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

Fluid Geochemistry and Volcanic Unrest: Dissolving the Haze in Time and Space

The heat and gas released by a degassing magma affects the overlying predominantly meteoric aquifers to form magmatic-hydrothermal systems inside the solid body of a volcano. This chapter reviews how fluid geochemical signals help to track the evolution throughout the various stages of volcanic unrest. A direct view into a degassing magma is possible at open-conduit degassing volcanoes. Nevertheless, in most cases gas is trapped (i.e. scrubbed) by abundant water, leading to the loss of the pure signal the magma ideally provides. Deciphering how magmatic gas rises through, reacts, and re-equilibrates with the liquids in the magmatic-hydrothermal system in time and space is the only way to trace back to the pure signal. The most indicative magmatic gas species (CO2, SO2–H2S, HCl and HF) are released as a function of their solubility in magma. The less soluble gas species are released early from a magma at higher pressure conditions (CO2) (deeper), whereas the more soluble species are released later, at lower pressures (SO2, HCl and HF) (shallower depth). When these gases hit the water during their rise towards the surface, they will be more or less scrubbed. Depending on the chemical equilibria inside the magmatic-hydrothermal system (e.g. SO2– H2S conversion, acidity), the gas that eventually reaches the surface will carry the history of its rise from bottom to top. Tracking volcanic unrest implies a time frame; the kinetics of magma degassing throughout the liquid cocktail inside the volcano impose the maximum resolution the volcano provides and hence the monitoring time window to be adopted for each volcano. Gas-dominated systems are “faster” and require a higher monitoring frequency, water-dominated systems are slower and require a lower monitoring frequency.Published4V. Processi pre-eruttiv