Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways

Our recent studies showed that transglutaminase-1 (TGase-1) is uniquely expressed in mouse renal proximal tubular cells (RPTC) and mediates cell proliferation. In this study, we investigated the role of TGase-1 in cell survival and the survival signaling pathways regulated by TGase-1 in RPTC following oxidant injury. Exposure of RPTC to hydrogen peroxide (H2O2) resulted in apoptosis and an increase in TGase activity. Inhibition of TGase activity with monodansylcadervine (MDC), a TGase inhibitor, or knockdown of TGase-1 with small interference (si)RNA enhanced apoptosis and decreased cell survival in H2O2-treated RPTC. Conversely, overexpression of TGase-1 rendered RPTC more resistant to H2O2 toxicity and MDC treatment blocked this response. Concurrent with RPTC apoptosis, phosphorylation of AKT, signal transducer and activator of transcription-3 (STAT3), and glucogen synthase kinase-3β (GSK-3β) were observed. Pretreatment of cells with MDC or TGase-1 siRNA inhibited phosphorylation of all these molecules. Inhibition of either the AKT or STAT3 pathway potentiated H2O2-induced cell death and increased GSK-3β activity by dephosphorylation at serine 9. Furthermore, treatment with GSK-3β inhibitors reduced H2O2-induced apoptosis and abolished the death-promoting effect of AKT and STAT3 inhibition. Therefore, we have identified TGase-1 as a novel survival factor in renal epithelial cells and it contributes to cell survival through activation of the AKT and STAT3 signaling pathways following oxidant injury

Pitfalls in Interpreting mp-MRI of the Prostate: A Pictorial Review with Pathologic Correlation

OBJECTIVES: The purpose of this pictorial review is to present a wide spectrum of prostate multiparametric MRI (mp-MRI) pitfalls that may occur in clinical practice, with radiological and pathological correlation. METHODS: All examinations were performed according to ESUR Guidelines protocols. RESULTS AND CONCLUSION: mp-MRI imaging of the prostate often leads to interpreting doubts and misdiagnosis due to the many interpretative pitfalls that a tissue, whether healthy or treated, may cause. These "false-positive" findings may occur in each stage of the disease history, from the primary diagnosis and staging, to the post-treatment stage, and whether they are caused by the tissue itself or are iatrogenic, their recognition is critical for proper treatment and management. Knowledge of these known pitfalls and their interpretation in the anatomical-radiological context can help radiologists avoid misdiagnosis and consequently mistreatment. MAIN MESSAGES: * Some physiological changes in the peripheral and central zone may simulate prostate cancer. * Technical errors, such as mispositioned endorectal coils, can affect the mp-MRI interpretation. * Physiological changes post-treatment can simulate recurrence

Nutrients: the environmental regulation of cardiovascular gene expression

The complexity of nutrient–gene interactions has led to the development of a new branch in the nutrition sciences, the nutrigenomics. The individual susceptibility to nutrients based on environment → genotype → phenotype interplay makes this new research field extremely promising although complex. In this review, we highlight and examine recent findings and the most relevant hypotheses on the role of the diet in the onset and progression of cardiovascular diseases. The effect of unbalanced diets on the cardiovascular system is considered one of the most important risk factors both for ischemic and degenerative myocardial pathologies. The concept that nutrigenomics could help in improving public and personal health is becoming tangible indicating future directions for basic and applied research in the pathophysiology of cardiovascular disease

Economic conditions, hypertension, and cardiovascular disease: analysis of the Icelandic economic collapse

Previous research has found a positive short-term relationship between the 2008 collapse and hypertension in Icelandic males. With Iceland's economy experiencing a phase of economic recovery, an opportunity to pursue a longer-term analysis of the collapse has emerged. Using data from a nationally representative sample, fixed-effect estimations and mediation analyses were performed to explore the relationship between the Icelandic economic collapse in 2008 and the longer-term impact on hypertension and cardiovascular health. A sensitivity analysis was carried out with pooled logit models estimated as well as an alternative dependent variable. Our attrition analysis revealed that results for cardiovascular diseases were affected by attrition, but not results from estimations on the relationship between the economic crisis and hypertension. When compared to the boom year 2007, our results point to an increased probability of Icelandic women having hypertension in the year 2012, when the Icelandic economy had recovered substantially from the economic collapse in 2008. This represents a deviation from pre-crisis trends, thus suggesting a true economic-recovery impact on hypertension.The project was funded by the Icelandic Research Fund (IRF grant number 130611-052) and The University of Iceland Eimskip Fund. The data collection was financed and carried out by the Directorate of Health Iceland (and formerly the Public Health Institute of Iceland). The authors would like to thank the Directorate for access to the data.Peer Reviewe