Genomic basis for RNA alterations in cancer

Transcript alterations often result from somatic changes in cancer genomes. Various forms of RNA alterations have been described in cancer, including overexpression, altered splicing and gene fusions; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer

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

Preservice Elementary Science Teachers' Argumentation Competence: Impact of a Training Programme

The recent literature has shown the importance of Preservice Elementary Science Teachers (PESTs) having a deep understanding of argumentation, as this factor may affect the nature of the class activities that are taught and what students learn. A lack of understanding of this factor may represent an obstacle in the development of science education programmes in line with the development of scientific competences. This paper presents the results of the design and implementation of a training programme of 6 sessions (12 hours of class participation plus 8 hours of personal homework) on argumentation. The programme was carried out by 57 Spanish PESTs from Malaga, Spain. The training programme incorporates the innovative use of certain strategies to improve competence in argumentation, such as teaching PESTs to identify the elements of arguments in order to design assessment rubrics or by including peer assessment during evaluation with and without rubrics. The results obtained on implementing the training programme were evaluated based on the development of PESTs’ argumentation competence using Toulmin’s argumentative model. Data collection methods involved two tasks carried out at the beginning and the end of the programme, i.e., pre-test and post-test, respectively. The conclusion of the study is that students made significant progress in their argumentation competence on completing the course. In addition, PESTs who followed the training programme achieved statistically better results at the end than those in the control group (n = 41), who followed a traditional teaching programme. A 6-month transfer task showed a slight improvement for the PESTs of the experimental group in relation to the control group in their ability to transfer argumentation to practice, especially to the extent to which they mentioned argumentation in their practice portfolios.This work is part of the “I+D Excelencia” project “Development and evaluation of scientific competences through context based and modelling teaching approaches” case studies (EDU2013-41952-P), funded by the Spanish Ministry of Economy and Finance through its 2013 research call

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Investigation of written arguments about akkuyu nuclear power plant [Akkuyu nükleer santrali konusunda Üretilen yazılı argümanların İncelenmesi]

The purpose of the study was to investigate and describe pre-service elementary science teachers’ written arguments related to Mersin-Akkuyu Nuclear Power Plant in terms of reasoning mode, Toulming argumentation model and argumentation levels. A single group pre/post-test design was administered to investigate participants written arguments about Akkuyu Nuclear Power Plant. The result of the study was that when the preservice science teachers’ knowledge about the socio-scientific issues increased, their multiple reasoning modes increased too. Furthermore, it was found that the most generated argument was ecologic oriented while the least was social oriented. The result of the study also showed that when the argumentation level increased, the reasoning mode tended to increase as well. © 2014, Ankara University. All rights reserved

Assessment of the potential of 1-methylcyclopropene treatments to maintain fruit quality of the common fig (Ficus carica L. cv. 'Bursa Siyahi') during refrigerated storage

The fig fruit is a unique, climacteric, highly perishable subject to rapid physiological breakdown. Application of 1-methylcyclopropene (1-MCP) was tested to delay ripening of black fig (Ficus carica L. cv. 'Bursa Siyahi') during storage over two growing seasons. Fruits were pre-cooled to 1 °C for 6 hours and afterwards treated with 500 or 1000 nl l-1 of 1-MCP for 24 hours. Treated fruits were stored for 10 days at 1 °C, 90-95% RH and then evaluated. 1-MCP treatments showed that ethylene production, respiration rate, weight loss and concentrations of glucose, fructose and total soluble solids (TSS) were negatively correlated to the 1-MCP doses during cold storage (with the exception of TSS in the first year of experiment and respiration rate in the second year of the experiment). In contrast, pulp firmness and colour (h°) during cold storage were positively correlated to the 1-MCP applied doses. Results of this study showed that although 1-methylcyclopropene applications slowed down fruit softening during the 10 days of storage, 1-methylcyclopropene appeared to have a relatively limited effect on slowing ripening of 'Bursa Siyahi' figs

Meme kanserli olgularda 3 alanlı koplanar teknikle tüm meme ışınlamasının kalp ve LAD dozlarına etkisi

Objectives We evaluate the effect of two conformal technique at Turkish women contour which developed order to reduce the lung dose in whole breast radiotherapy at European breast cancer patients. Methods CTV, PTV, lung, heart, contralateral breast and LAD were contoured on 20 patients referred for breast radiotherapy. Treatment planning were made as conventional technique (2F-C), two field non-coplanar conformal technical (2F-NC), 3 field coplanar conformal technique (3F-C) at Varian Eclipse TPS. Critical doses were evaluated at DVH. Conformity and homogeneity index was calculated. Comparison of three groups made by Kruskal-Wallis test, two separate groups by Mann-Whitney U test. Results Statistically significant differences in favor of 3F-C were detected on hearth, LAD, contralateral breast doses. Homogeneity and conformity index was higher for all patients in 3F-C technique. Conclusion 3F-C technique is adequate for dosimetric aspects and can be considered in Turkish women especially have coronary artery disease. © 2014 Turkish Society for Radiation Oncology