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

Life without light: microbial diversity and evidence of sulfur- and ammonium-based chemolithotrophy in Movile Cave

Microbial diversity in Movile Cave (Romania) was studied using bacterial and archaeal 16S rRNA gene sequence and functional gene analyses, including ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), soxB (sulfate thioesterase/thiohydrolase) and amoA (ammonia monooxygenase). Sulfur oxidizers from both Gammaproteobacteria and Betaproteobacteria were detected in 16S rRNA, soxB and RuBisCO gene libraries. DNA-based stable-isotope probing analyses using C-13-bicarbonate showed that Thiobacillus spp. were most active in assimilating CO2 and also implied that ammonia and nitrite oxidizers were active during incubations. Nitrosomonas spp. were detected in both 16S rRNA and amoA gene libraries from the 'heavy' DNA and sequences related to nitriteoxidizing bacteria Nitrospira and Candidatus 'Nitrotoga' were also detected in the 'heavy' DNA, which suggests that ammonia/nitrite oxidation may be another major primary production process in this unique ecosystem. A significant number of sequences associated with known methylotrophs from the Betaproteobacteria were obtained, including Methylotenera, Methylophilus and Methylovorus, supporting the view that cycling of one-carbon compounds may be an important process within Movile Cave. Other sequences detected in the bacterial 16S rRNA clone library included Verrucomicrobia, Firmicutes, Bacteroidetes, alphaproteobacterial Rhodobacterales and gammaproteobacterial Xanthomonadales. Archaeal 16S rRNA sequences retrieved were restricted within two groups, namely the Deep-sea Hydrothermal Vent Euryarchaeota group and the Miscellaneous Crenarchaeotic group. No sequences related to known sulfur-oxidizing archaea, ammonia-oxidizing archaea, methanogens or anaerobic methane-oxidizing archaea were detected in this clone library. The results provided molecular biological evidence to support the hypothesis that Movile Cave is driven by chemolithoautotrophy, mainly through sulfur oxidation by sulfur-oxidizing bacteria and reveal that ammonia-and nitrite-oxidizing bacteria may also be major primary producers in Movile Cave. The ISME Journal (2009) 3, 1093-1104; doi:10.1038/ismej.2009.57; published online 28 May 200

Burkitt’s lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis

Burkitt's lymphomas (BLs) acquire consistent point mutations in a conserved domain of Myc, Myc Box I. We report that the enhanced transforming activity of BL-associated Myc mutants can be uncoupled from loss of phosphorylation and increased protein stability. Furthermore, two different BL-associated Myc mutations induced similar gene expression profiles independently of T58 phosphorylation, and these profiles are dramatically different from MycWT. Nol5a/Nop56, which is required for ribosomal RNA methylation, was identified as a gene hyperactivated by the BL-associated Myc mutants. We show that Nol5a is necessary for Myc-induced cell transformation, enhances MycWT-induced cell transformation and increases the size of MycWT-induced tumors. Thus, Nol5a expands the link between Myc-induced regulation of nucleolar target genes, which are rate limiting for cell transformation and tumor growth.Oncogene advance online publication, 9 September 2013; doi:10.1038/onc.2013.338

Endovascular treatment of active splenic bleeding after colonoscopy: a systematic review of the literature.

PURPOSE: Colonoscopy is reported to be a safe procedure that is routinely performed for the diagnosis and treatment of colorectal diseases. Splenic rupture is considered to be a rare complication with high mortality and morbidity that requires immediate diagnosis and management. Nonoperative management (NOM), surgical treatment (ST), and, more recently, proximal splenic artery embolization (PSAE) have been proposed as treatment options. The goal of this study was to assess whether PSAE is safe even in high-grade ruptures. METHODS: We report two rare cases of post colonoscopy splenic rupture. A systematic review of the literature from 2002 to 2010 (first reported case of PSAE) was performed and the three types of treatment compared. RESULTS: All patients reviewed (77 of 77) presented with intraperitoneal hemorrhage due to isolated splenic trauma. Splenic rupture was high-grade in most patients when grading was possible. Six of 77 patients (7.8 %) were treated with PSAE, including the 2 cases reported herein. Fifty-seven patients (74 %) underwent ST. NOM was attempted first in 25 patients with a high failure rate (11 of 25 [44 %]) and requiring a salvage procedure, such as PSAE or ST. Previous surgery (31 of 59 patients), adhesions (10 of 13), diagnostic colonoscopies (49 of 71), previous biopsies or polypectomies (31 of 57) and female sex (56 of 77) were identified as risk factors. In contrast, splenomegaly (0 of 77 patients), medications that increase the risk of bleeding (13 of 30) and difficult colonoscopies (16 of 51) were not identified as risk factors. PSAE was safe and effective even in elderly patients with comorbidities and those taking medications that increase the risk of bleeding, and the length of the hospital stay was similar to that after ST. CONCLUSION: We propose a treatment algorithm based on clinical and radiological criteria. Because of the high failure rate after NOM, PSAE should be the treatment of choice to manage grade I through IV splenic ruptures after colonoscopy in hemodynamically stabilized patients