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

Silver toxicity across salinity gradients: the role of dissolved silver chloride species (AgCl x ) in Atlantic killifish (Fundulus heteroclitus) and medaka (Oryzias latipes) early life-stage toxicity

International audienceThe influence of salinity on Ag toxicity was investigated in Atlantic killifish (Fundulus heteroclitus) early life-stages. Embryo mortality was significantly reduced as salinity increased and Ag+ was converted to AgCl(solid). However, as salinity continued to rise (>5 ‰), toxicity increased to a level at least as high as observed for Ag+ in deionized water. Rather than correlating with Ag+, Fundulus embryo toxicity was better explained (R2 = 0.96) by total dissolved Ag (Ag+, AgCl2 −, AgCl3 2−, AgCl4 3−). Complementary experiments were conducted with medaka (Oryzias latipes) embryos to determine if this pattern was consistent among evolutionarily divergent euryhaline species. Contrary to Fundulus data, medaka toxicity data were best explained by Ag+ concentrations (R2 = 0.94), suggesting that differing ionoregulatory physiology may drive observed differences. Fundulus larvae were also tested, and toxicity did increase at higher salinities, but did not track predicted silver speciation. Alternatively, toxicity began to increase only at salinities above the isosmotic point, suggesting that shifts in osmoregulatory strategy at higher salinities might be an important factor. Na+ dysregulation was confirmed as the mechanism of toxicity in Ag-exposed Fundulus larvae at both low and high salinities. While Ag uptake was highest at low salinities for both Fundulus embryos and larvae, uptake was not predictive of toxicity

Isotopic Imprints of Mountaintop Mining Contaminants

Mountaintop mining (MTM) is the primary procedure for surface coal exploration within the central Appalachian region of the eastern United States, and it is known to contaminate streams in local watersheds. In this study, we measured the chemical and isotopic compositions of water samples from MTM-impacted tributaries and streams in the Mud River watershed in West Virginia. We systematically document the isotopic compositions of three major constituents: sulfur isotopes in sulfate (δ³⁴S_SO4), carbon isotopes in dissolved inorganic carbon (δ¹³C_DIC), and strontium isotopes (⁸⁷Sr/⁸⁶Sr). The data show that δ³⁴S_SO4, δ¹³C_DIC, Sr/Ca, and ⁸⁷Sr/⁸⁶Sr measured in saline- and selenium-rich MTM impacted tributaries are distinguishable from those of the surface water upstream of mining impacts. These tracers can therefore be used to delineate and quantify the impact of MTM in watersheds. High Sr/Ca and low ⁸⁷Sr/⁸⁶Sr characterize tributaries that originated from active MTM areas, while tributaries from reclaimed MTM areas had low Sr/Ca and high ⁸⁷Sr/⁸⁶Sr. Leaching experiments of rocks from the watershed show that pyrite oxidation and carbonate dissolution control the solute chemistry with distinct ⁸⁷Sr/⁸⁶Sr ratios characterizing different rock sources. We propose that MTM operations that access the deeper Kanawha Formation generate residual mined rocks in valley fills from which effluents with distinctive ⁸⁷Sr/⁸⁶Sr and Sr/Ca imprints affect the quality of the Appalachian watersheds

Isotopic Imprints of Mountaintop Mining Contaminants

Mountaintop mining (MTM) is the primary procedure for surface coal exploration within the central Appalachian region of the eastern United States, and it is known to contaminate streams in local watersheds. In this study, we measured the chemical and isotopic compositions of water samples from MTM-impacted tributaries and streams in the Mud River watershed in West Virginia. We systematically document the isotopic compositions of three major constituents: sulfur isotopes in sulfate (δ³⁴S_SO4), carbon isotopes in dissolved inorganic carbon (δ¹³C_DIC), and strontium isotopes (⁸⁷Sr/⁸⁶Sr). The data show that δ³⁴S_SO4, δ¹³C_DIC, Sr/Ca, and ⁸⁷Sr/⁸⁶Sr measured in saline- and selenium-rich MTM impacted tributaries are distinguishable from those of the surface water upstream of mining impacts. These tracers can therefore be used to delineate and quantify the impact of MTM in watersheds. High Sr/Ca and low ⁸⁷Sr/⁸⁶Sr characterize tributaries that originated from active MTM areas, while tributaries from reclaimed MTM areas had low Sr/Ca and high ⁸⁷Sr/⁸⁶Sr. Leaching experiments of rocks from the watershed show that pyrite oxidation and carbonate dissolution control the solute chemistry with distinct ⁸⁷Sr/⁸⁶Sr ratios characterizing different rock sources. We propose that MTM operations that access the deeper Kanawha Formation generate residual mined rocks in valley fills from which effluents with distinctive ⁸⁷Sr/⁸⁶Sr and Sr/Ca imprints affect the quality of the Appalachian watersheds