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.
BackgroundChromothripsis, a newly discovered type of complex genomic rearrangement, has been implicated in the evolution of several types of cancers. To date, it has been described in bone cancer, SHH-medulloblastoma and acute myeloid leukemia, amongst others, however there are still no formal or automated methods for detecting or annotating it in high throughput sequencing data. As such, findings of chromothripsis are difficult to compare and many cases likely escape detection altogether.ResultsWe introduce ShatterProof, a software tool for detecting and quantifying chromothriptic events. ShatterProof takes structural variation calls (translocations, copy-number variations, short insertions and loss of heterozygosity) produced by any algorithm and using an operational definition of chromothripsis performs robust statistical tests to accurately predict the presence and location of chromothriptic events. Validation of our tool was conducted using clinical data sets including matched normal, prostate cancer samples in addition to the colorectal cancer and SCLC data sets used in the original description of chromothripsis.ConclusionsShatterProof is computationally efficient, having low memory requirements and near linear computation time. This allows it to become a standard component of sequencing analysis pipelines, enabling researchers to routinely and accurately assess samples for chromothripsis. Source code and documentation can be found at http://search.cpan.org/~sgovind/Shatterproof.
Background: There is limited literature on the risk of venous thromboembolism (VTE) in emergency general surgery (EGS) patients. We undertook this study to identify the rate of symptomatic VTE for patients undergoing EGS operations. Methods: We conducted a retrospective cohort study evaluating EGS patients who underwent operative intervention between March and December 2014. Data collected included patient demographics, type of procedure, risk of VTE, VTE prophylaxis, development of symptomatic VTE, and mortality. Results: We included 767 patients in our analysis. The mean age was 53 ± 19.7 years, and 52.2% of patients were female. Eighteen patients (2.3%) experienced VTE in hospital and 12 (1.6%) experienced VTE after discharge. Only 66% of patients received appropriate VTE prophylaxis. High-risk patients had a higher VTE rate (7.4% v. 2.3%, p < 0.001) and higher mortality (17.6% v. 4.0%, p < 0.001) than lowto moderate-risk patients. Conclusion: The risk of VTE in patients requiring EGS is significant and persists after hospital discharge. Further studies on quality improvement with VTE prophylaxis are warranted. Contexte : La littérature sur le risque de thromboembolie veineuse (TEV) chez les patients soumis à une chirurgie générale urgente est limitée. Nous avons entrepris cette étude afin de mesurer le taux de TEV symptomatique chez les patients ayant subi une intervention urgente en chirurgie générale. Méthodes : Nous avons procédé à une étude de cohorte rétrospective sur les patients qui ont subi une chirurgie générale urgente entre mars et décembre 2014. Parmi les données recueillies, mentionnons données démographiques, type d'intervention, risque de TEV, thromboprophylaxie, apparition d'une TEV symptomatique et mortalité. Résultats : Nous avons inclus 767 patients dans notre analyse. L'âge moyen était de 53 ± 19,7 ans et 52,2 % des patients étaient de sexe féminin. Dix-huit patients (2,3 %) ont présenté une TEV en cours d'hospitalisation et 12 (1,6 %) après leur congé. Seulement 66 % des patients ont reçu une thromboprophylaxie adéquate. Les patients à haut risque ont présenté des taux de TEV (7,4 % c. 2,3 %, p < 0,001) et de mortalité (17,6 % c. 4,0 %, p < 0,001) plus élevés que les patients présentant un risque faible à modéré. Conclusion : Le risque de TEV chez les patients soumis à une chirurgie générale urgente est significatif et persiste après le congé hospitalier. Il faudra mener des études plus approfondies sur l'amélioration de la qualité de la thromboprophylaxie.
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