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Cll genomics

Santhilal Subhash, Per-Ola Andersson, Subazini Thankaswamy Kosalai, Chandrasekhar Kanduri, Meena Kanduri
BACKGROUND: Methyl-CpG-binding domain protein enriched genome-wide sequencing (MBD-Seq) is a robust and powerful method for analyzing methylated CpG-rich regions with complete genome-wide coverage. In chronic lymphocytic leukemia (CLL), the role of CpG methylated regions associated with transcribed long noncoding RNAs (lncRNA) and repetitive genomic elements are poorly understood. Based on MBD-Seq, we characterized the global methylation profile of high CpG-rich regions in different CLL prognostic subgroups based on IGHV mutational status...
2016: Clinical Epigenetics
S Kasar, J R Brown
Sequencing studies have been instrumental in understanding the genetic basis of chronic lymphocytic leukemia (CLL). Our recent whole-genome sequencing study focusing on lower cytogenetic risk CLL demonstrated that CLL mutations can be attributed to 3 key mutational processes-2 types of activation induced-cytidine deaminase (AID) signatures and an aging signature-that operate at different times throughout CLL evolution.
July 2016: Molecular & Cellular Oncology
Gian Matteo Rigolin, Elena Saccenti, Cristian Bassi, Laura Lupini, Francesca Maria Quaglia, Maurizio Cavallari, Sara Martinelli, Luca Formigaro, Enrico Lista, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Antonio Urso, Francesco Cavazzini, Massimo Negrini, Antonio Cuneo
BACKGROUND: In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations. METHODS: We performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression...
September 15, 2016: Journal of Hematology & Oncology
Y Jiang, H-C Chen, X Su, P A Thompson, X Liu, K-A Do, W Wierda, M J Keating, W Plunkett
Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients...
September 2, 2016: Blood Cancer Journal
Radhika Kandaswamy, Georgina P Sava, Helen E Speedy, Sílvia Beà, José I Martín-Subero, James B Studd, Gabriele Migliorini, Philip J Law, Xose S Puente, David Martín-García, Itziar Salaverria, Jesús Gutiérrez-Abril, Carlos López-Otín, Daniel Catovsky, James M Allan, Elías Campo, Richard S Houlston
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1...
August 23, 2016: Cell Reports
Lijian Yu, Haesook Kim, Siddha N Kasar, Parul Benien, Wei Du, Kevin Hoang, Andrew Aw, Bethany Tesar, Reina Improgo, Stacey Fernandes, Saranya Radhakrishnan, Josephine L Klitgaard, Charles Lee, Gad Getz, Sunita R Setlur, Jennifer R Brown
Purpose Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLL as well as wild type CLL and analyzed the genetic basis of their clinical heterogeneity...
August 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Romain Guièze, Mélanie Pages, Lauren Véronèse, Patricia Combes, Richard Lemal, Mathilde Gay-Bellile, Martine Chauvet, Mary Callanan, Fabrice Kwiatkowski, Bruno Pereira, Philippe Vago, Jacques-Olivier Bay, Olivier Tournilhac, Andreï Tchirkov
In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients...
July 29, 2016: Oncotarget
S Barrio, T D Shanafelt, J Ojha, K G Chaffee, C Secreto, K M Kortüm, S Pathangey, D L Van-Dyke, S L Slager, R Fonseca, N E Kay, E Braggio
High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution...
July 29, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Garima Kushwaha, Mikhail Dozmorov, Jonathan D Wren, Jing Qiu, Huidong Shi, Dong Xu
BACKGROUND: Methylation changes are frequent in cancers, but understanding how hyper- and hypomethylated region changes coordinate, associate with genomic features, and affect gene expression is needed to better understand their biological significance. The functional significance of hypermethylation is well studied, but that of hypomethylation remains limited. Here, with paired expression and methylation samples gathered from a patient/control cohort, we attempt to better characterize the gene expression and methylation changes that take place in cancer from B cell chronic lymphocyte leukemia (B-CLL) samples...
2016: Human Genomics
André F Rendeiro, Christian Schmidl, Jonathan C Strefford, Renata Walewska, Zadie Davis, Matthias Farlik, David Oscier, Christoph Bock
Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations...
2016: Nature Communications
Adrian M Dubuc, Matthew S Davids, Mirela Pulluqi, Olja Pulluqi, Kevin Hoang, Jesus M Hernandez-Sánchez, Cathy Schlich, Jesus M Hernández-Rivas, Jennifer R Brown, Paola Dal Cin
Despite significant advances in molecular genetic approaches, fluorescence in situ hybridization (FISH) remains the gold standard for the diagnostic evaluation of genomic aberrations in patients with chronic lymphocytic leukemia (CLL). Efforts to improve the diagnostic utility of molecular cytogenetic testing have led to the expansion of the traditional 4-probe CLL FISH panel. Not only do these efforts increase the cost of testing, they remain hindered by the inherent limitations of FISH studies - namely the inability to evaluate genomic changes outside of the targeted loci...
October 2016: American Journal of Hematology
Jiazhu Wu, Xiaojing Xu, Eun-Joon Lee, Austin Y Shull, Lirong Pei, Farrukh Awan, Xiaoling Wang, Jeong-Hyeon Choi, Libin Deng, Hong-Bo Xin, Wenxun Zhong, Jinhua Liang, Yi Miao, Yujie Wu, Lei Fan, Jianyong Li, Wei Xu, Huidong Shi
Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival...
June 10, 2016: Oncotarget
H Parker, M J J Rose-Zerilli, M Larrayoz, R Clifford, J Edelmann, S Blakemore, J Gibson, J Wang, V Ljungström, T K Wojdacz, T Chaplin, A Roghanian, Z Davis, A Parker, E Tausch, S Ntoufa, S Ramos, P Robbe, R Alsolami, A J Steele, G Packham, A E Rodríguez-Vicente, L Brown, F McNicholl, F Forconi, A Pettitt, P Hillmen, M Dyer, M S Cragg, C Chelala, C C Oakes, R Rosenquist, K Stamatopoulos, S Stilgenbauer, S Knight, A Schuh, D G Oscier, J C Strefford
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis...
November 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Dóra Marosvári, Donát Alpár, Attila Péter Király, Hajnalka Rajnai, Lilla Reiniger, Csaba Bödör
Chronic lymphocytic leukemia (CLL) is the most frequent mature B-cell non-Hodgkin's lymphoma in the Western countries. The recent next-generation sequencing (NGS) studies lead to an exponential increase in our knowledge of the pathogenesis and progression of CLL. Whole genome and exome sequencing studies revealed a remarkable inter- and intra-patient genetic heterogeneity with a significant therapy-induced clonal evolution in the majority of the patients. Driver mutations were identified in components of various signalling pathways and cellular processes with notable prognostic and therapeutic relevance...
June 6, 2016: Magyar Onkologia
Vipul Shukla, Ashima Shukla, Shantaram S Joshi, Runqing Lu
Molecular pathogenesis of Chronic Lymphocytic Leukemia (CLL) is not fully elucidated. Genome wide association studies have linked Interferon Regulatory Factor 4 (IRF4) to the development of CLL. We recently established a causal relationship between low levels of IRF4 and development of CLL. However, the molecular mechanism through which IRF4 suppresses CLL development remains unclear. Deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL...
July 5, 2016: Oncotarget
Juhi Ojha, Veryan Codd, Christopher P Nelson, Nilesh J Samani, Ivan V Smirnov, Nils R Madsen, Helen M Hansen, Adam J de Smith, Paige M Bracci, John K Wiencke, Margaret R Wrensch, Joseph L Wiemels, Kyle M Walsh
BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility. METHODS: We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case-control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1 RESULTS: Three of the eight LTL-associated SNPs were associated with CLL risk at P < 0...
July 2016: Cancer Epidemiology, Biomarkers & Prevention
Chien-Hung Yeh, Ramona Moles, Christophe Nicot
Small non-coding microRNAs (miRNAs) are epigenetic regulators that target specific cellular mRNA to modulate gene expression patterns and cellular signaling pathways. miRNAs are involved in a wide range of biological processes and are frequently deregulated in human cancers. Numerous miRNAs promote tumorigenesis and cancer progression by enhancing tumor growth, angiogenesis, invasion and immune evasion, while others have tumor suppressive effects (Hayes, et al., Trends Mol Med 20(8): 460-9, 2014; Stahlhut and Slack, Genome Med 5 (12): 111, 2013)...
2016: Molecular Cancer
James Buchanan, Sarah Wordsworth, Anna Schuh
BACKGROUND: Genomic information could help to reduce the morbidity effects of inappropriate treatment decisions in many disease areas, in particular cancer. However, evidence of the benefits that patients derive from genomic testing is limited. This study evaluated patient preferences for genomic testing in the context of chronic lymphocytic leukaemia (CLL). METHODS: We used a discrete choice experiment (DCE) survey to assess the preferences of CLL patients in the UK for genomic testing...
May 11, 2016: Patient
Jeremy D K Parker, Yaoqing Shen, Erin Pleasance, Yvonne Li, Jacqueline E Schein, Yongjun Zhao, Richard Moore, Joanna Wegrzyn-Woltosz, Kerry J Savage, Andrew P Weng, Randy D Gascoyne, Steven Jones, Marco Marra, Janessa Laskin, Aly Karsan
In an attempt to assess potential treatment options, whole-genome and transcriptome sequencing were performed on a patient with an unclassifiable small lymphoproliferative disorder. Variants from genome sequencing were prioritized using a combination of comparative variant distributions in a spectrum of lymphomas, and meta-analyses of gene expression profiling. In this patient, the molecular variants that we believe to be most relevant to the disease presentation most strongly resemble a diffuse large B-cell lymphoma (DLBCL), whereas the gene expression data are most consistent with a low-grade chronic lymphocytic leukemia (CLL)...
March 2016: Cold Spring Harbor Molecular Case Studies
Staci L Haney, G Michael Upchurch, Jana Opavska, David Klinkebiel, Ryan A Hlady, Abhinav Suresh, Samuel J Pirruccello, Vipul Shukla, Runqing Lu, Stefan Costinean, Angie Rizzino, Adam R Karpf, Shantaram Joshi, Patrick Swanson, Rene Opavsky
DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a(+/-) mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation...
May 10, 2016: Cell Reports
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