Cancer genetics articles within Nature

Featured

  • News & Views |

    Genomic analyses of tumours of the childhood cancer retinoblastoma reveal a low mutation rate, challenging the view that genomic instability is crucial for its progression. The work also identifies a new therapeutic target. See Article p.329

    • Julien Sage
    •  & Michael L. Cleary

  • News & Views |

    On binding to its target hormone, the oestrogen-receptor protein modulates the expression of many genes. Changes in the receptor's interaction with DNA have now been linked to clinical outcome in patients with breast cancer. See Letter p.389

    • Geneviève Deblois
    •  & Vincent Giguère

  • Article
    | Open Access

    Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.

    • Michael A. Chapman
    • , Michael S. Lawrence
    •  & Todd R. Golub

  • Letter |

    Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes.

    • Craig J. Ceol
    • , Yariv Houvras
    •  & Leonard I. Zon

  • Letter |

    Although it is known that tumours are genetically heterogeneous it has so far been difficult to dissect this heterogeneity at a single cell level. This paper combines whole-genome amplification and next-generation sequencing of flow-sorted nuclei from breast tumours to investigate their population structure and evolution. In contrast to gradual models of tumour progression, the results indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.

    • Nicholas Navin
    • , Jude Kendall
    •  & Michael Wigler

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • Letter |

    Here, whole-genome sequencing has been used to analyse primary pancreatic tumours and one or more metastases from the same patients. The findings show that tumours are composed of several geographically distinct subclones, and allow maps to be produced showing how metastatic cancer clones evolve within the primary tumour. Moreover, a quantitative analysis of the timing of the genetic evolution of pancreatic cancer has been performed.

    • Shinichi Yachida
    • , Siân Jones
    •  & Christine A. Iacobuzio-Donahue

  • Letter |

    The aberrant expression of microRNAs and of the enzymes that control their processing has been reported in tumours, but the mechanisms involved are not clear. It is now shown that TAp63, a member of the p53 family of tumour suppressors, suppresses tumorigeneis and metastasis by directly controlling the expression of Dicer (a microRNA-processing enzyme) and Dicer-regulated microRNAs.

    • Xiaohua Su
    • , Deepavali Chakravarti
    •  & Elsa R. Flores

  • Letter |

    Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. These authors provide a mechanistic basis for this association. They show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing RANKL (receptor activator of NF-KB ligand), which acts on mammary epithelial cells through the RANKL receptor RANK.

    • Daniel Schramek
    • , Andreas Leibbrandt
    •  & Josef M. Penninger

  • Article |

    Ultraviolet radiation causes damage to DNA in skin cells, blocking DNA replication and causing mutations that can lead to cancer. One way in which the cell deals with such damage involves specialized DNA polymerases, such as Polη, that can bypass lesions. Here the crystal structure is presented of Pol? in complex with a thymine–thymine dimer and with undamaged DNA. The bulky thymine dimer is accommodated in an atypically large active site, and stabilized by interactions not found in other polymerases.

    • Timothy D. Silverstein
    • , Robert E. Johnson
    •  & Aneel K. Aggarwal

  • Article |

    The canonical role of messenger RNA (mRNA) is in protein coding and synthesis. But could mRNAs also have a role that is related to their ability to compete for microRNA binding? Here, the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 is investigated. The results suggest that pseudogenes have a biological function, in sequestering microRNAs and so affecting their regulation of gene expression.

    • Laura Poliseno
    • , Leonardo Salmena
    •  & Pier Paolo Pandolfi

  • Letter |

    Complete genome sequencing has already provided insights into the mutation spectra of several cancer types. Here, the first complete sequences are provided of a primary lung tumour and adjacent normal tissue. Comparison of the two reveals a variety of somatic mutations in the cancer genome, including changes in the KRAS proto-oncogene. The results reveal a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes, and selection against mutations in promoter regions.

    • William Lee
    • , Zhaoshi Jiang
    •  & Zemin Zhang

  • Letter |

    CD95 is a classical death receptor protein that regulates tissue homeostasis by inducing cell death. Here it is shown, however, that cancer cells depend on CD95 for optimal growth. Without CD95, the incidence of ovarian cancer and liver cancer in mice is reduced, as is the size of any tumours. So CD95 is a double-edged sword, and it may be necessary to reduce, rather than enhance, its activity in order to kill tumour cells.

    • Lina Chen
    • , Sun-Mi Park
    •  & Marcus E. Peter

  • Journal Club |

    • Jean-Christophe Marine

  • Article |

    One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

    • Rameen Beroukhim
    • , Craig H. Mermel
    •  & Matthew Meyerson

  • Letter |

    Clear cell renal carcinoma, the most common form of adult kidney cancer, is often characterized by the presence of inactivating mutations in the VHL gene. A large survey for somatic mutations now identifies inactivating mutations in two genes encoding enzymes involved in histone modification, highlighting the role of mutations in components of the chromatin modification machinery in human cancer.

    • Gillian L. Dalgliesh
    • , Kyle Furge
    •  & P. Andrew Futreal

Browse broader subjects

Browse narrower subjects

Browse Cancer genetics across other nature.com journals