Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes that transmit the disease1. To gain a deeper understanding of how mosquito populations are evolving, we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, identifying over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide resistance genes, with multiple sweeps spreading over large geographical distances and between species. The design of novel tools for mosquito control using gene drive will need to take account of high levels of genetic diversity in natural mosquito populations.

Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.

No abstract

Pyrethroid-impregnated bednets have driven significant reductions in malaria morbidity and mortality in Africa since the beginning of the century 1. The intense selection pressure exerted by bednets has precipitated widespread and escalating pyrethroid resistance in African Anopheles populations, threatening to reverse gains made by malaria control 2. Here we show that a legenriched sensory appendage protein, SAP2, confers pyrethroid resistance in Anopheles gambiae. SAP2 expression is elevated in insecticide-resistant populations and is further induced upon Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

SUMMARY Here we present the first digital particle image velocimetry (DPIV)analysis of the flow field around the wings of an insect (the tobacco hawkmoth Manduca sexta, tethered to a 6-component force-moment balance in a wind tunnel). A leading-edge vortex (LEV) is present above the wings towards the end of the downstroke, as the net upward force peaks. Our DPIV analyses and smoke visualisations match the results of previous flow visualisation experiments at midwing, and we extend the experiments to provide the first analysis of the flow field above the thorax. Detailed DPIV measurements show that towards the end of the downstroke, the LEV structure is consistent with that recently reported in free-flying butterflies and dragonflies: the LEV is continuous across the thorax and runs along each wing to the wingtip, where it inflects to form the wingtip trailing vortices. The LEV core is 2-3 mm in diameter (approximately 10% of local wing chord) both at the midwing position and over the centreline at 1.2 m s-1 and at 3.5 m s-1flight speeds. At 1.2 m s-1 the measured LEV circulation is 0.012±0.001 m2 s-1 (mean ± s.d.) at the centreline and 0.011±0.001 m2 s-1 halfway along the wing. At 3.5 m s-1LEV circulation is 0.011±0.001 m2 s-1 at the centreline and 0.020±0.004 m2 s-1 at midwing. The DPIV measurements suggest that if there is any spanwise flow in the LEV towards the end of the downstroke its velocity is less than 1 m s-1. Estimates of force production show that the LEV contributes significantly to supporting body weight during bouts of flight at both speeds(more than 10% of body weight at 1.2 m s-1 and 35-65% of body weight at 3.5 m s-1).