma Benayed, Robert Cimera, Jiajing Wang, Ryan Denley, Mamta Rao, Ruth Aryeequaye, Kerry Mullaney, Long Cao, Marc Ladanyi, Meera Hameed
Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism array, which showed intragenic copy number changes in NTRK3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28432277/transforming-growth-factor-%C3%AE-1-promotes-invasion-of-human-jeg-3-trophoblast-cells-via-tgf-%C3%AE-smad3-signaling-pathway
#4
Zhongying Huang, Shangwei Li, Wei Fan, Qianhong Ma
Transforming growth factor (TGF)-β1 is involved invasion of human trophoblasts. However, the underlying mechanisms remain unclear. In this study, we performed Transwell assay and found that TGF-β1 promoted the invasion of trophoblast cell line JEG-3. Treatment with TGF-β1 up-regulated the expression of receptor-regulated Smad transcription factors Smad2 and Smad3, and two invasive-associated genes, namely, matrix metallopeptidase (MMP)-9 and MMP-2, in JEG-3 cells. Over-expressing activin receptor-like kinase (ALK) 5, the TGF-β type I receptor (TβRI) enhanced the up-regulation of Smad2, Smad3, MMP-9, and MMP-2 induced by TGF-β1, whereas application of TβRI inhibitor SB431542 diminished the stimulatory effects of TGF-β1 on these genes...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28431340/first-macrocyclic-3-rd-generation-alk-inhibitor-for-treatment-of-alk-ros1-cancer-clinical-and-designing-strategy-update-of-lorlatinib
#5
REVIEW
Sulman Basit, Zaman Ashraf, Kwangho Lee, Muhammad Latif
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2(nd)-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3(rd)-generation macrocyclic ALK-TKI that demonstrates many advantages over 2(nd)-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28428274/egfr-mediates-responses-to-small-molecule-drugs-targeting-oncogenic-fusion-kinases
#6
Aria Vaishnavi, Laura Schubert, Uwe Rix, Lindsay A Marek, Anh T Le, Stephen Keysar, Magdalena J Glogowska, Matthew A Smith, Severine L Kako, Natalia J Sumi, Kurtis D Davies, Kathryn E Ware, Marileila Varella-Garcia, Eric B Haura, Antonio Jimeno, Lynn E Heasley, Dara L Aisner, Robert C Doebele
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28427247/molecular-testing-of-lung-cancers
#7
Hyo Sup Shim, Yoon-La Choi, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Mee Sook Roh, Tae-Jung Kim, Seung Yeon Ha, Jin-Haeng Chung, Se Jin Jang, Geon Kook Lee
Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics...
April 21, 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28423587/the-correlation-between-programmed-death-ligand-1-expression-and-driver-gene-mutations-in-nsclc
#8
Haitao Yang, Huijuan Chen, Shuimei Luo, Lina Li, Sijing Zhou, Ruifen Shen, Heng Lin, Xianhe Xie
OBJECTIVES: This study aimed to evaluate the correlation between positive PD-L1 expression and driver gene mutations in NSCLC and to seek preliminary evidence in favor of the strategy of PD-L1 inhibitors plus targeted agents. RESULTS: The overall analyses revealed that positive PD-L1 expression had a significant relationship with KRAS status (RR = 1.26; 95% CI, 1.06-1.50, P = 0.010), but no correlation with clinical characteristics (gender, smoking status, histological types), driver gene status (EGFR, ALK) and overall survival (OS): male versus female (RR = 1...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423360/tiam1-variants-improve-clinical-outcome-in-neuroblastoma
#9
Elena Sanmartín, Yania Yáñez, Victoria Fornés-Ferrer, José L Zugaza, Adela Cañete, Victoria Castel, Jaime Font de Mora
Identification of tumor driver mutations is crucial for improving clinical outcome using a personalized approach to the treatment of cancer. Neuroblastoma is a tumor of the peripheral sympathetic nervous system for which only a few driver alterations have been described including MYCN amplification and ALK mutations. We assessed 106 primary neuroblastoma tumors by next generation sequencing using a customized amplicon-based gene panel. Our results reveal that genetic variants in TIAM1 gene associate with better clinical outcome, suggesting a role for these TIAM1 variants in preventing progression of this disease...
April 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415793/clinical-framework-for-next-generation-sequencing-based-analysis-of-treatment-predictive-mutations-and-multiplexed-gene-fusion-detection-in-non-small-cell-lung-cancer
#10
Kajsa Ericson Lindquist, Anna Karlsson, Per Levéen, Hans Brunnström, Christel Reuterswärd, Karolina Holm, Mats Jönsson, Karin Annersten, Frida Rosengren, Karin Jirström, Jaroslaw Kosieradzki, Lars Ek, Åke Borg, Maria Planck, Göran Jönsson, Johan Staaf
Precision medicine requires accurate multi-gene clinical diagnostics. We describe the implementation of an Illumina TruSight Tumor (TST) clinical NGS diagnostic framework and parallel validation of a NanoString RNA-based ALK, RET, and ROS1 gene fusion assay for combined analysis of treatment predictive alterations in non-small cell lung cancer (NSCLC) in a regional healthcare region of Sweden (Scandinavia). The TST panel was clinically validated in 81 tumors (99% hotspot mutation concordance), after which 533 consecutive NSCLCs were collected during one-year of routine clinical analysis in the healthcare region (~90% advanced stage patients)...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414323/pyrimidine-tract-binding-protein-1-mediates-pyruvate-kinase-m2-dependent-phosphorylation-of-signal-transducer-and-activator-of-transcription-3-and-oncogenesis-in-anaplastic-large-cell-lymphoma
#11
Steven R Hwang, Carlos Murga-Zamalloa, Noah Brown, Johnvesly Basappa, Scott Rp McDonnell, Veronica Mendoza-Reinoso, Venkatesha Basrur, Ryan Wilcox, Kojo Elenitoba-Johnson, Megan S Lim
PKM2 (pyruvate kinase M2), a critical regulator of glycolysis, is phosphorylated by numerous growth factor receptors and oncogenic tyrosine kinases including NPM-ALK which is expressed in a subset of aggressive T-cell non-Hodgkin lymphomas known as anaplastic large cell lymphoma, ALK-positive. Our previous work demonstrated that phosphorylation of Y105-PKM2 by NPM-ALK regulates a major metabolic shift to promote lymphomagenesis. In addition to its role in metabolism, recent studies have shown that PKM2 promotes oncogenesis by phosphorylating nuclear STAT3 (signal transducer and activator of transcription 3) and regulating transcription of genes involved in cell survival and proliferation...
April 17, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28409069/efficiency-of-crizotinib-on-an-alk-positive-inflammatory-myofibroblastic-tumor-of-the-central-nervous-system-a-case-report
#12
Anas Chennouf, Elizabeth Arslanian, David Roberge, France Berthelet, Michel Bojanowski, Jean-Paul Bahary, Laura Masucci, Karl Belanger, Marie Florescu, Philip Wong
Inflammatory myofibroblastic tumors (IMT) of the central nervous system (CNS) are rare entities that have a predilection for local recurrences. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in the over-expression of the anaplastic lymphoma kinase (ALK) gene. We hereby present the case of a patient diagnosed with a left parieto-occipital IMT that recurred after multiple surgeries and radiotherapy. Immuno-histochemical examination of the tumor demonstrated ALK overexpression and the presence of an ALK rearrangement observed in lung cancers...
March 2, 2017: Curēus
https://www.readbyqxmd.com/read/28378229/advances-in-the-development-of-molecularly-targeted-agents-in-non-small-cell-lung-cancer
#13
Saoirse O Dolly, Dearbhaile C Collins, Raghav Sundar, Sanjay Popat, Timothy A Yap
Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival...
April 4, 2017: Drugs
https://www.readbyqxmd.com/read/28370702/effects-of-smyd2-mediated-eml4-alk-methylation-on-the-signaling-pathway-and-growth-in-non-small-cell-lung-cancer-cells
#14
Rui Wang, Xiaolan Deng, Yuichiro Yoshioka, Theodore Vougiouklakis, Jae-Hyun Park, Takehiro Suzuki, Naoshi Dohmae, Koji Ueda, Ryuji Hamamoto, Yusuke Nakamura
A specific subtype of non-small cell lung cancer (NSCLC) characterized with an EML4-ALK fusion gene, which drives constitutive oncogenic activation of ALK kinase, shows a good clinical response to ALK inhibitors. We have reported multiple examples implying the biological significance of methylation on non-histone proteins including oncogenic kinases in human carcinogenesis. Through the process to search substrates for various methyltransferases using an in vitro methyltransferase assay, we found that a lysine methyltransferase SMYD2 could methylate lysine residues 1451, 1455 and 1610 in ALK protein...
April 1, 2017: Cancer Science
https://www.readbyqxmd.com/read/28369060/the-zic-family-homologue-odd-paired-regulates-alk-expression-in-drosophila
#15
Patricia Mendoza-García, Fredrik Hugosson, Mahsa Fallah, Michael L Higgins, Yasuno Iwasaki, Kathrin Pfeifer, Georg Wolfstetter, Gaurav Varshney, Dmitry Popichenko, J Peter Gergen, Korneel Hens, Bart Deplancke, Ruth H Palmer
The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression...
April 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28368455/tracking-a-cad-alk-gene-rearrangement-in-urine-and-blood-of-a-colorectal-cancer-patient-treated-with-an-alk-inhibitor
#16
G Siravegna, A Sartore-Bianchi, B Mussolin, A Cassingena, A Amatu, L Novara, M Buscarino, G Corti, G Crisafulli, A Bartolini, F Tosi, M Erlander, F Di Nicolantonio, S Siena, A Bardelli
Background: Monitoring response and resistance to kinase inhibitors is essential to precision cancer medicine, and is usually investigated by molecular profiling of a tissue biopsy obtained at progression. However, tumor heterogeneity and tissue sampling bias limit the effectiveness of this strategy. In addition, tissue biopsies are not always feasible and are associated with risks due to the invasiveness of the procedure. To overcome these limitations, blood-based liquid biopsy analysis has proven effective to non-invasively follow tumor's clonal evolution...
March 24, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28364271/alk-rearrangement-in-specific-subtypes-of-lung-adenocarcinoma-immunophenotypic-and-morphological-features
#17
Luciana Possidente, Matteo Landriscina, Giuseppe Patitucci, Ludovica Borgia, Vittoria Lalinga, Giulia Vita
Lung adenocarcinomas are characterized by a variety of genetic and epigenetic changes that lead to activation of specific signaling pathways. This allowed the classification of lung adenocarcinomas according to genetic alterations and the clinical development of novel anticancer agents that affect the activity of specific oncoproteins. In such a context, chromosomal rearrangements that cause constitutive activation of ALK gene define a category of lung adenocarcinomas that is amenable to targeted therapy with ALK inhibitors...
May 2017: Medical Oncology
https://www.readbyqxmd.com/read/28359267/aberrant-expression-of-alk-and-ezh2-in-merkel-cell-carcinoma
#18
Tuukka Veija, Virve Koljonen, Tom Bohling, Mia Kero, Sakari Knuutila, Virinder Kaur Sarhadi
BACKGROUND: Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC...
March 31, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28356934/a-malignant-inflammatory-myofibroblastic-tumor-of-the-hypopharynx-harboring-the-3a-b-variants-of-the-eml4-alk-fusion-gene
#19
Lucia Anna Muscarella, Giulio Rossi, Domenico Trombetta, Annamaria La Torre, Leonarda Di Candia, Maria Cecilia Mengoli, Angelo Sparaneo, Vito Michele Fazio, Paolo Graziano
Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion...
February 2017: Oncology Letters
https://www.readbyqxmd.com/read/28351340/molecular-pathology-of-anaplastic-thyroid-carcinomas-a-retrospective-study-of-144-cases
#20
Benjamin Bonhomme, Yann Godbert, Gaelle Perot, Abir Alghuzlan, Stéphane Bardet, Geneviève Belleannée, Lise Criniere, Christine Do Cao, Geneviève Fouilhoux, Serge Guyetant, Antony Kelly, Sophie Leboulleux, Camille Buffet, Emmanuelle Leteurtre, Jean-Jacques Michels, Frédérique Tissier, Marie-Elisabeth Toubert, Michel Wassef, Clémence Pinard, Isabelle Hostein, Isabelle Soubeyran
BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare tumor with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aim of this retrospective study was to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and identify the mutational profile of ATC including TERT promoter mutation. METHODS AND MATERIALS: One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors (TUTHYREF)...
March 28, 2017: Thyroid: Official Journal of the American Thyroid Association
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