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

Food and water security issues in Russia II : Water security in general population of Russian Arctic, Siberia and Far East, 2000-2011

Background. Poor state of water supply systems, shortage of water purification facilities and disinfection systems, low quality of drinking water generally in Russia and particularly in the regions of the Russian Arctic, Siberia and Far East have been defined in the literature. However, no standard protocol of water security assessment has been used in the majority of studies.Study design and methods. Uniform water security indicators collected from Russian official statistical sources for the period 2000ￜ2011 were used for comparison for 18 selected regions in the Russian Arctic, Siberia and Far East. The following indicators of water security were analyzed: water consumption, chemical and biological contamination of water reservoirs of Categories I and II of water sources (centralized ￜ underground and surface, and non-centralized) and of drinking water.Results. Water consumption in selected regions fluctuated from 125 to 340 L/person/day. Centralized water sources (both underground and surface sources) are highly contaminated by chemicals (up to 40ￜ80%) and biological agents (up to 55% in some regions), mainly due to surface water sources. Underground water sources show relatively low levels of biological contamination, while chemical contamination is high due to additional water contamination during water treatment and transportation in pipelines. Non-centralized water sources are highly contaminated (both chemically and biologically) in 32ￜ90% of samples analyzed. Very high levels of chemical contamination of drinking water (up to 51%) were detected in many regions, mainly in the north-western part of the Russian Arctic. Biological contamination of drinking water was generally much lower (2.5ￜ12%) everywhere except Evenki AO (27%), and general and thermotolerant coliform bacteria predominated in drinking water samples from all regions (up to 17.5 and 12.5%, correspondingly). The presence of other agents was much lower: Coliphages ￜ 0.2ￜ2.7%, Clostridia spores, Giardia cysts, pathogenic bacteria, Rotavirus ￜ up to 0.8%. Of a total of 56 chemical pollutants analyzed in water samples from centralized water supply systems, 32 pollutants were found to be in excess of hygienic limits, with the predominant pollutants being Fe (up to 55%), Cl (up to 57%), Al (up to 43%) and Mn (up to 45%).Conclusion. In 18 selected regions of the Russian Arctic, Siberia and Far East Category I and II water reservoirs, water sources (centralized ￜ underground, surface; non-centralized) and drinking water are highly contaminated by chemical and biological agents. Full-scale reform of the Russian water industry and water security system is urgently needed, especially in selected regions

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1