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      Splicing-factor alterations in cancers

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      Publication date (Print):
      Journal: RNA
      Publisher: Cold Spring Harbor Laboratory Press

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          Abstract

          Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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          Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

          Timothy Ley, Christopher Miller, Li Ding … (2013)
          Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).
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            Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged.

            Charles J David, James Manley (2010)
            Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.
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              Clinical and biological implications of driver mutations in myelodysplastic syndromes.

              Elli Papaemmanuil, Moritz Gerstung, Luca Malcovati … (2013)
              Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
              Article 0 comments Cited 337 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): RNA
                Journal ID (iso-abbrev): RNA
                Journal ID (publisher-id): RNA
                Title: RNA
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 1355-8382
                ISSN (Electronic): 1469-9001
                Publication date (Print): September 2016
                Volume: 22
                Issue: 9
                Pages: 1285-1301
                Affiliations
                Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
                Author notes
                [1]

                Present address: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA

                Article
                Medline ID: 9509184 Publisher ID: RA
                DOI: 10.1261/rna.057919.116
                PMC ID: 4986885
                PubMed ID: 27530828
                SO-VID: b790ab4c-7156-4200-85e5-6868df2d6f04
                Copyright © © 2016 Anczuków and Krainer; Published by Cold Spring Harbor Laboratory Press for the RNA Society
                License:

                This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Funding
                Funded by: National Cancer Institute http://dx.doi.org/10.13039/100000054
                Award ID: CA13106
                Award ID: K99CA178206
                Categories
                Subject: Review

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