Cancer articles within Nature

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  • Letter |

    In three different subtypes of B-cell lymphomas, two papers now report frequent somatic mutations in CREBBP and EP300, present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations found inactivate these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to therapeutic drugs.

    • Charles G. Mullighan
    • , Jinghui Zhang
    •  & James R. Downing

  • Letter |

    The maintenance and regeneration of the epithelium of the adult bladder is poorly understood yet it is a clinically relevant process during urinary tract infections and bladder cancer. This study provides insight into the cellular and molecular mechanisms underlying the regenerative response to injury within the mammalian urinary bladder. Upon injury by bacterial infection or chemical agents, a Shh and Wnt signalling feedback circuit between basal cells of the urothelium and the stromal cells that underlie them leads to regenerative proliferation of the bladder epithelia.

    • Kunyoo Shin
    • , John Lee
    •  & Philip A. Beachy

  • Article |

    In three different subtypes of B-cell lymphomas, two papers now report frequent somatic mutations in CREBBP and EP300, present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations found inactivate these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to therapeutic drugs.

    • Laura Pasqualucci
    • , David Dominguez-Sola
    •  & Riccardo Dalla-Favera

  • News & Views |

    Induced pluripotent stem cells have great therapeutic potential. But genomic and epigenomic analyses of these cells generated using current technology reveal abnormalities that may affect their safe use. See Articles p.58, p.63 & p.68

    • Martin F. Pera

  • Letter |

    This is one of two papers demonstrating that in several cancer types including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by the FBW7 tumour suppressor. This study finds that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors. Deletion or mutation of FBW7 found in cancer patients therefore can render tumours resistant to these therapies.

    • Hiroyuki Inuzuka
    • , Shavali Shaik
    •  & Wenyi Wei

  • Letter |

    Using whole-transcriptome sequencing, this paper identifies recurrent gene translocations in B-cell lymphomas that involve the MHC class II transactivator CIITA. These translocations lead to downregulation of cell surface HLA class II expression and, in the case of some fusion partners, overexpression of CD274/CD273 ligands, which have the potential to reduce the antitumour response against these lymphomas.

    • Christian Steidl
    • , Sohrab P. Shah
    •  & Randy D. Gascoyne

  • Letter |

    Misrepair of DNA double strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin and T-cell receptor loci has been implicated in the pathogenesis of lymphoid malignancies. Here, the RAG2 carboxy terminus is shown to be critical for maintaining genomic stability. Rag2c/c p53−/− mice, unlike Rag1c/c p53−/− and p53−/− mice, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcrα/δ and Igh loci. These results reveal a new 'genome guardian' role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2c/c p53−/− and Atm−/− mice.

    • Ludovic Deriano
    • , Julie Chaumeil
    •  & David B. Roth

  • Article |

    Reprogramming of somatic cells to induced pluripotent stem (iPS) cells that can be differentiated into many cell types has great potential for personalized therapy. This study finds that 22 human iPS cell lines that were reprogrammed using five different methods contain protein coding point mutations. Some mutations were pre existing in the somatic cells, others were new mutations that occurred during and after reprogramming. Therefore, it will be important to ensure iPS cell safety before clinical use.

    • Athurva Gore
    • , Zhe Li
    •  & Kun Zhang

  • News & Views |

    In 2–3% of cancers, a single genetic event may have led to hundreds of genomic rearrangements confined to just one or a few chromosomes. This finding challenges the conventional view of how mutations accumulate in oncogenesis.

    • Jose M. C. Tubio
    •  & Xavier Estivill

  • News & Views Forum |

    Variation in a genomic region that contains the cancer-associated gene ATM affects a patient's response to the diabetes drug metformin. Two experts discuss the implications for understanding diabetes and the link to cancer.

    • Morris J. Birnbaum
    •  & Reuben J. Shaw

  • Letter |

    This study shows, via a mouse model of intestinal cancer, that in the absence of CKIα, the loss of p53 dramatically enhances tumour progression and metastasis. p53 is shown to normally limit cancer cell invasion via the regulation of p21 and a set of invasion genes that include Prox1. This study adds important insights to the emerging picture that during tumour development the p53 tumour suppressor gene not only controls cell death and proliferation but also metastasis.

    • Ela Elyada
    • , Ariel Pribluda
    •  & Yinon Ben-Neriah

  • Article
    | Open Access

    Prostate cancer is a common cause of male cancer-related deaths. Complete sequencing of prostate cancer genomes now reveals previously unknown balanced rearrangements. Single-nucleotide resolution afforded by sequencing indicates that complex rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

    • Michael F. Berger
    • , Michael S. Lawrence
    •  & Levi A. Garraway

  • News & Views |

    Fragile sites are genomic regions prone to deletions or other alterations during DNA replication. The reason for the susceptibility of these sites to damage may be simple: they contain few replication initiation sites. See Letter p.120

    • Kay Huebner

  • Letter |

    Recruitment of 53BP1 to double-strand DNA breaks is an important step in the cellular response to DNA damage. Here, the histone methyltransferase MMSET is shown to be responsible for localized increases in a histone modification that is involved in recruiting 53BP1. The mechanism of MMSET recruitment to DNA damage sites is also investigated.

    • Huadong Pei
    • , Lindsey Zhang
    •  & Zhenkun Lou

  • Article |

    Analysing human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample and the evolutionary path by which different subclones have emerged. Leukaemia-initiating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-initiating cells.

    • Faiyaz Notta
    • , Charles G. Mullighan
    •  & John E. Dick

  • News |

    University officials admit data withheld from review panel before misconduct charges arose.

    • Eugenie Samuel Reich

  • News & Views |

    Protein factors can regulate gene expression by binding to specifically modified DNA-associated proteins. Small molecules that selectively interfere with such interaction may be of therapeutic value. See Article p.1067 & Letter p.1119

    • Sean D. Taverna
    •  & PhiliP A. Cole

  • Letter |

    The histone variant mH2A is shown to be expressed at reduced levels in many melanomas. Loss of mH2A promotes tumour growth and metastasis via transcriptional upregulation of CDK8, a known oncogene. This study therefore reveals a new tumour suppression mechanism exerted by epigenetic modifications.

    • Avnish Kapoor
    • , Matthew S. Goldberg
    •  & Emily Bernstein

  • Letter |

    This study finds frequent mutations in MYD88 in the activated B-cell-like subtype of diffuse large B-cell lymphoma and, with lower frequency, in mucosa-associated lymphoid tissue lymphomas. MYD88 mediates signalling by Toll-like receptors, and the mutations, most of which affect the same amino acid, are shown to activate the pathway and promote cancer cell survival.

    • Vu N. Ngo
    • , Ryan M. Young
    •  & Louis M. Staudt

  • Editorial |

    Irresponsible policies could cause an epidemic of malignant lung disease.

  • News & Views |

    The promise of an exciting new drug that inhibits the mutant B-RAF protein in skin cancer is marred by the fact that most patients relapse within a year. Fresh data hint at how such resistance emerges. See Letters p.968 & p.973

    • David Solit
    •  & Charles L. Sawyers

  • Article |

    Analysing single cells from human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample, the evolutionary path by which different subclones have emerged, and ongoing dynamic changes associated with relapse. Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells.

    • Kristina Anderson
    • , Christoph Lutz
    •  & Mel Greaves

  • Article |

    A crystal structure of the tandem PHD and bromodomain regions of the transcription and chromatin regulator TRIM24 reveals combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer.

    • Wen-Wei Tsai
    • , Zhanxin Wang
    •  & Michelle Craig Barton

  • News Feature |

    Cancer epidemics in Turkey could hold the secret to staving off a public health disaster in North Dakota.

    • Brendan Maher

  • Letter |

    The TET family of enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Mutations in the gene encoding TET2 are frequently observed in myeloid malignancies. Here it is shown that these disease-associated mutations compromise TET2 catalytic activity; bone marrow samples from patients with TET2 mutations have low levels of 5hmC in genomic DNA, and TET2 is required for normal haematopoietic differentiation. Measurement of genomic 5hmC levels may prove valuable as a diagnostic tool in myeloid cancers.

    • Myunggon Ko
    • , Yun Huang
    •  & Anjana Rao

  • Technology Feature |

    Developing techniques are helping researchers to build the protein interaction networks that underlie all cell functions.

    • Laura Bonetta

  • Letter |

    Medulloblastomas are the most common malignant childhood brain tumours and are thought to arise from the cerebellum. There is substantial heterogeneity among medulloblastomas and some are thought to arise following aberrant Sonic Hedgehog pathway activation. It is now shown that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered WNT signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment.

    • Paul Gibson
    • , Yiai Tong
    •  & Richard J. Gilbertson

  • News & Views |

    Resistance of tumour cells to chemotherapy can severely affect the efficacy of this anticancer treatment. The non-tumour cells of the organ in which the tumour resides may aid the emergence of such resistance.

    • Urban Emmenegger
    •  & Robert S. Kerbel

  • Letter |

    Here, single nucleotide variants within the LMO1 locus are shown to be associated with inherited susceptibility to neuroblastoma, a childhood cancer of the sympathetic nervous system. Acquired structural variation in the same locus was also frequently found in neuroblastoma patients, leading to the suggestion that loci identified through genome-wide association studies might be also prone to somatic alterations and therefore identify potential therapy targets and/or biomarkers of tumour aggressiveness.

    • Kai Wang
    • , Sharon J. Diskin
    •  & John M. Maris

  • Article |

    Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long-term regenerative capacity. Here the tumour suppressor Lkb1 is shown to promote stem-cell maintenance and tissue regeneration by regulating energy metabolism and by preventing aneuploidy.

    • Daisuke Nakada
    • , Thomas L. Saunders
    •  & Sean J. Morrison

  • Article |

    Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long term regenerative capacity. Here the tumour suppressor Lkb1 is shown to have a crucial role in maintaining energy homeostasis in haematopoietic cells — an effect largely independent of AMPK and mTOR signalling.

    • Sushma Gurumurthy
    • , Stephanie Z. Xie
    •  & Nabeel Bardeesy

  • News |

    Learning how melanoma fights back may yield new therapies.

    • Heidi Ledford

  • News & Views |

    It is hoped that reactivating the tumour-suppressor protein p53 will help to combat cancer. However, fresh evidence suggests it is unlikely that all cells in a tumour will respond to such treatment. See Letters p.567 & p.572

    • Anton Berns

  • Letter |

    p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours.

    • David M. Feldser
    • , Kamena K. Kostova
    •  & Tyler Jacks

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