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

Effects of observed and experimental climate change on terrestrial ecosystems in northern Canada: results from the Canadian IPY program

Published VersionTundra and taiga ecosystems comprise nearly 40 % of the terrestrial landscapes of Canada. These permafrost ecosystems have supported humans for more than 4500 years, and are currently home to ca. 115,000 people, the majority of whom are First Nations, Inuit and Métis. The responses of these ecosystems to the regional warming over the past 30–50 years were the focus of four Canadian IPY projects. Northern residents and researchers reported changes in climate and weather patterns and noted shifts in vegetation and other environmental variables. In forest-tundra areas tree growth and reproductive effort correlated with temperature, but seedling establishment was often hindered by other factors resulting in sitespecific responses. Increased shrub cover has occurred in sites across the Arctic at the plot and landscape scale, and this was supported by results from experimental warming. Experimental warming increased vegetation cover and nutrient availability in most tundra soils; however, resistance to warming was also found. Soil microbial diversity in tundra was no different than in other biomes, although there were shifts in mycorrhizal diversity in warming experiments. All sites measured were sinks for carbon during the growing season with expected seasonal and latitudinal patterns. Modeled responses of a mesic tundra system to climate change showed that the sink status will likely continue for the next 50–100 years, after which these tundra systems will likely become a net source of carbon dioxide to the atmosphere. These IPY studies were the first comprehensive assessment of the state and change in Canadian northern terrestrial ecosystems and showed that the inherent variability in these systems is reflected in their site-specific responses to changes in climate. They also showed the importance of using local traditional knowledge and science, and provided extensive data sets, sites and researchers needed to study and manage the inevitable changes in the Canadian North

Detection of alternative lengthening of telomeres by telomere quantitative PCR

Alternative lengthening of telomeres (ALT) is one of the two known telomere length maintenance mechanisms that are essential for the unlimited proliferation potential of cancer cells. Existing methods for detecting ALT in tumors require substantial amounts of tumor material and are labor intensive, making it difficult to study prevalence and prognostic significance of ALT in large tumor cohorts. Here, we present a novel strategy utilizing telomere quantitative PCR to diagnose ALT. The protocol is more rapid than conventional methods and scrutinizes two distinct characteristics of ALT cells concurrently: long telomeres and the presence of C-circles (partially double-stranded circles of telomeric C-strand DNA). Requiring only 30 ng of genomic DNA, this protocol will facilitate large-scale studies of ALT in tumors and can be readily adopted by clinical laboratories. © 2012 The Author(s)

Debridement of painful forefoot plantar callosities in rheumatoid arthritis: the CARROT randomised controlled trial

The objective of this study was to evaluate the long-term benefits of sharp scalpel debridement of painful forefoot plantar callosities in rheumatoid arthritis (RA). The null hypothesis: sharp scalpel debridement would offer no additional long-term advantage in terms of pain and function. Sixty-five people with RA were randomised to receive regular sharp scalpel debridement of painful forefoot plantar callosities in conjunction with a combined therapeutic approach or a combined therapeutic approach alone. The primary outcome measure was change at 18 months in participant-reported forefoot plantar pain measured by a 100-mm visual analogue scale (VAS). Secondary outcome measures were recorded at baseline and study exit and included revised Foot Function Index, Health Assessment Questionnaire, Foot Impact Scale and gait parameters. At 18 months, there were no differences between groups for the primary outcome VAS-measured forefoot plantar pain (left foot (F = 0.23, p = 0.635), right foot (F = 2.14, p = 0.148)). Within-group changes were highly significant (treatment arm, difference = 16.9 (95 % confidence interval (CI) 9.4, 24.4), t = 4.6, p < 0.0001; control arm, difference = 17.5 (95 % CI 9.4, 25.5), t = 4.4, p < 0.0001). There was little change in scores of overall function and foot impact in either group and there were no significant changes in gait parameters noted. The long-term effects of sharp scalpel debridement of painful forefoot plantar callosities in people with RA, when used in conjunction with a combined therapeutic approach, produced no additional benefit over the combined therapeutic approach alone

Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres

© 2017 The Authors Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ∼50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy

Condition-dependent sex allocation by clones of a galling aphid

Local mate competition (LMC) has been postulated to be the primary factor of female-biased sex allocation. In animals such as aphids that exhibit seasonal alternations of clonal and sexual reproduction, there is a high possibility of intra-clonal mating and LMC. This possibility is more plausible for more fecund clones, but out-breeding is predicted for less fecund clones. We hypothesize that clones that are more fecund will gain higher fitness returns by reducing investment in males because of more intense LMC among clonal males. We tested this hypothesis by elucidating the clonal sex allocation patterns of the galling aphid Kaltenbachiella japonica, in which inbreeding and LMC appear to be common. Winged mothers that emerge from a gall, belonging to the same clone, produced males and sexual females asexually on a branch, without dispersing to other trees. The heavier the gall, the more winged mothers were produced from the gall. Individual mothers produced a constant number of males and a variable number of females. The clonal sex allocation to males was 39.8%, on average, and decreased with increasing gall weight. This result showed that clones that were more fecund exhibited more female-biased sex allocation and thus supported our hypothesis. Furthermore, our results corroborated Stubblefield and Seger's hypothesis for sex allocation in patch structure rather than Yamaguchi's constant male hypothesis. We conclude that K. japonica clones are able to adjust their sex allocation patterns adaptively depending on the quality of resources in the galls