Cancer genetics articles within Nature

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  • Letter |

    Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

    • Kyriaki Michailidou
    • , Sara Lindström
    •  & Douglas F. Easton

  • Letter |

    A protocol producing orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy demonstrates proof of principle for using these tumours for basic and translational research on paediatric solid tumours.

    • Elizabeth Stewart
    • , Sara M. Federico
    •  & Michael A. Dyer

  • Letter |

    An in vivo RNA interference screening strategy in glioblastoma enabled the identification of a host of epigenetic targets required for glioblastoma cell survival that were not identified by parallel standard screening in cell culture, including the transcription pause–release factor JMJD6, and could be a powerful tool to uncover new therapeutic targets in cancer.

    • Tyler E. Miller
    • , Brian B. Liau
    •  & Jeremy N. Rich

  • Letter |

    ENL, identified in a genome-scale loss-of-function screen as a crucial requirement for proliferation of acute leukaemia, is required for leukaemic gene expression, and its YEATS chromatin-reader domain is essential for leukaemic growth.

    • Michael A. Erb
    • , Thomas G. Scott
    •  & James E. Bradner

  • Letter |

    SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.

    • Ying-Nan P. Chen
    • , Matthew J. LaMarche
    •  & Pascal D. Fortin

  • Article |

    Recent analyses have suggested that the intrinsic behaviour of tissue stem cells may be responsible for malignant transformation and cancer progression, raising questions regarding the influence of extrinsic factors on tumourigenesis; here, both data-driven and model-driven evidence show that such intrinsic risk factors contribute only marginally to cancer development, indicating that cancer risk is heavily influenced by extrinsic factors.

    • Song Wu
    • , Scott Powers
    •  & Yusuf A. Hannun

  • Letter |

    Common fragile sites (CFSs) are difficult-to-replicate regions of eukaryotic genomes that are sensitive to replication stress and that require resolution by the MUS81–EME1 endonuclease to re-initiate POLD3-dependent DNA synthesis in early mitosis; this study defines the specific pathway of events causing the CFS fragility phenotype.

    • Sheroy Minocherhomji
    • , Songmin Ying
    •  & Ian D. Hickson

  • Letter |

    A causal variant is identified at the LMO1 oncogene locus that drives the genetic association of LMO1 with neuroblastoma susceptibility; the causal SNP disrupts a GATA transcription factor binding site within a tissue-specific super-enhancer element in the first intron of LMO1, thereby affecting LMO1 expression.

    • Derek A. Oldridge
    • , Andrew C. Wood
    •  & John M. Maris

  • Article |

    Using the CRISPR/Cas9 system, up to four frequently occurring colorectal cancer mutations were introduced alone or in combination into stem cell organoids derived from human small intestinal or colon tissue, allowing an in-depth investigation of the contribution of these mutations to cancer progression.

    • Jarno Drost
    • , Richard H. van Jaarsveld
    •  & Hans Clevers

  • Letter |

    Whole-exome sequencing is used to compare the mutational landscape of adenomas from three mouse models of non-small-cell lung cancer, induced either by exposure to carcinogens or by genetic mutation of Kras; the results reveal that the two types of tumour have different mutational profiles and adopt different routes to tumour development.

    • Peter M. K. Westcott
    • , Kyle D. Halliwill
    •  & Allan Balmain

  • Letter |

    The CRISPR/Cas system has been used in mice for genome editing to introduce genetic alterations found in human lung tumours, and these genome modifications resulted in mouse lung tumours showing different histopathologies depending on the genes altered; the CRISPR/Cas system offers improved and faster ways to create animal models of human diseases such as cancer.

    • Francisco J. Sánchez-Rivera
    • , Thales Papagiannakopoulos
    •  & Tyler Jacks

  • Letter |

    Inappropriate activation of the tumour-suppressor protein p53 during development can promote phenotypes similar to those of CHARGE syndrome, suggesting that p53 activation not only has a beneficial function in suppressing cancer but also a deleterious function in promoting developmental syndromes.

    • Jeanine L. Van Nostrand
    • , Colleen A. Brady
    •  & Laura D. Attardi

  • Article |

    The translation of many messenger RNAs that encode important oncogenes and transcription factors depends on the eIF4A RNA helicase to resolve G-quadruplex structures, implying eIF4A inhibition as an effective cancer therapy.

    • Andrew L. Wolfe
    • , Kamini Singh
    •  & Hans-Guido Wendel

  • Letter |

    Exposing mice with the BRAF (V600E) mutation to levels of ultraviolet radiation that mimic mild sunburn in humans is shown to induce mutations in the tumour suppressor Trp53 (TP53 in humans), accelerating the development of melanoma; these results support the use of sunscreen in individuals at risk of this cancer.

    • Amaya Viros
    • , Berta Sanchez-Laorden
    •  & Richard Marais

  • Outlook |

    A subterranean species that seems to be cancer-proof is providing promising clues on how we might prevent the disease in humans.

    • Sarah Deweerdt

  • Outlook |

    Even as cancer therapies improve, basic questions about drug resistance, tumour spread and the role of normal tissue remain unanswered.

    • Katherine Bourzac

  • Outlook |

    Tailoring cancer treatment to individual and evolving tumours is the way of the future, but scientists are still hashing out the details.

    • Lauren Gravitz

  • Article |

    At least two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of nuclear factor-κB (NF-κB) signalling, and uncharacterized gene C11orf95; C11orf95–RELA fusion proteins translocate spontaneously to the nucleus to activate NF-κB target genes, and rapidly transform neural stem cells to form tumours in mice

    • Matthew Parker
    • , Kumarasamypet M. Mohankumar
    •  & Richard J. Gilbertson

  • Article |

    The authors identify pre-leukaemic haematopoietic stem cells (HSCs) in patients with acute myeloid leukaemia; these pre-leukaemic HSCs have the capacity of normal multi-lineage haematopoietic differentiation with a competitive growth advantage over wild-type HSCs, and owing to their persistence may serve as a reservoir for therapeutic resistance and relapse.

    • Liran I. Shlush
    • , Sasan Zandi
    •  & John E. Dick

  • Outlook |

    Technologies that rapidly sequence DNA reveal deep genetic diversity both within and among individuals with leukaemia.

    • Sarah DeWeerdt

  • Letter |

    Rare truncating mutations in the p53-inducible protein phosphatase PPM1D are shown to be associated with predisposition to breast cancer and ovarian cancer; notably, all of the mutations are mosaic in white blood cells but are not present in tumours, and probably have a gain-of-function effect.

    • Elise Ruark
    • , Katie Snape
    •  & Nazneen Rahman

  • News & Views |

    Sun exposure indisputably increases the risk of skin cancer. Mouse studies suggest that, in red-haired individuals, genetic factors also contribute through a mechanism that acts independently of exposure to sunlight. See Letter p.449

    • Mizuho Fukunaga-Kalabis
    •  & Meenhard Herlyn

  • Letter |

    Individuals with the red hair/fair skin phenotype usually carry a polymorphism in the gene encoding the melanocortin 1 receptor (Mc1r) that results in the production of pigment containing a high pheomelanin-to-eumelanin ratio; here it is shown in a mouse model that inactivation of Mc1r promotes melanoma formation in the presence of the Braf oncogene, thus suggesting that pheomelanin synthesis is carcinogenic by an ultraviolet-radiation-independent mechanism.

    • Devarati Mitra
    • , Xi Luo
    •  & David E. Fisher

  • Article
    | Open Access

    The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

    • Daniel C. Koboldt
    • , Robert S. Fulton
    •  & Jacqueline D. Palchik

  • News & Views |

    Some mutations in tumour cells play no part in causing cancer, but they generate cellular weak spots that may allow tumour cells to be selectively killed by drugs. See Article p.337

    • Ben Lehner
    •  & Solip Park

  • Article |

    The ‘collateral’ homozygous deletion of essential redundant housekeeping genes in cancer genomes is shown to confer therapeutic vulnerability on cancer cells with the deletion, without affecting genomically intact normal non-cancerous cells, suggesting new therapeutic opportunities.

    • Florian L. Muller
    • , Simona Colla
    •  & Ronald A. DePinho

  • Letter
    | Open Access

    Medulloblastoma is the most common brain tumour in children; using whole-genome sequencing of tumour samples the authors show that the clinically challenging Group 3 and 4 tumours can be tetraploid, and reveal the expression of the first medulloblastoma fusion genes identified.

    • David T. W. Jones
    • , Natalie Jäger
    •  & Peter Lichter

  • Article
    | Open Access

    Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.

    • Paul A. Northcott
    • , David J. H. Shih
    •  & Michael D. Taylor

  • Letter |

    Medulloblastoma is the most common brain tumour in children; using exome sequencing of tumour samples the authors show that these cancers have low mutation rates and identify 12 significantly mutated genes, among them the gene encoding RNA helicase DDX3X.

    • Trevor J. Pugh
    • , Shyamal Dilhan Weeraratne
    •  & Yoon-Jae Cho

  • Letter
    | Open Access

    This paper reports one of the largest breast cancer whole-exome and whole-genome sequencing efforts so far, identifying previously unknown recurrent mutations in CBFB, deletions of RUNX1 and recurrent MAGI1–AKT3 fusion; the fusion suggests that the use of ATP-competitive AKT inhibitors should be evaluated in clinical trials.

    • Shantanu Banerji
    • , Kristian Cibulskis
    •  & Matthew Meyerson

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