Genomic hallmarks of localized, non-indolent prostate cancer.

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.

ShatterProof: operational detection and quantification of chromothripsis.

BACKGROUND: Chromothripsis, 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. RESULTS: We 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. CONCLUSIONS: ShatterProof 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.

Geographic Variation in Appendiceal Perforation Rates in Canada: a Population-Based Cohort Study.

BACKGROUND: We hypothesized that patients living in rural neighborhoods experience delayed access to surgical services manifesting in increased appendiceal perforation rates in cases of appendicitis. METHODS: This population-based cohort study included adult patients with acute appendicitis in Canada (excluding Quebec) between April 2008 and March 2015. The main outcome of interest was rate of perforation. Predictors of interest included socioeconomic, geographic, and individual predictors of perforation. Spatial analysis was used to analyze spatial clustering of perforation. RESULTS: We identified 143,195 patients throughout the course of the study. The average perforation rate across our study was 35.9% (n = 51,456). Cluster analysis identified 286 (24%) neighborhoods with perforation rates greater than the average. Rural neighborhoods had a 1.89 times higher odds of being in a high perforation cluster (95% CI 1.08-3.08, p = 0.024). Compared to neighborhoods > 75 km from the admitting hospital, closer neighborhoods were less likely to be in a high perforation cluster (0-35 km OR 0.64, 95% CI 0.38-0.98, p = 0.049; 36-75 km OR 0.60, 95% CI 0.37-0.92, p = 0.019). Patients admitted to small community hospitals had a 0.51 times lower odds of perforation than those admitted to academic centers (95% CI 0.47-0.54, p < 0.001) and those who lived in high perforation clusters had a 1.42 times higher odds of perforation (95% CI 1.39-1.46, p < 0.001). CONCLUSION: Neighborhoods located far from hospitals have increased appendiceal perforation rates. Also, patients with appendicitis treated at small community hospitals have significantly lower odds of perforation. From a policy point of view, patients with symptoms of appendicitis can be safely treated at the nearest hospital.

A 15 year cohort review of in-hospital pediatric trauma center mortality: A catalyst for injury prevention programming.

BACKGROUND: The objective of our study was to identify the most common mechanisms of injury leading to death in our pediatric population. METHODS: A retrospective cohort of fatally injured children 0-17 years old treated at our trauma center during 2000-2015. RESULTS: The mortality rate in our population was 8% (n = 103). Fifty-five percent were male. The majority (76%) of fatal injuries were blunt. Overall, motor vehicle collisions (MVCs) were the most common mechanism of injury (61%), followed by assault/abuse (9%). Of the deaths caused by MVCs, 37 (59%) were occupants, 11 (17%) were pedestrians, and 6 (10%) were cyclists. In the infant sub-population, assault/abuse was the most common mechanism of injury. CONCLUSION: MVCs were the leading cause of death in this population. In the infant subpopulation (<1 year), abusive head trauma emerged as the leading mechanism. Injury prevention programming should target abusive head trauma in infants and teen road safety.

Spatial genomic heterogeneity within localized, multifocal prostate cancer.

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.