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

Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria

During transcription, the nascent RNA can invade the DNA template, forming extended RNA-DNA duplexes (R-loops). Here we employ ChIP-seq in strains expressing or lacking RNase H to map targets of RNase H activity throughout the budding yeast genome. In wild-type strains, R-loops were readily detected over the 35S rDNA region, transcribed by Pol I, and over the 5S rDNA, transcribed by Pol III. In strains lacking RNase H activity, R-loops were elevated over other Pol III genes, notably tRNAs, SCR1 and U6 snRNA, and were also associated with the cDNAs of endogenous TY1 retrotransposons, which showed increased rates of mobility to the 5'-flanking regions of tRNA genes. Unexpectedly, R-loops were also associated with mitochondrial genes in the absence of RNase H1, but not of RNase H2. Finally, R-loops were detected on actively transcribed protein-coding genes in the wild-type, particularly over the second exon of spliced ribosomal protein genes

Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by Klebsiella pneumoniae Carbapenemase-producing K-pneumoniae

Background. Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods. We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results. The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index >= 3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions. CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia

Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study

Background: A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Methods: We retrospectively analyzed observational data on the use and outcomes of CAZ-AVI therapy for infections caused by KPC-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens vs. CAZ-AVI monotherapy. Results: The cohort comprised 577 adults with bloodstream infections (BSIs) (n=391) or non-bacteremic infections (nBSIs) involving mainly the urinary tract, lower respiratory tract, intra-abdominal structures. All received treatment with CAZ-AVI alone (n=165) or with one or more other active antimicrobials (n=412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no statistically significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs. 25.0%, P=0.79). In multivariate analysis, mortality was positively associated with the presence at infection onset of septic shock (P=0.002), neutropenia (P <0.001), or an INCREMENT score >8 (P=0.01); with LRTI (P=0.04); and with CAZ-AVI dose adjustment for renal function (P=0.01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P=0.006). All associations remained significant after propensity score adjustment. Conclusions: CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug's seemingly more limited efficacy in LRTIs and the potential survival benefits of prolonging CAZ-AVI infusions to 3 hours or more