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https://www.readbyqxmd.com/read/29227476/the-molecular-landscape-of-pediatric-acute-myeloid-leukemia-reveals-recurrent-structural-alterations-and-age-specific-mutational-interactions
#1
Hamid Bolouri, Jason E Farrar, Timothy Triche, Rhonda E Ries, Emilia L Lim, Todd A Alonzo, Yussanne Ma, Richard Moore, Andrew J Mungall, Marco A Marra, Jinghui Zhang, Xiaotu Ma, Yu Liu, Yanling Liu, Jaime M Guidry Auvil, Tanja M Davidsen, Patee Gesuwan, Leandro C Hermida, Bodour Salhia, Stephen Capone, Giridharan Ramsingh, Christian Michel Zwaan, Sanne Noort, Stephen R Piccolo, E Anders Kolb, Alan S Gamis, Malcolm A Smith, Daniela S Gerhard, Soheil Meshinchi
We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults...
December 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29226803/quantitative-missense-variant-effect-prediction-using-large-scale-mutagenesis-data
#2
Vanessa E Gray, Ronald J Hause, Jens Luebeck, Jay Shendure, Douglas M Fowler
Large datasets describing the quantitative effects of mutations on protein function are becoming increasingly available. Here, we leverage these datasets to develop Envision, which predicts the magnitude of a missense variant's molecular effect. Envision combines 21,026 variant effect measurements from nine large-scale experimental mutagenesis datasets, a hitherto untapped training resource, with a supervised, stochastic gradient boosting learning algorithm. Envision outperforms other missense variant effect predictors both on large-scale mutagenesis data and on an independent test dataset comprising 2,312 TP53 variants whose effects were measured using a low-throughput approach...
December 1, 2017: Cell Systems
https://www.readbyqxmd.com/read/29225165/cross-talk-between-tp53-and-c-myc-in-the-pathophysiology-of-diamond-blackfan-anemia-evidence-from-rpl11-deficient-in-vivo-and-in-vitro-models
#3
Anirban Chakraborty, Tamayo Uechi, Yukari Nakajima, Hanna T Gazda, Marie-Françoise O'Donohue, Pierre-Emmanuel Gleizes, Naoya Kenmochi
Mutations in genes encoding ribosomal proteins have been identified in Diamond-Blackfan anemia (DBA), a rare genetic disorder that presents with a prominent erythroid phenotype. TP53 has been implicated in the pathophysiology of DBA with ribosomal protein (RP) L11 playing a crucial role in the TP53 response. Interestingly, RPL11 also controls the transcriptional activity of c-Myc, an oncoprotein that positively regulates ribosome biogenesis. In the present study, we analyzed the consequences of rpl11 depletion on erythropoiesis and ribosome biogenesis in zebrafish...
December 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29225033/mutant-p53-gains-its-function-via-c-myc-activation-upon-cdk4-phosphorylation-at-serine-249-and-consequent-pin1-binding
#4
Peng Liao, Shelya X Zeng, Xiang Zhou, Tianjian Chen, Fen Zhou, Bo Cao, Ji Hoon Jung, Giannino Del Sal, Shiwen Luo, Hua Lu
TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS's nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization...
November 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29222670/venetoclax-for-treating-chronic-lymphocytic-leukaemia-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#5
REVIEW
Hema Mistry, Chidozie Nduka, Martin Connock, Jill Colquitt, Theodoros Mantopoulos, Emma Loveman, Renata Walewska, James Mason
Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities...
December 8, 2017: PharmacoEconomics
https://www.readbyqxmd.com/read/29222276/optimizing-frontline-therapy-of-cll-based-on-clinical-and-biological-factors
#6
REVIEW
Kirsten Fischer, Michael Hallek
The heterogeneity of the clinical course of chronic lymphocytic leukemia (CLL) ranges from an indolent course, where patients do not require therapy for many years, to a very aggressive disease, where treatment is required soon after diagnosis and relapses may occur early. The improved tools for prognostication allow predicting the outcome of patients with increasing reliability. Some markers also allow selecting more specific therapies with improved activity in the presence of certain genetic or clinical features of CLL...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222275/the-mutational-landscape-of-chronic-lymphocytic-leukemia-and-its-impact-on-prognosis-and-treatment
#7
REVIEW
Gianluca Gaidano, Davide Rossi
The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29221181/analysis-of-ctcl-cell-lines-reveals-important-differences-between-mycosis-fungoides-s%C3%A3-zary-syndrome-vs-htlv-1-leukemic-cell-lines
#8
Elena Netchiporouk, Jennifer Gantchev, Matthew Tsang, Philippe Thibault, Andrew K Watters, John-Douglas Matthew Hughes, Feras M Ghazawi, Anders Woetmann, Niels Ødum, Denis Sasseville, Ivan V Litvinov
HTLV-1 is estimated to affect ~20 million people worldwide and in ~5% of carriers it produces Adult T-Cell Leukemia/Lymphoma (ATLL), which can often masquerade and present with classic erythematous pruritic patches and plaques that are typically seen in Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most recognized variants of Cutaneous T-Cell Lymphomas (CTCL). For many years the role of HTLV-1 in the pathogenesis of MF/SS has been hotly debated. In this study we analyzed CTCL vs. HTLV-1+ leukemic cells...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29218851/clinical-experience-with-the-bcl2-inhibitor-venetoclax-in-combination-therapy-for-relapsed-and-refractory-acute-myeloid-leukemia-and-related-myeloid-malignancies
#9
Courtney D DiNardo, Caitlin R Rausch, Christopher Benton, Tapan Kadia, Nitin Jain, Naveen Pemmaraju, Naval Daver, Wendy Covert, Kayleigh R Marx, Morgan Mace, Elias Jabbour, Jorge Cortes, Guillermo Garcia-Manero, Farhad Ravandi, Kapil N Bhalla, Hagop Kantarjian, Marina Konopleva
INTRODUCTION: Venetoclax (VEN), a selective BCL2 inhibitor, has single-agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML) and efficacy in lower-intensity combinations for treatment-naïve elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported. METHODS: All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed...
December 8, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29218432/the-2016-revision-of-the-who-classification-of-central-nervous-system-tumours-retrospective-application-to-a-cohort-of-diffuse-gliomas
#10
Te Whiti Rogers, Gurvinder Toor, Katharine Drummond, Craig Love, Kathryn Field, Rebecca Asher, Alpha Tsui, Michael Buckland, Michael Gonzales
The classification of central nervous system tumours has more recently been shaped by a focus on molecular pathology rather than histopathology. We re-classified 82 glial tumours according to the molecular-genetic criteria of the 2016 revision of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Initial diagnoses and grading were based on the morphological criteria of the 2007 WHO scheme. Because of the impression of an oligodendroglial component on initial histological assessment, each tumour was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH-1 and 2) genes...
December 7, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29217530/the-impact-of-smoking-and-tp53-mutations-in-lung-adenocarcinoma-patients-with-targetable-mutations-the-lung-cancer-mutation-consortium-lcmc2
#11
Dara L Aisner, Lynette M Sholl, Lynne Berry, Michael Rossi, Heidi Chen, Junya Fujimoto, Andre L Moreira, Suresh Ramalingam, Liza C Villaruz, Gregory A Otterson, Eric B Haura, Katerina Politi, Bonnie S Glisson, Jeremy Cetnar, Edward Garon, Joan Schiller, Saiama Waqar, Lecia V Sequist, Julie R Brahmer, Yu Shyr, Kelly Kugler, Ignacio Ivan Wistuba, Bruce E Johnson, John D Minna, Mark G Kris, Paul A Bunn, David J Kwiatkowski
PURPOSE Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. PATIENTS AND METHODS Sixteen U.S. institutions enrolled 1367 lung cancer patients in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and immunohistochemistry...
December 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29211816/clinical-outcome-and-molecular-characterisation-of-chemorefractory-metastatic-colorectal-cancer-patients-with-long-term-efficacy-of-regorafenib-treatment
#12
Erika Martinelli, Vincenzo Sforza, Claudia Cardone, Anna Capasso, Anna Nappi, Giulia Martini, Stefania Napolitano, Anna Maria Rachiglio, Nicola Normanno, Salvatore Cappabianca, Alfonso Reginelli, Maurizio Di Bisceglie, Tiziana Pia Latiano, Evaristo Maiello, Michele Orditura, Fernando De Vita, Floriana Morgillo, Fortunato Ciardiello, Teresa Troiani
HASH(0x525b0a8) Background: To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment. Methods: Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (<7 and ≥7)...
2017: ESMO Open
https://www.readbyqxmd.com/read/29211306/telomerase-reverse-transcriptase-promoter-alterations-across-cancer-types-as-detected-by-next-generation-sequencing-a-clinical-and-molecular-analysis-of-423-patients
#13
Maria Schwaederle, Nithya Krishnamurthy, Gregory A Daniels, David E Piccioni, Santosh Kesari, Paul T Fanta, Richard B Schwab, Sandip P Patel, Barbara A Parker, Razelle Kurzrock
BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015...
December 6, 2017: Cancer
https://www.readbyqxmd.com/read/29207176/p4hb-and-pdia3-are-associated-with-tumor-progression-and-therapeutic-outcome-of-diffuse-gliomas
#14
Hecun Zou, Chunjie Wen, Zhigang Peng, Ying-Υing Shao, Lei Hu, Shuang Li, Cuilin Li, Hong-Hao Zhou
Diffuse gliomas are the most common type of primary brain and central nervous system (CNS) tumors. Protein disulfide isomerases (PDIs) such as P4HB and PDIA3 act as molecular chaperones for reconstructing misfolded proteins, and are involved in endoplasmic reticulum stress and the unfolded protein response. The present study focused on the role of P4HB and PDIA3 in diffuse gliomas. Analysis of GEO and HPA data revealed that the expression levels of P4HB and PDIA3 were upregulated in glioma datasets. their increased expression was then validated in 99 glioma specimens compared with 11 non-tumor tissues...
December 4, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29206995/concordance-of-circulating-tumor-dna-and-matched-metastatic-tissue-biopsy-in-prostate-cancer
#15
Alexander W Wyatt, Matti Annala, Rahul Aggarwal, Kevin Beja, Felix Feng, Jack Youngren, Adam Foye, Paul Lloyd, Matti Nykter, Tomasz M Beer, Joshi J Alumkal, George V Thomas, Robert E Reiter, Matthew B Rettig, Christopher P Evans, Allen C Gao, Kim N Chi, Eric J Small, Martin E Gleave
Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling...
December 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29206716/primary-epithelioid-angiosarcoma-of-finger-masquerading-as-epithelioid-hemangioma-report-of-a-case-and-analysis-of-mutational-pattern-in-epithelioid-hemangiomas-and-angiosarcomas-by-next-generation-sequencing
#16
Manish M Subramaniam, Nur L Salleh, Bingcheng Wu, Michelle A Rozario, HueyJin Lim, Mark E Puhaindran, Richie Soong, Victor K Lee
AIMS: We report an unusual case of epithelioid angiosarcoma (AS) mimicking an epithelioid hemangioma (EH) and analyze mutational patterns in EHs and ASs. METHODS AND RESULTS: A 58-year-old woman presented with a finger lump and metastatic lung nodules. Initial needle biopsies showed an EH, with only focal atypical histologic features. The patient underwent finger amputation and resection of lung nodules. The amputation specimen and lung nodules revealed features of AS...
January 2018: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29203461/identifying-and-targeting-sporadic-oncogenic-genetic-aberrations-in-mouse-models-of-triple-negative-breast-cancer
#17
Hui Liu, Charles J Murphy, Florian A Karreth, Kristina B Emdal, Forest M White, Olivier Elemento, Alex Toker, Gerburg M Wulf, Lewis C Cantley
Triple negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole exome sequencing (WES) and RNAseq to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expressions or oncoprotein-containing fusions, respectively, as well as frame-shift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated...
December 4, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29202330/genetic-alterations-in-sporadic-triple-negative-breast-cancer
#18
Laura-Ancuta Pop, Roxana-Maria Cojocneanu-Petric, Valentina Pileczki, Gabriela Morar-Bolba, Alexandru Irimie, Vladimir Lazar, Claudio Lombardo, Angelo Paradiso, Ioana Berindan-Neagoe
BACKGROUND: Recent studies have aimed to identify gene mutation profiles to explain the cause of TNBC therapy limitations. METHODS: The purpose of our study was to use Next Generation Sequencing (NGS) of 46 genes with a well-defined role in cancer in a cohort of TNBC patients in order to identify novel markers that could lead to the development of strategic, adjuvant, gene-targeted therapies. RESULTS: A total of 118 gene mutations in 35 genes, 75 mutations in BRCA1 and 92 mutations in BRCA2 were identified...
December 1, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/29196926/glioblastoma-and-acute-myeloid-leukemia-malignancies-with-striking-similarities
#19
REVIEW
Eric Goethe, Bing Z Carter, Ganesh Rao, Naveen Pemmaraju
Acute myeloid leukemia (AML) and glioblastoma (GB) are two malignancies associated with high incidence of treatment refractoriness and generally, uniformly poor survival outcomes. While the former is a hematologic (i.e. a "liquid") malignancy and the latter a solid tumor, the two diseases share both clinical and biochemical characteristics. Both diseases exist predominantly in primary (de novo) forms, with only a small subset of each progressing from precursor disease states like the myelodysplastic syndromes or diffuse glioma...
December 1, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29192130/transplantation-for-therapy-related-tp53-mutated-myelodysplastic-syndrome-not-because-we-can-but-because-we-should
#20
EDITORIAL
Corey Cutler
No abstract text is available yet for this article.
December 2017: Haematologica
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