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https://www.readbyqxmd.com/read/28076841/clonal-evolution-in-therapy-related-neoplasms
#1
Emiliano Fabiani, Giulia Falconi, Luana Fianchi, Marianna Criscuolo, Tiziana Ottone, Laura Cicconi, Stefan Hohaus, Simona Sica, Massimiliano Postorino, Antonino Neri, Marta Lionetti, Giuseppe Leone, Francesco Lo-Coco, Maria Teresa Voso
Therapy-related myeloid neoplasms (t-MN) may occur as a late effect of cytotoxic therapy for a primary malignancy or autoimmune diseases in susceptible individuals. We studied the development of somatic mutations in t-MN, using a collection of follow-up samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months (range 18-108) from primary cancer diagnosis.Using Sanger and next generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the t-ALL patient had a t(4,11) translocation, resulting in the KMT2A/AFF1 fusion gene...
January 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28070990/a-targeted-next-generation-sequencing-in-the-molecular-risk-stratification-of-adult-acute-myeloid-leukemia-implications-for-clinical-practice
#2
Po-Han Lin, Huei-Ying Li, Sheng-Chih Fan, Tzu-Hang Yuan, Ming Chen, Yu-Hua Hsu, Yu-Hsuan Yang, Long-Yuan Li, Su-Peng Yeh, Li-Yuan Bai, Yu-Min Liao, Chen-Yuan Lin, Ching-Yun Hsieh, Ching-Chan Lin, Che-Hung Lin, Ming-Yu Lien, Tzu-Ting Chen, Yen-Hsuan Ni, Chang-Fang Chiu
Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable-risk groups; however, patients with intermediate-risk cytogenetics represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next-generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1(mutation) /FLT3- internal tandem duplication (ITD)(negative) were independent prognostic factors for the entire cohort...
January 10, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28063196/asxl2-mutations-are-frequently-found-in-pediatric-aml-patients-with-t-8-21-runx1-runx1t1-and-associated-with-a-better-prognosis
#3
Genki Yamato, Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Hara, Kentaro Ohki, Jun Okubo, Haruna Okuno, Kenichi Chiba, Hiroko Tanaka, Akitoshi Kinoshita, Hiroshi Moritake, Nobutaka Kiyokawa, Daisuke Tomizawa, Myoung-Ja Park, Manabu Sotomatsu, Takashi Taga, Souichi Adachi, Akio Tawa, Keizo Horibe, Hirokazu Arakawa, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric AML patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years)...
January 7, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28058097/genetics-and-epigenetics-of-myelodysplastic-syndromes-and-response-to-drug-therapy-new-insights
#4
REVIEW
Saeid Shahrabi, Abbas Khosravi, Mohammad Shahjahani, Fakher Rahim, Najmaldin Saki
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied...
October 10, 2016: Oncology Reviews
https://www.readbyqxmd.com/read/28055972/integrative-genomic-and-transcriptomic-analysis-for-pinpointing-recurrent-alterations-of-plant-homeodomain-genes-and-their-clinical-significance-in-breast-cancer
#5
Huimei Yu, Yuanyuan Jiang, Lanxin Liu, Wenqi Shan, Xiaofang Chu, Zhe Yang, Zeng-Quan Yang
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients...
December 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028029/genetic-basis-and-molecular-pathophysiology-of-classical-myeloproliferative-neoplasms
#6
William Vainchenker, Robert Kralovics
The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN restricted driver mutations including those in JAK2, calreticulin (CALR) and MPL abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the three main myeloid cytokine receptors (EPOR, G-CSFR and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28028025/genomics-of-chronic-neutrophilic-leukemia
#7
Julia E Maxson, Jeffrey W Tyner
Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the Colony Stimulating Factor 3 Receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization (WHO) guidelines have been updated to include CSF3R mutations as a part of the diagnostic criteria for CNL. Due to the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28027687/asxl1-mutations-in-myeloid-neoplasms-pathogenetic-considerations-impact-on-clinical-outcomes-and-survival
#8
Juliana Alvarez Argote, Constantin Dasanu
BACKGROUND: ASXL1 gene mutations include nonsense, missense, and frameshift mutations. Although their clinical significance is still debated, they may play an important role in the pathogenesis of several hematologic malignancies. METHODS: Herein, we offer a comprehensive review on ASXL1 mutations, and link them with survival and clinical outcomes in patients with various myeloid neoplasms. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2016...
December 27, 2016: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/27992414/dynamics-of-clonal-evolution-in-myelodysplastic-syndromes
#9
Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Mikkael A Sekeres, Tomas Radivoyevitch, Hiromichi Suzuki, Bartlomiej Przychodzen, Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Cassandra Hirsch, Teodora Kuzmanovic, Yusuke Sato, Aiko Sato-Otsubo, Thomas LaFramboise, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, Hiroko Tanaka, Yusuke Shiozawa, Inés Gómez-Seguí, Holleh D Husseinzadeh, Swapna Thota, Kathryn M Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, Jaroslaw P Maciejewski
To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones...
December 19, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27991718/polycythemia-vera-and-essential-thrombocythemia-2017-update-on-diagnosis-risk-stratification-and-management
#10
Ayalew Tefferi, Tiziano Barbui
DISEASE OVERVIEW: Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely...
January 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/27983727/the-complexity-of-interpreting-genomic-data-in-patients-with-acute-myeloid-leukemia
#11
A Nazha, A Zarzour, K Al-Issa, T Radivoyevitch, H E Carraway, C M Hirsch, B Przychodzen, B J Patel, M Clemente, S R Sanikommu, M Kalaycio, J P Maciejewski, M A Sekeres
Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML)...
December 16, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27978508/targeted-next-generation-sequencing-of-pediatric-neuro-oncology-patients-improves-diagnosis-identifies-pathogenic-germline-mutations-and-directs-targeted-therapy
#12
Cassie N Kline, Nancy M Joseph, James P Grenert, Jessica van Ziffle, Eric Talevich, Courtney Onodera, Mariam Aboian, Soonmee Cha, David R Raleigh, Steve Braunstein, Joseph Torkildson, David Samuel, Michelle Bloomer, Alejandra G de Alba Campomanes, Anuradha Banerjee, Nicholas Butowski, Corey Raffel, Tarik Tihan, Andrew W Bollen, Joanna J Phillips, W Michael Korn, Iwei Yeh, Boris C Bastian, Nalin Gupta, Sabine Mueller, Arie Perry, Theodore Nicolaides, David A Solomon
BACKGROUND: Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients. METHODS: We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes. RESULTS: Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor...
November 14, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27913526/update-from-the-latest-who-classification-of-mpns-a-user-s-manual
#13
Francesco Passamonti, Margherita Maffioli
The 2016 multiparameter World Health Organization (WHO) classification for Philadelphia-negative myeloproliferative neoplasms (MPNs) integrates clinical features, morphology, and genetic data to diagnose polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The main novelties are: (1) the reduction of the hemoglobin (Hb) level threshold to diagnose PV, now established at 16.5 g/dL for men and 16 g/dL for women (based on the identification of MPN patients with PV-consistent bone marrow [BM] features and a Hb level lower than that established in the 2008 WHO classification for PV); (2) the recognition of prefibrotic/early PMF, distinguishable from ET on the basis of BM morphology, an entity having a higher tendency to develop overt myelofibrosis or acute leukemia, and characterized by inferior survival; (3) the central role of BM morphology in the diagnosis of ET, prefibrotic/early PMF, PMF, and PV with borderline Hb values; megakaryocyte number and morphology (typical in ET, atypical in both PMF forms) accompanied by a new distinction of reticulin fibrosis grade in PMF (grade 1 in prefibrotic/early PMF and grade 2-3 in PMF) constitute diagnostic criteria; and (4) the inclusion of all mutually exclusive MPN driver mutations (JAK2, CALR, and MPL) as major diagnostic criteria in ET and PMF; 10% to 15% of these patients are triple negative, and in these cases the search for an additional clonal marker (eg, mutations in ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, and SF3B1) is warranted...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27870387/primary-myelofibrosis-2017-update-on-diagnosis-risk-stratification-and-management
#14
Ayalew Tefferi
: Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR or MPL mutation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival. DIAGNOSIS: Diagnosis is based on bone marrow morphology...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27849645/current-management-of-patients-with-chronic-myelomonocytic-leukemia
#15
Ana Alfonso, Guillermo Montalban-Bravo, Guillermo Garcia-Manero
PURPOSE OF REVIEW: The present review will focus on the current management of patients with chronic myelomonocytic leukemia (CMML) as well as in future therapeutic perspectives. RECENT FINDINGS: CMML is a clonal hematopoietic stem cell disorder characterized by peripheral blood monocytosis and myelodysplastic and myeloproliferative alterations in the bone marrow. Clinical behavior of the disease can be heterogeneous, with some patients having an indolent form of the disease, whereas others experience an aggressive course with decreased survival and eventual transformation to leukemia...
January 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/27777939/tet2-mutations-were-predictive-of-inferior-prognosis-in-the-presence-of-asxl1-mutations-in-patients-with-chronic-myelomonocytic-leukemia
#16
Yajuan Cui, Hongyan Tong, Xin Du, Bing Li, Robert Peter Gale, Tiejun Qin, Jinqin Liu, Zefeng Xu, Yue Zhang, Gang Huang, Jie Jin, Liwei Fang, Hongli Zhang, Lijuan Pan, Naibo Hu, Shiqiang Qu, Zhijian Xiao
BACKGROUND: Somatic mutations involving epigenetic regulators, histone modification and chromatin regulation, splicing components, transcription factors and signaling regulator genes are common in chronic myelomonocytic leukemia (CMML) patients. It has been consensus that ASXL1 mutations have adversely impact on overall survival (OS), while the effect of TET2 mutations remains controversial and undefined. METHODS: ASXL1 and TET2 mutations were analyzed in 141 patients with CMML using Sanger sequencing, with the aim to identify the interplay of ASXL1 and TET2 mutations in the prognosis of CMML...
2016: Stem Cell Investigation
https://www.readbyqxmd.com/read/27766616/genomics-of-primary-chemoresistance-and-remission-induction-failure-in-paediatric-and-adult-acute-myeloid-leukaemia
#17
Fiona C Brown, Paolo Cifani, Esther Drill, Jie He, Eric Still, Shan Zhong, Sohail Balasubramanian, Dean Pavlick, Bahar Yilmazel, Kristina M Knapp, Todd A Alonzo, Soheil Meshinchi, Richard M Stone, Steven M Kornblau, Guido Marcucci, Alan S Gamis, John C Byrd, Mithat Gonen, Ross L Levine, Alex Kentsis
Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases...
January 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/27736885/dynamic-asxl1-exon-skipping-and-alternative-circular-splicing-in-single-human-cells
#18
Winston Koh, Veronica Gonzalez, Sivaraman Natarajan, Robert Carter, Patrick O Brown, Charles Gawad
Circular RNAs comprise a poorly understood new class of noncoding RNA. In this study, we used a combination of targeted deletion, high-resolution splicing detection, and single-cell sequencing to deeply probe ASXL1 circular splicing. We found that efficient circular splicing required the canonical transcriptional start site and inverted AluSx elements. Sequencing-based interrogation of isoforms after ASXL1 overexpression identified promiscuous linear splicing between all exons, with the two most abundant non-canonical linear products skipping the exons that produced the circular isoforms...
2016: PloS One
https://www.readbyqxmd.com/read/27736271/asxl1-mutations-are-frequent-in-de-novo-aml-with-trisomy-8-and-confer-an-unfavorable-prognosis
#19
Xiangping Zong, Hong Yao, Lijun Wen, Liang Ma, Qinrong Wang, Zhiluo Yang, Tongtong Zhang, Suning Chen, Wu Depei
No abstract text is available yet for this article.
October 13, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27733013/dnmt3a-mutations-are-associated-with-inferior-overall-and-leukemia-free-survival-in-chronic-myelomonocytic-leukemia
#20
Mrinal M Patnaik, Daniela Barraco, Terra L Lasho, Christy M Finke, Curtis A Hanson, Rhett P Ketterling, Naseema Gangat, Ayalew Tefferi
DNMT3A mutations are seen in ∼5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n = 261). DNMT3A mutations were seen in 6% (n = 16); 56% (n = 9) male, with a median age of 64 years. Eighty-one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes...
January 2017: American Journal of Hematology
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